Publications & Presentations

Ongoing Work: Probing Inflammation and Reward Sensitivity in Alcohol Use Disorder

Abstract:

This study aims to examine the role of neuroinflammation in modulating reward response and negative mood in Alcohol Use Disorder (AUD). Chronic alcohol exposure has been shown in animal models to increase both neural and systemic markers of inflammation. Alcohol-induced inflammation has been linked to both chronic alcohol seeking and the behavioral and neurotoxic effects of alcohol. However, the literature on inflammatory signaling and AUD is overwhelmingly preclinical and it is unknown if this relationship can be extrapolated to humans. Therefore, translation to clinical samples is necessary. In humans, addiction is often conceptualized as a reward deficit disorder. Negative emotionality is also implicated in AUD, such that individuals with AUD demonstrate higher levels of negative mood, with a high comorbidity between mood disorders and AUD. Neuroinflammation is associated with negative emotionality, such that cytokines have been shown to play a causal role in the onset of negative mood. Further, brain activation in response to reward stimuli is decreased after inflammation-provoking endotoxin infusion. However, associations between AUD, inflammation, and behavioral outcomes have not yet been established.

The current study aims to fill this gap in the literature by examining the role of inflammation in negative mood and reward response in a clinical sample of individuals with AUD and light-drinking healthy controls. We will experimentally provoke a systemic inflammatory response, measurable by plasma levels of proinflammatory cytokines. Participants will receive a low dose of endotoxin that has been shown to increase cytokine levels without significant changes in vital signs, therefore safely and acutely mimicking a low-grade inflammatory response. Over the course of 4 hours post-infusion of endotoxin (or placebo) – during which cytokine levels peak at 2 hours and return to near-baseline by hour 4 – participants will be assessed for negative mood at hourly intervals and reward response at peak (hour 2). The first aim of the project is to examine the effects of neuroinflammation on negative mood in AUD versus controls. The second aim is to examine the effects of acute inflammation on reward response in AUD and controls. Our findings will help to elucidate the role that inflammation plays in modulating mood and reward response in AUD.

Peer-Reviewed Publications

Nieto, S.J., Venegas, A., Burnette, E.M., MacKillop, J., & Ray, L.A. (2021). Additive roles of tobacco and cannabis co-use in relation to delay discounting in a sample of heavy drinkers. Psychopharmacology, IN PRESS.

Abstract:

Rationale: Alcohol use disorder (AUD) is associated with steeper delay discounting rates; however, it is unknown whether substance co-use, particularly cannabis use, has an additive effect on discounting rates among heavy drinkers. Furthermore, it is unclear whether substance co-use and delay discounting are independently associated with AUD severity.

Objectives: The purpose of this study was to determine whether alcohol, tobacco, and cannabis co-use impacts delay discounting rates. We also sought to determine whether substance co-use and delay discounting were associated with AUD symptom counts.

Methods: The study sample was culled from several human laboratory studies and consisted of 483 heavy drinking individuals who completed a baseline visit (prior to experimental procedures). Participants were divided into groups based on self-reported alcohol, tobacco, and cannabis use during the past 30 days: alcohol only (n = 184), alcohol + cigarettes (n = 89), alcohol + cannabis (n = 82), and tri-use (n = 128). We examined discounting rates across the 4 groups and used multiple linear regression to test whether co-use and delay discounting were associated with AUD symptoms.

Results: After adjusting for covariates, individuals in the alcohol + cannabis group and the tri-use group had steeper discounting rates relative to the alcohol-only group. In addition, tri-use and delay discounting rates were independently correlated with a greater number of AUD symptoms.

Conclusions: Delay discounting rates were significantly greater among subgroups reporting cannabis use providing partial support for an additive effect, while also highlighting the importance of co-use substance type. Both tri-use and delay discounting were associated with greater AUD severity, which may provide relevant intervention targets.

Burnette, E.M., Ray, L.A., Irwin, M.R., & Grodin, E.N. (2021). Ibudilast attenuates alcohol cue-elicited frontostriatal functional connectivity in Alcohol Use Disorder. Alcoholism: Clinical and Experimental Research, IN PRESS.

Abstract:

Background: Ibudilast, a novel neuroimmune modulator being studied to treat alcohol use disorder (AUD), was shown in a randomized controlled trial (NCT03489850) to reduce ventral striatum (VS) activation in response to visual alcohol cues. The present study extended this finding by probing the effects of ibudilast on alcohol cue-elicited functional connectivity (i.e., temporally correlated activation) with the VS seed. The study also tests the association between functional connectivity and alcohol use during the trial.

Methods: Non-treatment-seeking participants (n = 45) with current alcohol use disorder were randomized to receive twice-daily dosing with either ibudilast (50 mg; n = 20) or placebo (n = 25). Upon reaching the target dosagee of the medication or placebo, participants completed a functional neuroimaging alcohol cue reactivity paradigm. Drinks per drinking day were assessed at baseline and daily during the 2-week trial.

Results: Ibudilast reduced alcohol cue-elicited functional connectivity between the VS seed and reward-processing regions including the orbitofrontal and anterior cingulate cortices compared with placebo (p < 0.05). Cue-elicited functional connectivity was correlated with drinks per drinking day (R2 = 0.5351, p < 0.001), and ibudilast reduced this association in similar reward-processing regions compared with placebo.

Conclusions: Ibudilast's effects on drinking outcomes may be related to the attenuation of functional connectivity in frontostriatal circuits related to reward processing. These results provide an important proof of concept for this novel pharmacotherapy and support the clinical utility of incorporating neuroimaging-and especially functional connectivity-analyses into medication development.

Grodin, E.N., Burnette, E., Towns, B., Venegas, A., & Ray, L.A. (2021). Effect of tobacco and cannabis co-use on gray matter volume in heavy drinkers. Psychology of Addictive Behaviors, 35(6):760-768.

Abstract:

Objective: Alcohol, tobacco, and cannabis are the three most frequently used drugs in the United States and co-use is common. Alcohol, tobacco, and cannabis use has been separately associated with altered brain structure, and alcohol and tobacco co-use results in decreases in gray matter volume. Less is known about the effect of alcohol and cannabis co-use, and alcohol, tobacco, and cannabis tri-use. Therefore, this study examined the effect of co- and tri-use on gray matter volume, a measure of brain cell density, in heavy drinkers.

Method: Heavy drinkers (n = 237; 152m/85f; age = 32.52; white = 111; black = 28; Latino = 9; American Indian = 2; Pacific Islander = 4; Asian = 59; mixed = 15; other = 9) were classified into four groups based on their alcohol, tobacco, and cannabis use: alcohol only users (n = 70), alcohol and tobacco co-users (n = 90), alcohol and cannabis co-users (n = 35), and alcohol, tobacco, and cannabis tri-users (n = 42). All participants completed a structural MRI scan. Voxel-based morphometry was conducted to evaluate the effect of co-use on gray matter volume, with alcohol only users as the reference group. Age, sex, and scanner were included as covariates.

Results: Alcohol and tobacco co-users had significantly decreased left orbitofrontal gray matter volume relative to alcohol only users (Cohen's d = .79). There were no differences in gray matter volume between the alcohol only and alcohol and cannabis co-users, or between the alcohol only and tri-user groups.

Conclusion: The additive effect of tobacco co-use on gray matter volumes in heavy drinkers was limited and localized. The effect of tri-use of alcohol, tobacco, and cannabis may have interacted, such that overlapping cannabis and tobacco use masked volume differences present in separate co-using groups.

Meredith, L.R., Burnette, E.M., Grodin, E.N., Irwin, M.R., & Ray, L.A. (2021). Immune Treatments for Alcohol Use Disorder: A Translational Framework. Brain, Behavior, and Immunity, 97:349-364.

Abstract:

While the immune system is essential for survival, an excessive or prolonged inflammatory response, such as that resulting from sustained heavy alcohol use, can damage the host and contribute to psychiatric disorders. A growing body of literature indicates that the immune system plays a critical role in the development and maintenance of alcohol use disorder (AUD). As such, there is enthusiasm for treatments that can restore healthy levels of inflammation as a mechanism to reduce drinking and promote recovery. In this qualitative literature review, we provide a conceptual rationale for immune therapies and discuss progress in medications development for AUD focused on the immune system as a treatment target. This review is organized into sections based on primary signaling pathways targeted by the candidate therapies, namely: (a) toll-like receptors, (b) phosphodiesterase inhibitors, (c) peroxisome proliferator-activated receptors, (d) microglia and astrocytes, (e) other immune pharmacotherapies, and (f) behavioral therapies. As relevant within each section, we examine the basic biological mechanisms of each class of therapy and evaluate preclinical research testing the role of the therapy on mitigating alcohol-related behaviors in animal models. To the extent available, translational findings are reviewed with discussion of completed and ongoing randomized clinical trials and their findings to date. An applied and clinically focused approach is taken to identify the potential clinical applications of the various treatments reviewed. We conclude by delineating the most promising candidate treatments and discussing future directions by considering opportunities for immune treatment development and personalized medicine for AUD.

Grodin, E.N., Burnette, E.M, Green, R., Lim, A.C, Miotto, K., & Ray, L.A. (2021). Combined Varenicline and Naltrexone Attenuates Alcohol Cue-Elicited Activation in Heavy Drinking Smokers. Drug and Alcohol Dependence, IN PRESS.

Abstract:

Background: There is a strong bidirectional relationship between the use of alcohol and cigarettes which results in various challenges for treating those who co-use both substances. While varenicline and naltrexone each have FDA-approval for nicotine and alcohol use disorder, respectively, there is evidence that their clinical benefit may extend across the two disorders. Critically, the effect of combined varenicline and naltrexone on neural reactivity to alcohol cues among heavy drinking smokers has not yet been studied. Probing the effect of the combination therapy on alcohol cue-reactivity may give insight to the mechanisms underlying its efficacy.

Methods: Forty-seven heavy drinking smokers enrolled in two medication studies were randomized to receive varenicline alone (n = 11), varenicline plus naltrexone (n = 11), or placebo (n = 25). Participants completed an fMRI alcohol cue-reactivity task and rated their in-scanner alcohol craving. Whole-brain analyses examined the effect of medication on alcohol cue-elicited neural response.

Results: Varenicline plus naltrexone attenuated alcohol cue-elicited activation in mesolimbic regions relative to varenicline alone and to placebo (Z > 2.3, p < 0.05). The combination varenicline and naltrexone group also endorsed lower in-scanner alcohol craving relative to varenicline alone group (p = 0.04).

Conclusions: These findings provide evidence for the benefit of combined therapy of varenicline and naltrexone over varenicline alone for the attenuation of alcohol cue-elicited neural activation. This study provides a preliminary proof-of-mechanism for this combination pharmacotherapy and suggests that naltrexone may be driving the reductions in cue-elicited alcohol craving in the brain. Further clinical studies using the combined therapy to treat heavy drinking smokers are warranted.

Grodin, E.N., Bujarski, S., Towns, B., Burnette, E., Nieto, S., Lim, A., Lin, J., Miotto, K., Gillis, A., Irwin, M., Evans, C., & Ray, L.A. (2021). Ibudilast for the treatment of Alcohol Use Disorder: A randomized placebo-controlled experimental study. Translational Psychiatry, 11(1), 355.

Abstract:

Ibudilast, a neuroimmune modulator which selectively inhibits phosphodiesterases (PDE)-3, -4, -10, and -11, and macrophage migration inhibitory factor (MIF), shows promise as a novel pharmacotherapy for alcohol use disorder (AUD). However, the mechanisms of action underlying ibudilast's effects on the human brain remain largely unknown. Thus, the current study examined the efficacy of ibudilast to improve negative mood, reduce heavy drinking, and attenuate neural reward signals in individuals with AUD. Fifty-two nontreatment-seeking individuals with AUD were randomized to receive ibudilast (n = 24) or placebo (n = 28). Participants completed a 2-week daily diary study during which they filled out daily reports of their past day drinking, mood, and craving. Participants completed an functional magnetic resonance imaging (fMRI) alcohol cue-reactivity paradigm half-way through the study. Ibudilast did not have a significant effect on negative mood (β = -0.34, p = 0.62). However, ibudilast, relative to placebo, reduced the odds of heavy drinking across time by 45% (OR = 0.55, (95% CI: 0.30, 0.98)). Ibudilast also attenuated alcohol cue-elicited activation in the ventral striatum (VS) compared to placebo (F(1,44) = 7.36, p = 0.01). Alcohol cue-elicited activation in the VS predicted subsequent drinking in the ibudilast group (F(1,44) = 6.39, p = 0.02), such that individuals who had attenuated ventral striatal activation and took ibudilast had the fewest number of drinks per drinking day in the week following the scan. These findings extend preclinical and human laboratory studies of the utility of ibudilast to treat AUD and suggest a biobehavioral mechanism through which ibudilast acts, namely, by reducing the rewarding response to alcohol cues in the brain leading to a reduction in heavy drinking.

Burnette, E.M., Grodin, E.N., Eisenberger, N.I., & Ray, L.A. (2021). Endotoxin for Alcohol Research: A call for experimental medicine using lipopolysaccharide challenge. Alcohol and Alcoholism, IN PRESS.

Abstract:

Studies of inflammation in alcohol use disorder (AUD) are overwhelmingly preclinical, and translation to clinical samples is necessary. Endotoxin administration has been used successfully in humans to study mood disorders, offering a translational, reliable and safe model that may be validated in AUD research. We argue for the use of endotoxin challenge to elucidate the interplay between AUD and inflammation.

Burnette, E.M., Grodin, E.N., Ghahremani, D.G., Galván, A., Kohno, M., Ray, L.A., & London, E.D. (2021). Diminished cortical response to risk and loss during risky decision making in Alcohol Use Disorder. Drug and Alcohol Dependence, 218, 108391.

Abstract:

Background: Risky decision-making is an important facet of addiction. Individuals with alcohol dependence show abnormalities in gambling and other risk-taking tasks. In one such measure, the Balloon Analogue Risk Task (BART), participants sequentially choose to pump a virtual balloon to increase potential reward while the risk of explosion increases, or to cash-out and take earnings. In a prior study, alcohol-dependent participants differed from controls in brain activation during decision-making on the BART, but the relationship between risk/reward magnitude and brain activation was not studied, nor were participants compared to controls. Here we compared the degree to which risk and magnitude of reward influenced brain activation in alcohol-dependent participants vs. controls during decision-making on the BART.

Methods: Thirty-two participants (16 alcohol-dependent, 16 control; 5 females/group) performed the BART during fMRI. A parametric analysis tested for a relationship between risk/reward magnitude and activation in rDLPFC and bilateral striatum regions of interest when participants chose to take risk or to cash out. An exploratory whole-brain voxel-wise analysis of mean activation during pumping, cash-out, and explosion events was also conducted.

Results: Compared with controls, alcohol-dependent participants displayed less modulation of activation in the rDLPFC when taking risk. Exploratory analyses found that alcohol-dependent participants showed less activation than controls during explosions in a cluster including the insula. No differences were seen in striatal activation.

Conclusions: Insensitivity of the rDLPFC to risk and of the insula to loss may contribute to decision-making deficits in alcohol dependence.

Burnette, E.M., Grodin, E.N., Schacht, J.P., & Ray, L.A. (2021). Clinical and neural correlates of reward and relief drinking. Alcoholism: Clinical and Experimental Research, 45(1), 194-203.

Abstract:

Background: Alcohol use disorder (AUD) is heterogenous. One approach to parsing this heterogeneity is to phenotype individuals by their underlying motivation to drink, specifically drinking for reward (i.e. positive reinforcement) or for relief (i.e. negative reinforcement/normalizing). Reward- vs. relief-motivated behavior is thought to be associated with a shift from ventral to dorsal striatal signaling. The present study examined whether reward and relief drinking were differentially associated with other clinical characteristics and with alcohol cue-elicited activation of the ventral and dorsal striatum.

Methods: Non-treatment-seeking heavy drinkers (N=184; 61 female, 123 male) completed the UCLA Reward, Relief, Habit Drinking Scale (RRHDS) and the Reasons for Heavy Drinking Questionnaire (RHDQ), to categorize drinking motivation. Measures of alcohol use, alcohol problems, mood, and craving were also collected. A subset of participants (N=45; 17 female, 28 male) also completed a functional neuroimaging alcohol cue reactivity task.

Results: RRHDS-designated relief/habit drinkers scored lower than reward drinkers on the RHDQ Reinforcement subscale (p=0.04) and higher on the RHDQ Normalizing subscale (p=0.004). Relief/habit drinkers also demonstrated greater AUD severity on a host of clinical measures. Relief/habit drinkers displayed higher cue-elicited dorsal striatal activation compared to reward drinkers (p=0.04), while ventral striatal cue-elicited activation did not significantly differ between groups.

Conclusions: Our findings support and extend the differentiation of reward from relief/habit-motivated drinking and suggest that differences in dorsal striatal response to conditioned alcohol cues may underlie this distinction. Elucidating neurobiological and clinical differences between these subtypes may facilitate treatment matching and precision medicine for AUD.

Baskerville, W.A., Nieto, S.J., Ho, D., Towns, B., Grodin, E.N., Li, C., Burnette, E., Donato, S., & Ray, L.A. (2021). Baseline drinking patterns in non-treatment-seeking problem drinkers. Alcohol and Alcoholism, 56(1), 57-63.

Abstract:

Aims: Natural processes of change have been documented in treatment-seekers who begin to reduce their drinking in anticipation of treatment. The study examined whether non-treatment-seeking problem drinkers would engage in drinking reduction in anticipation of participating in a research study.

Methods: Non-treatment-seeking problem drinkers (n = 935) were culled from five behavioral pharmacology studies. Participants reported on their alcohol use during the past 30 days using the Timeline Followback. Cluster analysis identified distinct groups/clusters based on drinking patterns over the 30-day pre-visit period. The identified clusters were compared on demographic and clinical measures.

Results: Three distinct clusters were identified (a) heavy-decreasing drinking group (n = 255, 27.27%); (b) a moderate-stable drinking group (n = 353, 37.75%) and (c) low-stable drinking group (n = 327, 34.97%). The three clusters differed significantly on a host of measures including pre-visit drinking (age at first drink, drinking days, drinks per week, drinks per drinking day), alcohol use severity, alcohol craving, readiness for change, depression and anxiety levels. These differences were alcohol dose-dependent such that the heavier drinking group reported the highest levels on all constructs, followed by the moderate group, and the low drinking group last.

Conclusions: Baseline drinking patterns of non-treatment-seekers were generally stable and pre-visit reductions were only observed among the heavy drinking group. This generally stable pattern stands in contrast to previous reports for treatment-seeking samples. Nevertheless, the heavier drinking group, which is most similar to treatment-seekers, displayed pre-study drinking reduction. Overall, naturalistic processes of change may pose less of a threat to randomization and testing in this population.

Burnette, E.M., Baskerville, W.A., Grodin, E.N., & Ray, L.A. (2020). Ibudilast for Alcohol Use Disorder: Study Protocol for a phase II clinical trial. Trials, 21(1), 779.

Abstract:

Background: Alcohol use disorder (AUD) is a chronic and relapsing condition for which current pharmacological treatments are only modestly effective. The development of efficacious medications for AUD remains a high research priority with recent emphasis on identifying novel molecular targets for AUD treatment and to efficiently screen new compounds aimed at those targets. Ibudilast, a phosphodiesterase inhibitor, has been advanced as a novel addiction pharmacotherapy that targets neurotrophin signaling and neuroimmune function.

Methods: This study will conduct a 12-week, double-blind, placebo controlled randomized clinical trial of ibudilast (50 mg BID) for AUD treatment. We will randomize 132 treatment-seeking men and women with current AUD. We will collect a number of alcohol consumption outcomes. Primary among these is percent heavy drinking days (PHDD); secondary drinking outcomes include drinks per day, drinks per drinking day, percent days abstinent, percent subjects with no heavy drinking days, and percent subjects abstinent, as well as measures of alcohol craving and negative mood. Additionally, participants will have the option to opt-in to a neuroimaging session in which we examine the effects of ibudilast on neural activation to psychosocial stress and alcohol cues. Finally, we will also collect plasma levels of proinflammatory markers, as well as subjective and biological (salivary cortisol) markers of stress response.

Discussion: This study will further develop ibudilast, a safe and promising novel compound with strong preclinical and clinical safety data for AUD, and will probe biological mechanisms underlying the effects of Ibudilast on stress, neuroinflammation, and alcohol cue-reactivity and craving. If ibudilast proves superior to placebo in this study, it will set the stage for a confirmatory multi-site trial leading to FDA approval of a novel AUD treatment.

Trial registration: ClinicalTrials.gov NCT03594435 "Ibudilast for the Treatment of Alcohol Use Disorder". Registered on 20 July 2018.

Lim, A.C., Green, R., Grodin, E.N., Venegas, A., Meredith, L.M., Donato, S., Burnette, E., & Ray, L.A. (2020). Alcohol cue-induced ventral striatum activity predicts subsequent alcohol self-administration. Alcoholism: Clinical and Experimental Research, 44(6), 1224-1233.

Abstract:

Background: Human laboratory paradigms are a pillar in medication development for alcohol use disorders (AUD). Neuroimaging paradigms, in which individuals are exposed to cues that elicit neural correlates of alcohol craving (e.g., mesocorticolimbic activation), are increasingly utilized to test the effects of AUD medications. Elucidation of the translational effects of these neuroimaging paradigms on human laboratory paradigms, such as self-administration, is warranted. The current study is a secondary analysis examining whether alcohol cue-induced activation in the ventral striatum is predictive of subsequent alcohol self-administration in the laboratory.

Methods: Non-treatment-seeking heavy drinkers of East Asian descent (n = 41) completed a randomized, placebo-controlled, double-blind, crossover experiment on the effects of naltrexone on neuroimaging and human laboratory paradigms. Participants completed 5 days of study medication (or placebo); on day 4, they completed a neuroimaging alcohol taste cue-reactivity task. On the following day (day 5), participants completed a 60-minute alcohol self-administration paradigm.

Results: Multilevel Cox regressions indicated a significant effect of taste cue-elicited ventral striatum activation on latency to first drink, Wald χ2 = 2.88, p = 0.05, such that those with higher ventral striatum activation exhibited shorter latencies to consume their first drink. Similarly, ventral striatum activation was positively associated with total number of drinks consumed, F(1, 38) = 5.90, p = 0.02. These effects were significant after controlling for alcohol use severity, OPRM1 genotype, and medication. Other potential regions of interest (anterior cingulate, thalamus) were not predictive of self-administration outcomes.

Conclusions: Neuroimaging alcohol taste cue paradigms may be predictive of laboratory paradigms such as self-administration. Elucidation of the relationships among different paradigms will inform how these paradigms may be used synergistically in experimental medicine and medication development.

Corlier, J., Burnette, E., Wilson, A., Lou, J., Landeros, A., Minzenberg, M.J., & Leuchter, A.F. (2020). Effect of repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD) on cognitive control. Journal of Affective Disorders, 265, 272-277.

Abstract:

Background: Major Depressive Disorder (MDD) is commonly accompanied by cognitive control dysfunction that may persist after remission of clinical symptoms with antidepressant medication treatment. Repetitive Transcranial Magnetic Stimulation (rTMS) is an effective treatment alternative for medication-resistant MDD. In this study, we investigated whether rTMS treatment had a beneficial effect not only on depressive symptoms, but on also cognitive control dysfunction.

Methods: 77 subjects with MDD received a 30-session treatment course of 10 Hz rTMS administered at the left dorsolateral prefrontal cortex (DLPFC). Treatment efficacy was assessed using the Inventory of Depressive Symptomatology Self-Rated (IDS-SR) before and after treatment, with clinical response defined as 50% or greater decrease in the IDS-SR score at treatment 30. Cognitive control function was assessed before and after treatment using the Stroop word-color interference task. We examined changes in Stroop accuracy and reaction time for congruent and incongruent trials, as well as in relation to changes in depressive symptoms.

Results: Performance accuracy improved particularly for the rTMS responders in the incongruent condition, with older subjects benefitting most from the rTMS treatment. Improvement in reaction times was positively associated with clinical improvement, especially in the incongruent condition.

Limitations: We used a single cognitive task in a naturalistic setting without control for individual rTMS treatment parameters or concomitant medication.

Conclusions: Overall, these results indicate that rTMS treatment for MDD has beneficial effects on psychomotor speed and cognitive control. Future studies should extend these findings to larger patient populations and other cognitive domains.

Burnette, E., Grodin, E.N., Lim, A., MacKillop, J., Karno, M., & Ray, L.A. (2019). Association between impulsivity and neural activation to alcohol cues in heavy drinkers. Psychiatry Research: Neuroimaging, 293, 110986.

Abstract:

This study examines associations between two measures of impulsivity and brain response to alcohol taste cues. Impulsivity is both a risk factor for and a consequence of alcohol use and misuse. Frontostriatal circuits are linked to both impulsivity and addiction-related behaviors, including response to alcohol cues. Non-treatment-seeking heavy drinkers (n = 55) completed (i) an fMRI alcohol taste cue-reactivity paradigm; (ii) the monetary choice questionnaire (MCQ), a measure of choice impulsivity where participants choose between smaller, sooner rewards and larger, delayed rewards; (iii) and the UPPS-P Impulsive Behavior Scale, a self-report measure assessing five impulsivity factors. General linear models identified associations between neural alcohol taste cue-reactivity and impulsivity, adjusting for age, gender, and smoking status. Self-reported sensation seeking was positively associated with alcohol taste cue-elicited activation in frontostriatal regions, such that individuals who reported higher sensation seeking displayed greater neural response to alcohol taste cues. Conversely, delay discounting was negatively associated with activation in frontoparietal regions, such that individuals who reported greater discounting showed less cue-elicited activation. There were no significant associations between other self-reported impulsivity subscales and alcohol taste cue-reactivity. These results indicate that sensation seeking is associated with reward responsivity, while delay discounting is associated with recruitment of self-control circuitry.

Burnette, E., Piker, E., & Frank-Ito, D. (2018). Reevaluating order effects in the binaural bithermic caloric test. American Journal of Audiology, 27(1), 104-109.

Abstract:

Purpose: The purpose of this study was to determine whether a significant order effect exists in the binaural bithermal caloric test.

Method: Fifteen volunteers (mean age = 24.3 years, range = 18-38 years) with no history of vestibular disorder, hearing loss, concussion, or neurological disease underwent caloric testing on 3 occasions. Irrigations were randomized using 8 possible order combinations. The parameters of interest included unilateral weakness, directional preponderance, total response from the right ear, and total response from the left ear.

Results: Order effects were analyzed using 2 methods. The first analysis was done looking at the 8 possible orders. We also had an a priori established hypothesis that the first irrigation tested would influence the calculation of unilateral weakness more than the other 3 irrigations. To test this hypothesis, the 8 orders were condensed into 4 order conditions based on the first irrigation. The effect of order was determined using analysis of variance tests. Although the first irrigation tended to be the largest, no significant effects were observed.

Conclusions: This experiment demonstrated that while there is great inter-individual and intra-individual variability in caloric test results, the order of irrigations had no significant effect in the test. Future studies may explore the effects of nonphysiological factors on test results.

Invited Talks

Burnette, E.M., Grodin, E.N., Lim, A.C., MacKillop, J., Karno, M., & Ray, L.A. (2021*). Association between impulsivity and neural activation to alcohol cues in heavy drinkers. In E.N. Grodin (Chair), Translational Studies in Alcohol Use Disorder. Symposium presented at Collaborative Perspectives on Addiction Annual Meeting. *Meeting held virtually due to COVID-19.

Abstract:

This study examines associations between two measures of impulsivity and brain response to alcohol taste cues. Impulsivity is both a risk factor for and a consequence of alcohol use and misuse. Frontostriatal circuits are linked to both impulsivity and addiction-related behaviors, including response to alcohol cues. Non-treatment-seeking heavy drinkers (n = 55) completed (i) an fMRI alcohol taste cue-reactivity paradigm; (ii) the monetary choice questionnaire (MCQ), a measure of choice impulsivity where participants choose between smaller, sooner rewards and larger, delayed rewards; (iii) and the UPPS-P Impulsive Behavior Scale, a self-report measure assessing five impulsivity factors. General linear models identified associations between neural alcohol taste cue-reactivity and impulsivity, adjusting for age, gender, and smoking status. Self-reported sensation seeking was positively associated with alcohol taste cue-elicited activation in frontostriatal regions, such that individuals who reported higher sensation seeking displayed greater neural response to alcohol taste cues. Conversely, delay discounting was negatively associated with activation in frontoparietal regions, such that individuals who reported greater discounting showed less cue-elicited activation. There were no significant associations between other self-reported impulsivity subscales and alcohol taste cue-reactivity. These results indicate that sensation seeking is associated with reward responsivity, while delay discounting is associated with recruitment of self-control circuitry.

Poster Presentations

Burnette, E.M., Bass, L.C., Munier, J.J., Evans, C.J., & Romero-Calderón, R. (2021*). Effectiveness of a virtual undergraduate student-led drug outreach program. Society for Neuroscience. *Meeting held virtually due to COVID-19.

Abstract:

Substance misuse and Substance use disorder (SUD) represent a persistent societal burden amounting to over $420 billion USD/year in lost productivity, healthcare and criminal justice costs. Prevention can not only reduce this societal cost, but also improve the quality of life for those that would have become afflicted. Programs aimed at adolescent outreach may be particularly impactful, since drug use beginning in adolescence greatly increases risk for development of a SUD. However, efficacy of widely popularized programs (such as Drug Abuse Resistance Education; DARE) is insignificant with small effect sizes. Changes in adolescent substance use have also been seen over the course of the COVID-19 pandemic, including increases in solitary substance use, increased frequency of alcohol and cannabis use, high levels of nicotine and cannabis vaping, and increases in stimulant use among younger adolescents. Drug Outreach, Promoting Awareness (DOPA) is an undergraduate outreach program targeting high school students with the goal of conveying the neurobiological basis, risks, harms, and addictive potential of commonly abused drugs. Undergraduate neuroscience students are instructed in the neurobiology, physiology, and policy of drugs and subsequently trained in active learning methods and the development of engaging presentations, interactive activities, and other educational materials. Over the 2020 and 2021 academic year Spring quarters, DOPA was conducted as a virtual setting via Zoom. Of particular interest is the comparison between virtual DOPA outreach and the traditional in-person model, which has been previously evaluated and shown to increase high schoolers’ perception of addictive potential and risk associated with drugs. In 2021, DOPA visited 178 students at 7 high schools in the US and Canada. Before and one week following the outreach session, participants were given a survey to evaluate 1) How common used of a specific drug was amongst their peers, 2) How harmful a specific drug was perceived to be, 3) How addictive a drug was, 4) open-ended perceived risks and harms of a drug, and 5) What they would do if a peer approached them about seeking treatment for a substance abuse problem. Using the 93 pre- and post-visit surveys that were successfully matched, we explored the effects of virtual-format drug outreach on high schoolers’ perception and attitudes about drugs and compared this effectiveness to that of the traditional in-classroom format. Answers regarding how common a drug was amongst their peers was generally representative of national prevalence. Cannabis was seen as significantly more harmful post-session, and perceptions of addiction risk were significantly increased for stimulants and sedative club drugs. These results indicate that virtual outreach was effective specifically regarding drugs for which use has increased among adolescents during the COVID-19 pandemic; however, virtual DOPA outreach was overall less effective than in-person outreach, despite reaching a greater number of students. Future directions should explore ways in which virtual outreach platforms can specifically improve drug awareness and harm reduction.

Burnette, E.M., Ray, L.A., Irwin, M.R., & Grodin, E.N. (2021*). Ibudilast attenuates alcohol cue-elicited frontostriatal functional connectivity in Alcohol Use Disorder. PsychoNeuroImmunology Research Society. *Meeting held virtually due to COVID-19.

Abstract:

Background: Ibudilast, a novel neuroimmune modulator being studied to treat alcohol use disorder (AUD), was shown in a randomized controlled trial (NCT03489850) to reduce ventral striatum (VS) activation in response to visual alcohol cues. The present study extended this finding by probing the effects of ibudilast on alcohol cue-elicited functional connectivity (i.e., temporally correlated activation) with the VS seed. The study also tests the association between functional connectivity and alcohol use during the trial.

Methods: Non-treatment-seeking participants (n = 45) with current alcohol use disorder were randomized to receive twice-daily dosing with either ibudilast (50 mg; n = 20) or placebo (n = 25). Upon reaching the target dosagee of the medication or placebo, participants completed a functional neuroimaging alcohol cue reactivity paradigm. Drinks per drinking day were assessed at baseline and daily during the 2-week trial.

Results: Ibudilast reduced alcohol cue-elicited functional connectivity between the VS seed and reward-processing regions including the orbitofrontal and anterior cingulate cortices compared with placebo (p < 0.05). Cue-elicited functional connectivity was correlated with drinks per drinking day (R2 = 0.5351, p < 0.001), and ibudilast reduced this association in similar reward-processing regions compared with placebo.

Conclusions: Ibudilast's effects on drinking outcomes may be related to the attenuation of functional connectivity in frontostriatal circuits related to reward processing. These results provide an important proof of concept for this novel pharmacotherapy and support the clinical utility of incorporating neuroimaging - and especially functional connectivity - analyses into medication development.

Burnette, E.M., Grodin, E.N., & Ray, L.A. (2020*). Risk taking and Alcohol Use Disorder Severity: An fMRI study. Research Society on Alcoholism. *Meeting held virtually due to COVID-19.

Abstract:

Purpose: Studies have shown a complex relationship between risk-taking behavior and substance use disorders (SUDs), including alcohol use disorder (AUD). This study examined associations between activation during risk-taking behavior and AUD by performing fMRI neuroimaging during the Balloon Analogue Risk Task (BART). Given that the sample was comprised exclusively of individuals with current AUD, we modeled associations between AUD severity and neural activation during BART performance.

Methods: Non-treatment seeking individuals with current AUD (n=18; 6F/12M, age=30±9.143) completed an fMRI BART paradigm. Participants make decisions about the amount of risk they are willing to accept to inflate a computer-generated balloon and obtain rewards. As the balloon inflates, reward and explosion probability both increase. Participants press buttons to either “pump” or “cash out” to avoid further risk and obtain the reward accrued thus far. If the risk function of the program is exceeded, the balloon explodes, forfeiting reward for that trial. Our fMRI BART task also included a balloon with no risk function in order to control for neural response to visual stimulus and button-pressing movements. Subjects’ standardized AUD severity z-scores were calculated by a principal components analysis across multiple AUD metrics. General linear models were run in FSL to identify associations between activation during the BART and AUD severity z-score. Age, gender, and smoking (cigarettes/day) were included as covariates.

Results: AUD severity was positively associated with frontal pole activation during parametric (modulating by level of risk as indicated by pump number) explosion events (Z>2.3, p<0.05, corrected). AUD severity was also positively associated with precuneus activation during average (across all risk levels) cash-out events (Z>2.3, p<0.05, corrected).

Conclusions: This study highlights both the multifaceted nature of risk and the nuance of responses assessed by the BART. Participants with more severe AUD showed stronger frontal pole activation during higher-risk explosions, possibly indicating that subjects with more severe AUD do not form logical expectations of explosion as risk level increases, so they may experience more surprise or subjective loss during an explosion event. Participants with more severe AUD also showed stronger precuneus activation during cash-out events regardless of risk level, a region previously shown to be part of a frontoparietal network involved in self-control.

Grodin, E.N.*, Burnette, E., Lim, A.C., MacKillop, J., Karno, M. & Ray, L.A. (2019). Association between impulsivity and neural activation to alcohol cues in heavy drinkers. International Conference on Applications of Neuroimaging to Alcoholism, New Haven, CT.
*Presented by
E.N. Grodin.

Abstract:

Purpose: Impulsivity is a multifaceted construct. Convergent preclinical and clinical evidence indicates that impulsivity is both a risk factor for and a consequence of alcohol use and misuse. Moreover, frontostriatal circuits have been linked to both impulsivity and addiction-related behaviors, including neural response to alcohol cues. The present study aimed to extend the literature on impulsivity and neural alcohol cue-reactivity by examining associations between two measures of impulsivity, behavioral via the delay discounting task and self-reported via the UPPS-P, and brain response to alcohol taste cues.

Methods: Non-treatment-seeking heavy drinkers (n=55; 32M/23F; age = 34.00±11.99) completed an fMRI alcohol taste cue-reactivity paradigm. They also completed two impulsivity questionnaires: (1) the monetary choice questionnaire (MCQ), a behavioral impulsivity measure where participants were asked to make a series of choices between smaller, sooner rewards and larger, later rewards; and (2) the UPPS-P Impulsive Behavior Scale, a self-report measure which assess five impulsivity factors: negative urgency, lack of premeditation, lack of perseverance, sensation seeking, and positive urgency. General linear models were run in FSL to identify associations between neural alcohol taste cue-reactivity and behavioral and self-reported impulsivity. Age, gender, and smoking status were included as nuisance covariates.

Results: Sensation seeking was positively associated with brain activation to alcohol taste cues in the caudate, thalamus, insula, and cingulate (Z>2.3, p<0.05, corrected). Delay discounting scores were negatively associated with alcohol taste cue-reactivity in the posterior cingulate, precuneus, occipital cortex, and middle frontal gyrus (Z>2.3, p<0.05, corrected). There were no significant associations between the other selfreported impulsivity sub-scales and brain activation to alcohol taste cues.

Conclusions: This study highlights the multifaceted nature of impulsivity. Self-reported sensation seeking was positively associated with alcohol taste cue-elicited activation in frontostriatal regions, such that individuals who reported higher sensation seeking displayed greater neural response to alcohol taste cues. Conversely, delay discounting was negatively associated with alcohol taste cue-elicited activation in frontoparietal regions, such that individuals who reported greater discounting had less neural response to alcohol taste cues. Together these results indicate that sensation seeking is associated with reward responsivity, while delay discounting is associated with recruitment of self-control circuity.

Burnette, E., Moody, T.D., Wu, M.S., Sheen, C., Goldbeck, J., Strober, M. & Feusner, J. (2019). Reward and anxiety network activity predicts psychometrics in anorexia nervosa and anxious controls. Organization for Human Brain Mapping, Rome, Italy.

Abstract:

Introduction: Anorexia Nervosa (AN) has the highest mortality rate of any psychiatric disorder and is correlated with anxiety phenotypes appearing prior to disease onset. As children, individuals who later develop AN seem uneasy when exposed to novel high-reward environments and show low reward responsiveness and fun-seeking behavior. Positive valence (reward) systems, including the orbitofrontal cortex, caudate, nucleus accumbens, and ventral tegmental area, and negative valence (anxiety) systems, including the insular cortex, medial prefrontal cortex, anterior cingulate cortex, amygdala, and extended amygdala, likely interact antagonistically based on prevailing or anticipated reward or threat stimuli. This study aims to characterize interactions between these neural circuits and how they relate to anxiety, reward, and eating disorder symptoms. We hypothesized that anxiety system activity would predict lower measures of reward due to the anxious state interfering with the subjective experience of reward.

Methods: Participants included 20 adolescent partially or fully weight-restored females (ages 12-18) with AN and 21 mildly anxious adolescents (ages 13-19) as a comparison group in order to dimensionalize relationships between AN and anxiety. All participants completed several measures of anxiety, behavioral approach/inhibition, and eating disorder pathology. During fMRI scanning (Siemens 3T Trio scanner), participants performed a reward task in which they classified an image, followed by a word they previously rated as anxiety-provoking or neutral, then either monetary reward or non-reward feedback. Data preprocessing, registration, and analysis were done in FSL. We extracted eigenvalues from reward and anxiety system activity. Relationships between clinical and neural data were analyzed using Partial Least Squares (PLS) regression analysis.

Results: Across groups, anxiety system eigenvalues predicted anxiety psychometrics (Hamilton Anxiety Scale, DASS-21 anxiety subscale, Behavioral Inhibition Scale (BIS), Penn State Worry Questionnaire) in PLS regression (p=0.009). Behavioral Approach Scale scores (BAS, measuring reward) were predicted by reward region activity (p=0.038). As hypothesized, anxiety system activity negatively predicted BAS scores (p=0.006). The converse, reward system activity predicting anxiety psychometrics, was not significant (p=0.164). An exploratory analysis using PLS to predict measures of eating disorder symptoms (Yale-Brown-Cornell Eating Disorder Total Severity Scale, Eating Disorder Examination Questionnaire Shape Concern Subscale and Global Scale) in participants with AN found significant associations with activity in reward (p=0.033) but not anxiety (p=0.151) regions. In a between-groups GLM analysis, participants with AN showed higher anxiety system activity than comparisons during positive feedback (p=0.046).

Conclusions: As hypothesized, participants with higher anxiety system activity had lower reward psychometrics, suggesting that the anxious state may negatively impact the ability to experience reward, though reward network activation may not significantly impact the subjective experience of anxiety. Participants with AN had higher anxiety region activity than comparisons despite similar word ratings, indicating increased brain reactivity to similar subjective experiences of anxiety during the task. Reward but not anxiety system activity predicted eating disorder symptom severity, suggesting that reward network activity may have a stronger direct relationship to eating disorder symptoms. However, participants with AN showed significantly higher anxiety psychometric scores than comparisons. These results may have treatment implications: a treatment focusing on improving the ability to experience reward and/or the brain's response to rewarding stimuli may impact eating disorder symptomology. In addition, subjective experience of anxiety remains a prominent symptom domain necessitating treatment for individuals with AN.

Burnette, E., Ocampo, G., Wander, R., Walker, Q., Zucker, N. & Kuhn, C. (2017). Adolescents show conditioned food aversion: A strategy to study disordered eating? Society for Neuroscience, Washington, D.C.

Abstract:

Anorexia Nervosa (AN) is the leading cause of mortality due to psychiatric causes. Current animal models focus on anorexia associated with food restriction, extreme stress and or excess physical activity and no current animal model captures the key characteristics of visceral hypersensitivity leading to learned food avoidance, adolescent onset and female dominance. The present study developed a food aversion task that involved no food deprivation to investigate the developmental and sex specificity of conditioned food avoidance (CFA) in adolescent (PN 28-30) and adult (PN 60-62) rats (N = 8-16/group). Rats were placed in novel feeding cage and allowed to eat a novel cereal (Cheerios, Ch) for one hour. Twenty-four hours later, they were injected with saline or LiCl (19 mg/kg) and were allowed to eat a novel, palatable food (Froot Loops, FL). Pica was quantitated in a subset of animals for 1 hr. as a measure of nausea. Twenty four hours later, rats were given the opportunity to eat FL and another novel cereal, Apple Jacks (AJ). Cereal intake (g/kg bw) were quantitated for each cereal. Results were analyzed by 3-way ANOVA (drug x age x sex). LiCl caused pica that was greater in adults than adolescents (p < .002 effect of drug, p < .002 age x dose). Adolescents ate more of a novel food (Ch) than adults (p < .001 for effect of age, p < .0002 age x sex). All animals showed marked CFA to FL (p < .001 effect of drug), and adolescents showed more CFA than adults (p < .003 effect of age, p < .007 age x sex x treatment). Furthermore, females generalized the CFA to include a novel food not previously paired with LiCl more than males (AJ) p < .001 effect of drug, (p < .0002 effect of age, p < .002 effect of sex, and there was a trend for greater generalization in adolescents (p < ;06 for age x treatment). The results contrast markedly with reports from this laboratory and others of lower adolescent sensitivity in standard conditioned taste aversion tasks, and suggest that this approach may prove useful in characterizing the neural mechanisms responsible for the development of disordered eating in adolescents.