Attentional Bias, Pupillometry, and Spontaneous Blink Rate: Eye Characteristic Assessment Within a Translatable Nicotine Cue Virtual Reality Paradigm.

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 (F1,106=47.95; P<.001). Greater mean eye-gaze fixation time (F1,106=48.34; P<.001) and pupil diameter (F1,102=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.

Harnessing Immersive Virtual Reality: A Comprehensive Scoping Review of its Applications in Assessing, Understanding, and Treating Eating Disorders.

BACKGROUND: Immersive Virtual Reality (IVR) has shown promise in the assessment, understanding, and treatment of eating disorders (EDs), providing a dynamic platform for clinical innovation. This scoping review aims to synthesize the recent advancements and applications of IVR in addressing these complex psychological disorders. METHODS: This review followed the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols, focusing on studies published in the past five years. It included peer-reviewed papers that used IVR for ED assessment, examination, or treatment. A comprehensive database search provided a selection of relevant articles, which were then methodically screened and analyzed. RESULTS: Twenty studies met the inclusion criteria, with a primary focus on Anorexia Nervosa (AN), Bulimia Nervosa (BN), and Binge Eating Disorder (BED). The application of IVR was categorized into three areas: assessment, understanding, and treatment. IVR was found to be an effective tool in assessing body image distortions and emotional responses to food, providing insights that are less accessible through traditional methods. Furthermore, IVR offers innovative treatment approaches by facilitating exposure therapy, modifying body-related biases, and enabling emotional regulation through embodied experiences. The studies demonstrate IVR's potential to improve body image accuracy, reduce food-related anxieties, and support behavioral changes in ED patients. CONCLUSION: IVR stands out as a transformative technology in the field of EDs, offering comprehensive benefits across diagnostic, therapeutic, and experiential domains. The IVR's ability to simulate the brain's predictive coding mechanisms provides a powerful avenue for delivering embodied, experiential interventions that can help recalibrate distorted body representations and dysfunctional affective predictive models implicated in EDs. Future research should continue to refine these applications, ensuring consistent methodologies and wider clinical trials to fully harness IVR's potential in clinical settings.

Validation of a laboratory craving assessment and evaluation of 4 different interventions on cravings among adults with overweight or obesity.

Food cue reactivity (FCR) is an appetitive trait associated with overeating and weight gain. We developed a laboratory craving assessment to objectively evaluate cognitive aspects of FCR. This study examined the preliminary construct and criterion validity of this craving assessment and evaluated 4 different interventions, 2 of which incorporated cue-exposure treatment for food, on craving over treatment and follow-up. 271 treatment-seeking adults with overweight/obesity (body mass index = 34.6[5.2]; age = 46.5[11.8]; 81.2% female; 61.6% non-Latinx White) completed the Food Cue Responsivity Scale and the laboratory craving assessment, during which they alternated holding and smelling a highly craved food and provided craving ratings over 5 min. Participants were subsequently randomized to 26 treatment sessions over 12-months of ROC, Behavioral Weight Loss (BWL), a combined arm (ROC+) and an active comparator (AC), and repeated the craving assessment at post-treatment and 12-month follow-up. Linear mixed-effects models assessed associations between trial type (holding vs. smelling), trial number, pre-treatment FCR, treatment arm, assessment time point, and craving. Cravings were greater when smelling vs. holding food (b = 0.31, p < 0.001), and cravings decreased over time (b = -0.02, p < 0.001). Participants with higher pre-treatment FCR reported elevated cravings (b = 0.29, p < 0.001). Longitudinally, we observed a significant 3-way interaction in which treatment arm modified the relationship between pre-treatment FCR and craving over time (F(17,5122) = 6.88, p < 0.001). An attenuated FCR-craving relationship was observed in ROC+ and BWL from baseline to post-treatment but was only sustained in BWL at follow-up. This attenuation was also observed in ROC and AC from post-treatment to follow-up. The preliminary validity of this laboratory craving assessment was supported; however, greater craving reductions over time in ROC/ROC+ compared to BWL and AC were not consistently observed, and thus do not appear to fully account for the moderating effect of FCR on weight losses observed in the trial.

Virtual reality cue-exposure therapy in reducing cocaine craving: the Promoting Innovative COgnitive behavioral therapy for Cocaine use disorder (PICOC) study protocol for a randomized controlled trial.

BACKGROUND: Cocaine craving is a central symptom of cocaine use disorders (CUD). Virtual reality cue-exposure therapy for craving (VRCET) allows more immersive, realistic, and controllable exposure than traditional non-VR cue-exposure therapy (CET), whose efficacy is limited in treating substance use disorders. The purpose of this study is to evaluate the efficacy and acceptability of VRCET, as a stand-alone and add-on intervention (i.e., combined with cognitive therapy), compared to a picture-based CET (PCET), in reducing self-reported cocaine craving in inpatients hospitalized for CUD. METHODS: Fifty-four inpatients hospitalized for CUD will be randomized in one of two intensive 3-week treatment arms: 10 meetings/2-week treatment of VRCET plus 5 meetings/1-week treatment of memory-focused cognitive therapy (MFCT; experimental arm), or 15 meetings/3-week treatment of PCET (active control arm). The Craving Experience Questionnaire (CEQ - F & S) will be used to assess the primary outcome, i.e., the post-treatment decrease of self-reported cocaine craving frequency (within the past 2 weeks) and intensity scores (in VR exposure to cocaine cues). Secondary endpoints include urinary, physiological, and self-reported cocaine use-related measures. Assessments are scheduled at pretreatment, after 2 weeks of treatment (i.e., VRCET vs. PCET), post-treatment (3 weeks, i.e., VRCET + MFCT vs. PCET), and at 1-month follow-up. Acceptability will be evaluated via (i) the Spatial Presence for Immersive Environments - Cybersickness along VRCET and (ii) the Client Satisfaction Questionnaires after 2 weeks of treatment and post-treatment. DISCUSSION: This study will be the first to evaluate the acceptability and efficacy of VRCET for CUD, as a psychotherapeutic add-on, to reduce both cocaine craving frequency and intensity. Additionally, this study will provide evidence about the specific interest of VRCET, compared to a non-VR-based CET, as a cue reactivity and exposure paradigm for treating substance use disorders. TRIAL REGISTRATION: NCT05833529 [clinicaltrials.gov]. Prospectively registered on April 17, 2023.

Towards virtual reality exposure therapy for cocaine use disorder: A feasibility study of inducing cocaine craving through virtual reality.

Background: Craving is a core symptom of cocaine use disorders (CUD). Inducing craving in exposure to substance cues is of relevant interest for numerous clinical applications. Virtual reality exposure (VRE) might be a promising candidate for improving cue-exposure paradigms but remains almost not studied for cocaine. This feasibility study's main aim is to assess whether VRE to cocaine cues is capable to induce cocaine craving compared with VRE to neutral cues. Methods: We conducted a within-subjects controlled trial in which cocaine users performed 3 consecutive 10 mins-tasks: VRE to neutral and cocaine cues, and a relaxation-based resting procedure. The primary outcome was the change in Cocaine Craving Questionnaire-Brief (CCQ-Brief) scores between VRE to neutral and cocaine cues. Secondary outcomes included between-tasks changes in scores of cocaine craving, pleasant/unpleasant emotions as well as self-efficacy to cope with craving. Results: We recruited 11 chronic cocaine users including mostly crack smokers (45 %), cocaine snorters (36 %) and injectors (18 %), with 73 % of participants meeting DSM-IV criteria for cocaine dependence and/or abuse. Non-parametrical sign tests indicated significant large increases of CCQ-Brief scores from neutral to cocaine cue-VRE (S(11) = 11, p < 0.01, Cliff's Δ = 0.65, 95 % CI: 0.17-0.88). Exploratory comparative analyses indicated significant changes after our post-cues VRE relaxation procedure, with cocaine craving and emotions restored to baseline. Conclusions: VRE to cocaine cues was feasible and capable to induce cocaine craving in cocaine users. This second VRE-based cue-reactivity study in cocaine paves the way for unexplored research on VRE clinical applications for CUD.

The effects of a retrieval cue on renewal of conditioned responses in human appetitive conditioning.

Contextual renewal of reward anticipation may be one potential mechanism underlying relapse in eating and substance use disorders. We therefore tested retrieval cues, a method derived from an inhibitory retrieval-based model of extinction learning to attenuate contextual renewal using an appetitive conditioning paradigm. A pilot study was carried out in Experiment 1 to validate a differential chocolate conditioning paradigm, in which a specific tray was set up as a conditioned stimulus (CS) for eating chocolate (unconditioned stimulus, US). Using an ABA renewal design in Experiment 2, half of the participants were presented with a retrieval cue in the acquisition phase (group AC) and the other half in the extinction phase (group EC). Presentation of the retrieval cue in the EC was associated with reduced renewal of US-expectancy, while there was a clear renewal effect for US-expectancy in the AC. One limitation was the difference in cue presentations between both groups due to the number of trials in acquisition and extinction. Experiment 3 therefore aimed at replicating the results of Experiment 2, but with fewer cue presentations for the EC to match the AC. No significant group differences were observed indicating no effect of the retrieval cue. Theoretical and clinical implications in light of the differing results are discussed.

Neural correlates of increased alcohol demand following alcohol cue exposure in adult heavy drinkers.

Alcohol use disorder is associated with overvaluation of alcohol relative to other rewards, in part due to dynamic increases in value in response to alcohol-related cues. In a neuroeconomic framework, alcohol cues increase behavioral economic demand for alcohol, but the neural correlates these cue effects are unknown. This functional magnetic resonance imaging study combined a neuroeconomic alcohol purchase task with an alcohol cue exposure in 72 heavy drinkers with established sensitivity to alcohol cues (51 % female; mean age=33.74). Participants reported how many drinks they would consume from $0-$80/drink following exposure to neutral and alcohol images in a fixed order. Participants purchased significantly more drinks in the alcohol compared to the neutral condition, which was also evident for demand indices (i.e., intensity, breakpoint, Omax, elasticity; ps<0.001; ds=0.46-0.92). Alcohol purchase decisions were associated with activation in rostral middle and medial frontal gyri, anterior insula, posterior parietal cortex, and dorsal striatum, among other regions. Activation was lower across regions in the alcohol relative to neutral cue condition, potentially due to greater automaticity of choices in the presence of alcohol cues or attenuation of responses due to fixed cue order. These results contribute to growing literature using neuroeconomics to understand alcohol misuse and provide a foundation for future research investigating decision-making effects of environmental alcohol triggers.

Cue-exposure treatment influences resting-state functional connectivity-a randomized controlled fMRI study in alcohol use disorder.

RATIONALE: Cue-exposure therapy (CET) consists of exposing patients to the cause of their affliction in a controlled environment and after psychological preparation. Ever since it was conceived, it has been suggested as a treatment for different types of behavioural impairments, from anxiety disorders to substance abuse. In the field of addictive behaviour, many different findings have been shown regarding the effectiveness of this therapy. OBJECTIVES: This study aims to examine the underlying neurobiological mechanisms of the effects of CET in patients with alcohol use disorder using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: In a randomized, controlled study, we examined patients after inpatient detoxification as well as healthy controls. Patients underwent nine sessions of CET spaced over 3 weeks. Rs-fMRI was conducted before treatment and 3 weeks after treatment onset in patients, healthy controls received only one rs-fMRI measurement. The final participant sample with complete data included 35 patients in the CET group, 17 patients in the treatment-as-usual group, and 43 HCs. RESULTS: Our results show differences in the Salience Network when comparing the CET group to the treatment-as-usual group (TAU). Functional connectivity between the anterior cingulate Cortex (ACC) and the insula was increased after CET, whereas it was decreased from ACC to the putamen and globus pallidus. Further, increased connectivity with the precuneus was found in the dorsal attention network after cue exposure treatment. CONCLUSIONS: These findings suggest that cue exposure therapy changes the resting-state brain connectivity with additional effects to the standard psychotherapy treatment. Hence, our study results suggest why including CET in standard therapies might improve the preparation of patients in front of daily situations.

New Approaches to Addiction Treatment Based on Learning and Memory.

Preclinical studies suggest that physiological learning processes are similar to changes observed in addiction at the molecular, neuronal and structural levels. Based on the importance of classical and instrumental conditioning in the development and maintenance of addictive disorders, many have suggested cue-exposure-based extinction training of conditioned, drug-related responses as a potential treatment of addiction. Recently, the development of virtual reality-assisted cue-exposure treatment has put forward new approaches to extinction training. Recent data indicated that it may also be possible to facilitate this extinction training through pharmacological interventions that strengthen memory consolidation during cue exposure. Another potential therapeutic intervention is based on the so-called reconsolidation theory. According to this hypothesis, already-consolidated memories return to a labile state when reactivated, allowing them to undergo another phase of consolidation - reconsolidation - which can be interfered with by pharmacological and behavioural interventions. These approaches suggest that the extinction of drug-related memories may represent a viable treatment strategy in the future treatment of addiction.

Effects of virtual reality-based cue exposure therapy on craving and physiological responses in alcohol-dependent patients-a randomised controlled trial.

BACKGROUND: Cue exposure therapy is used to treat alcohol dependence. However, its effectiveness is controversial due to the limitations of the clinical treatment setting. Virtual reality technology may improve the therapeutic effect. The aim of this study is to explore whether virtual reality-based cue exposure therapy can reduce the psychological craving and physiological responses of patients with alcohol dependence. METHODS: Forty-four male alcohol-dependent patients were recruited and divided into the study group (n = 23) and the control group (n = 21) according to a random number table. The control group received only conventional clinical treatment for alcohol dependence. The study group received conventional clinical treatment with the addition of VR cue exposure (treatment). The primary outcome was to assess psychological craving and physiological responses to cues of patients before and after treatment. RESULTS: After virtual reality-based cue exposure therapy, the changes in VAS and heart rate before and after cue exposure in the study group were significantly lower than those in the control group (P < 0.05), while the changes in skin conductance and respiration between the study group and the control group were not significantly different (P > 0.05). The changes in VAS and heart rate before and after cue exposure in the study group were significantly lower than those before treatment (P < 0.05), while the changes in skin conductance and respiration were not significantly different from those before treatment (P > 0.05). The changes in VAS, heart rate, skin conductance and respiration before and after cue exposure in the control group were not significantly different from those before treatment (P > 0.05). CONCLUSION: Virtual reality-based cue exposure therapy can reduce the psychological craving and part of the physiological responses of alcohol-dependent patients during cue exposure in the short term and may be helpful in the treatment of alcohol dependence. TRIAL REGISTRATION: The study protocol was registered at the China Clinical Trial Registry on 26/02/2021 ( www.chictr.org.cn ; ChiCTR ID: ChiCTR2100043680).

Effectiveness of Reducing Craving in Alcohol Use Disorder Using a Serious Game (SALIENCE): Randomized Controlled Trial.

BACKGROUND: Alcohol use disorder (AUD) has become a major global health problem. Therapy for this condition is still a great challenge. Recently, it has become increasingly evident that computer-based training is a valuable addition to the treatment of addictive disorders. OBJECTIVE: This study aims to evaluate the web-based serious game SALIENCE (Stop Alcohol in Everyday Life-New Choices and Evaluations) as an add-on therapy for AUD. It combines the cue-exposure therapy approach with elements of decision-making training, enhanced by interactive panoramic images. The effects of SALIENCE training on levels of craving, attention, and cognitive bias are investigated. METHODS: In a randomized controlled trial, 62 participants with AUD undergoing 3 weeks of an extended alcohol detoxification program were randomly allocated to an intervention and a control group. A total of 49 individuals (mean age 44.04 y; 17/49, 35% female) completed all sessions and were included in the analysis. Only pretreatment data were available from the other 13 patients. Participants answered questionnaires related to alcohol consumption and craving and completed neuropsychological tasks at the beginning of the study and 2 weeks later to evaluate levels of attention and cognitive biases. During the 2-week period, 27 of the participants additionally performed the SALIENCE training for 30 minutes 3 times a week, for a total of 6 sessions. RESULTS: We observed a significant decrease in craving in both groups: the control group (mean 15.59, SD 8.02 on the first examination day vs mean 13.18, SD 8.38 on the second examination day) and the intervention group (mean 15.19, SD 6.71 on the first examination day vs mean 13.30, SD 8.47 on the second examination day; F1,47=4.31; P=.04), whereas the interaction effect was not statistically significant (F1,47=0.06; P=.80). Results of the multiple linear regression controlling for individual differences between participants indicated a significantly greater decrease in craving (ß=4.12; t36=2.34; P=.03) with the SALIENCE intervention. Participants with lower drinking in negative situations reduced their craving (ß=.38; t36=3.01; P=.005) more than people with higher drinking in negative situations. CONCLUSIONS: The general effectiveness of SALIENCE training as an add-on therapy in reducing alcohol craving was not confirmed. Nevertheless, taking into account individual differences (gender, duration of dependence, stress, anxiety, and drinking behavior in different situations), it was shown that SALIENCE training resulted in a larger reduction in craving than without. Notably, individuals who rarely consume alcohol due to negative affect profited the most from SALIENCE training. In addition to the beneficial effect of SALIENCE training, these findings highlight the relevance of individualized therapy for AUD, adapted to personal circumstances such as drinking motivation. TRIAL REGISTRATION: ClinicalTrials.gov NCT03765476; https://clinicaltrials.gov/show/NCT03765476.

An explorative single-arm clinical study to assess craving in patients with alcohol use disorder using Virtual Reality exposure (CRAVE)-study protocol.

BACKGROUND: Alcohol use disorder (AUD) belongs to the most burdensome clinical disorders worldwide. Current treatment approaches yield unsatisfactory long-term effects with relapse rates up to 85%. Craving for alcohol is a major predictor for relapse and can be intentionally induced via cue exposure in real life as well as in Virtual Reality (VR). The induction and habituation of craving via conditioned cues as well as extinction learning is used in Cue Exposure Therapy (CET), a long-known but rarely used strategy in Cognitive Behavioral Therapy (CBT) of AUD. VR scenarios with alcohol related cues offer several advantages over real life scenarios and are within the focus of current efforts to develop new treatment options. As a first step, we aim to analyze if the VR scenarios elicit a transient change in craving levels and if this is measurable via subjective and psychophysiological parameters. METHODS: A single-arm clinical study will be conducted including n = 60 patients with AUD. Data on severity of AUD and craving, comorbidities, demographics, side effects and the feeling of presence in VR will be assessed. Patients will use a head-mounted display (HMD) to immerse themselves into three different scenarios (neutral vs. two target situations: a living room and a bar) while heart rate, heart rate variability, pupillometry and electrodermal activity will be measured continuously. Subjective craving levels will be assessed before, during and after the VR session. DISCUSSION: Results of this study will yield insight into the induction of alcohol craving in VR cue exposure paradigms and its measurement via subjective and psychophysiological parameters. This might be an important step in the development of innovative therapeutic approaches in the treatment of patients with AUD. TRIAL REGISTRATION: This study was approved by the Charité-Universitätsmedizin Berlin Institutional Review Board (EA1/190/22, 23.05.2023). It was registered on ClinicalTrials.gov (NCT05861843).

Be more mindful: Targeting addictive responses by integrating mindfulness with cognitive bias modification or cue exposure interventions.

This review provides an overview of the most prominent neurocognitive effects of cognitive bias modification (CBM), cue-exposure therapy and mindfulness interventions for targeting addictive responses. It highlights the key insights that have stemmed from cognitive neuroscience and brain imaging research and combines these with insights from behavioural science in building a conceptual model integrating mindfulness with response-focused CBM or cue-exposure interventions. This furthers our understanding of whether and how mindfulness strategies may i) facilitate or add to the induced response-focused effects decreasing cue-induced craving, and ii) further weaken the link between craving and addictive responses. Specifically, awareness/monitoring may facilitate, and decentering may add to, response-focused effects. Combined awareness acceptance strategies may also diminish the craving-addiction link. The conceptual model presented in this review provides a specific theoretical framework to deepen our understanding of how mindfulness strategies and CBM or cue-exposure interventions can be combined to greatest effect. This is important in both suggesting a roadmap for future research, and for the further development of clinical interventions.

Effects of acceptance-based strategies on psychological responses to disorder-relevant stimuli in inpatients with obsessive-compulsive disorder: An experimental study.

BACKGROUND AND OBJECTIVES: Preliminary findings suggest that acceptance and commitment therapy-informed exposure therapy may be an effective treatment for obsessive-compulsive disorder (OCD). However, there is a lack of experimental studies that have examined immediate effects of acceptance-based strategies during exposure to disorder-relevant stimuli in persons with OCD. METHODS: Fifty-three inpatients (64% female) with OCD participated in an experimental study during which they were exposed to obsessive-compulsive washing-relevant pictures and were instructed to either passively view these pictures for 5 s (neutral condition), to accept their feelings (acceptance condition) or to intensify their feelings (exposure condition) for 90 s each. RESULTS: The acceptance condition led to higher acceptance and lower unpleasantness of patients' current feelings compared to the neutral condition and to lower strength of obsessions and urge to perform compulsions but only when compared to the exposure condition. Higher self-reported OCD symptom severity related to higher unpleasantness and strength of obsessions, particularly in the neutral condition. LIMITATIONS: Future studies need to test whether the current findings translate to other stimuli and other forms of obsessions and compulsions. Due to the short duration, the exposure condition might have only mimicked the early phase of exposure and response prevention. CONCLUSIONS: Acceptance-based strategies during cue exposure immediately increase acceptance of and reduce unpleasant feelings. In line with the rationale of acceptance-based treatment approaches, which do not aim at immediate disorder-specific symptom reductions, effects on obsessions and compulsions may be more delayed or require repeated training sessions.

Process Analyses of Impulsive Behavior in Binge-Eating Disorder During the Randomized Controlled IMPULS Trial.

Impulsivity represents a risk factor for patients with binge-eating disorder, and we therefore investigated the treatment process of impulsive behaviors including binge-eating episodes in the randomized controlled IMPULS trial. Using 8 weekly online questionnaires throughout the assessment period, we compared 41 patients participating in the IMPULS program, which emphasized impulsive eating behavior (IG), with 39 control patients who received no intervention (CG). We assessed the frequency of binge eating, other impulsive behaviors, situations in which such behaviors could be inhibited, and the execution of alternative behaviors. Results indicate a stronger binge-eating reduction in the IG compared to the CG at the fifth, seventh, and eighth treatment weeks. Overall, both groups reduced other impulsive behaviors. They did not differ in the amount of inhibited impulsive behaviors and showed similar alternative behaviors, "distraction" most frequently used. IG patients evaluated the IMPULS program as very helpful. The stronger reduction of binge eating in the IG and positive evaluation of the treatment indicate a specific treatment effect regarding impulsive eating behavior. The reduction of other impulsive behaviors across both groups, and the initial reduction of binge eating within the CG, could be explained by an increased degree of self-observation.

Virtual reality cue exposure therapy for tobacco relapse prevention: a comparative study with standard intervention.

BACKGROUND: Successful interventions have been developed for smoking cessation although the success of smoking relapse prevention protocols has been limited. Cognitive behavioural therapy (CBT) in particular has been hampered by a high relapse rate. Because relapse can be due to conditions associated with tobacco consumption (such as drinking in bars with friends), virtual reality cue exposure therapy (VRCE) can be a potential tool to generate 3D interactive environments that simulate risk situations for relapse prevention procedures. METHODS: To assess the effectiveness of VRCE with CBT, a comparative trial involving 100 smoking abstinent participants was designed with all required virtual environments (VE) created with an inexpensive graphic engine/game level editor. RESULTS: Outcome measures confirmed the immersive and craving eliciting effect of these VEs. Results demonstrated that more participants in the VRCE group did not experience smoking relapse and that VRCE is at least as efficacious as traditional CBT in terms of craving reduction and decrease in nicotine dependence. Dropout and relapse rate in the VRCE group was noticeably lower than the CBT group. Aside from mood scores, no significant differences were found regarding the other scales. CONCLUSION: The present clinical trial provides evidence that VRCE was effective in preventing smoking relapse. Improvement in technology and methodology for future research and applications is delineated.

Modeling cue-exposure therapy for alcohol use disorder in rhesus monkeys: Effects of putative cognitive enhancers.

BACKGROUND: Cue-exposure therapy (CET) is an effective approach for anxiety-related disorders, but its effectiveness for substance use disorders is less clear. One potential means of improving CET outcomes is to include a cognitive-enhancing pharmacotherapy. This study evaluated d-cycloserine (DCS) and RY-023, putative cognitive enhancers targeting glutamate and GABA systems, respectively, in a monkey model of CET for alcohol use disorder. METHODS: Male rhesus monkeys (n = 4) underwent multiple cycles of the CET procedure. During baseline (Phase 1), monkeys self-administered an ethanol solution under a fixed-ratio schedule and limited access conditions such that every 5th response in a 3-h session resulted in 30-s access to a drinking spout and a change in ethanol-paired cue lights from white to red. Behavior then was extinguished (Phase 2) by omitting the ethanol solution yet retaining the ethanol-paired stimulus lights. Monkeys also received injections of vehicle, DCS (3 mg/kg), a partial agonist at the glycine modulatory site on glutamatergic NMDA receptors, or the α5GABAA receptor-selective inverse agonist RY-023 (0.03 or 0.3 mg/kg). Once responding declined, monkeys underwent a cue reactivity test (Phase 3), and then returned to self-administration the following day to assess reacquisition (Phase 4). RESULTS: Through multiple cycles, self-administration remained stable. Compared to vehicle, DCS facilitated extinction of ethanol seeking (Phase 2) and delayed reacquisition of ethanol self-administration (Phase 4). In contrast, RY-023 facilitated extinction (Phase 2) and reduced cue reactivity (Phase 3). CONCLUSIONS: Adjunctive pharmacotherapy can improve CET outcomes, but the choice of pharmacotherapy should be dependent on the outcome of interest.

Alcohol cues increase behavioral economic demand and craving for alcohol in nontreatment-seeking and treatment-seeking heavy drinkers.

BACKGROUND: Behavioral economic research has revealed significant increases in alcohol demand following exposure to alcohol-related cues. Prior research has focused exclusively on nontreatment-seeking heavy drinkers, included only male participants, or used heterogeneous methods. The current studies sought to replicate and extend existing findings in treatment-seeking and nontreatment-seeking heavy drinkers while also examining sex effects and moderation by alcohol use disorder (AUD) severity. METHODS: Study 1 included 117 nontreatment-seeking heavy drinkers (51.5% women; M age 34.69; 56.4% AUD+), and Study 2 included 89 treatment-seeking heavy drinkers with AUD (40.4% women; M age = 41.35). In both studies, alcohol demand was measured using a hypothetical alcohol purchase task (APT), and subjective alcohol craving was measured using visual analog scales. Measures were collected following exposure to neutral (water) cues in a standard room and alcohol cues in a bar lab. RESULTS: Alcohol demand (intensity, Omax , breakpoint, and elasticity) and craving were significantly increased following alcohol cues compared to neutral cues (ps < 0.005) with effect sizes ranging from small to large (ηp 2 = 0.074-0.480). Participants with AUD (Study 1) or with higher AUD severity (Study 2) reported higher craving and higher demand for most indices (i.e., main effects; ps < 0.032, ηp 2 = 0.043-0.239). A larger alcohol cue increase in Omax was found for AUD+ participants in Study 1 compared to non-AUD participants (p = 0.028, ηp 2 = 0.041) but not for any other indices in Study 1 or Study 2. There were no significant sex effects. CONCLUSIONS: These findings replicate and extend prior research by offering additional insight into alcohol cue effects on the reinforcing value of alcohol and subjective motivation to drink. The results also suggest that sex and AUD severity do not meaningfully impact cue effects across most indices of demand.

Smokers' Self-Report and Behavioral Reactivity to Combined Personal Smoking Cues (Proximal + Environment + People): A Pilot Study.

Cue reactivity (CR) among smokers exposed to smoking-related stimuli, both proximal (e.g., cigarettes, lighter) and distal (environments, people), has been well-demonstrated. Furthermore, past work has shown that combining proximal smoking cues with smoking environment cues increases cue-provoked craving and smoking behavior above that elicited by either cue type alone. In this pilot study, we examined the impact of combining three personal cues, proximal + environment + people, on subjective and behavioral cue reactivity among smokers. To further understand the impact of this method, we also tested reactivity under the conditions of both smoking satiety and deprivation. In addition, we examined the extent to which cue-induced craving predicted immediate subsequent smoking. Fifteen smokers completed six sessions, of which two focused on the intake and development of personal cues and four involved personal cue reactivity sessions: (1) deprived, smoking cue combination, (2) deprived, nonsmoking cue combination, (3) sated, smoking combination, and (4) sated, nonsmoking cue combination. Cue-provoked craving was greater and smokers were quicker to light a cigarette and smoked more during their exposure to smoking rather than nonsmoking cues and in deprived compared to sated conditions, with no interaction between these variables. While deprived, greater cue-provoked craving in response to smoking cues was correlated with a quicker latency to light a cigarette. This work supports the feasibility of presenting three personal smoking-related combinations of cues within a cue reactivity paradigm and highlights the robust reactivity that this methodology can evoke in smokers.

Augmented reality as a novel approach for addiction treatment: development of a smoking cessation app.

OBJECTIVE: Augmented reality (AR) is a rapidly developing technology that has substantial potential as a novel approach for addiction treatment, including tobacco use. AR can facilitate the delivery of cue exposure therapy (CET) such that individuals can experience the treatment in their natural environments as viewed via a smartphone screen, addressing the limited generalizbility of extinction learning. Previously, our team developed a basic AR app for smoking cessation and demonstrated the necessary mechanisms for CET. Specifically, we showed that the AR smoking cues, compared to neutral cues, elicited substantial cue reactivity (i.e. increased urge) and that repeated exposure to the AR smoking cues reduced urge (i.e. extinction) in a laboratory setting. Here we report the next step in the systematic development of the AR app, in which we assessed the usability and acceptability of the app among daily smokers in their natural environments. METHOD: Daily smokers (N = 23, 78.3% female, Mean Age = 43.4, Mean Cigarettes/Day = 14.9), not actively quitting, were instructed to use the AR app in locations and situations where they smoke (e.g. home, bar) at least 5 times per day over one week. The study is registered in clinicaltrials.gov (NCT04101422). RESULTS: Results indicated high usability and acceptability. Most of the participants (73.9%) used the AR app on at least 5 days. Participants found the AR cues realistic and well-integrated in their natural environments. The AR app was perceived as easy to use (Mean = 4.1/5) and learn (mean of 2 days to learn). Overall satisfaction with the app was also high. Secondary analyses found that 56.5% reported reduced smoking, with an average 26% reduction in cigarettes per day at follow-up. CONCLUSIONS: These findings set the stage for a randomized controlled trial testing the AR app as an adjuvant therapy for treating tobacco dependence, with potential applicability to other substances. KEY MESSAGEThis study found that the augmented reality (AR) smartphone application that utlized cue exposure treatment for smoking cessation was perceived as easy to use and learn in the natural, day-to-day environment of daily smokers. Findings set the stage for a larger clinical trial testing the AR app as an adjuvant therapy for treating tobacco dependence, with potential applicability to other addictive behaviors.