Cue Exposure Research Articles

Oxytocin Reduces Noradrenergic-Induced Opioid-Like Withdrawal Symptoms in Individuals on Opioid Agonist Therapy

BackgroundIntranasal administration of the neuropeptide oxytocin has been explored as a potential therapeutic agent for opioid use disorder (OUD). Oxytocin was effective in reducing stress and withdrawal symptoms in individuals with OUD. MethodThis phase 1 crossover, randomized, double-blind, placebo-controlled trial tested the safety, tolerability, and efficacy of intranasal oxytocin (80 international units) twice a day for 7 days in participants (n = 20) with OUD who were taking an opioid agonist therapy. In the laboratory, participants underwent opioid cue exposure paired with noradrenergic activation produced by yohimbine or placebo. Assessments included 1) subjective response: craving, withdrawal, anxiety, and stress; 2) biomedical markers: hypothalamic-pituitary-adrenal axis response (cortisol) and noradrenergic activation (α-amylase); and 3) safety measures: hemodynamics and adverse event evaluation. Generalized linear model with model-based estimator in the covariance matrix was used, with medication (oxytocin/placebo) and noradrenergic activation (yohimbine/placebo) as within-subject factors. ResultsOxytocin significantly reduced opioid-like withdrawal, anxiety symptoms, and cortisol levels elicited by cue exposure under noradrenergic activation produced by yohimbine. This effect was specific because oxytocin did not reduce craving, hemodynamics, or α-amylase levels increased by yohimbine administration. A single dose of yohimbine elicited the noradrenergic stimulation, and 7-day oxytocin administration was safe and well tolerated among individuals diagnosed with OUD and taking opioid agonist therapy. ConclusionThe findings of this study suggest that oxytocin alleviates opioid-like withdrawal symptoms and anxiety by modulating the hypothalamic-pituitary-adrenal axis.

Genetic associations with consumption of palatable foods in the absence of hunger in response to food cues in children.

The objective of this study is to evaluate obesity-related genetic factors in relation to excess consumption and assess if food cues modify associations. Children (9-12 years) completed a randomized crossover experiment. During two visits, children ate a preload and then snacks ad libitum while watching television, embedded with food or non-food advertisements to assess eating in the absence of hunger (EAH). Primary exposures were obesity-associated genotypes, FTO rs9939609 and MC4R rs571312, and a paediatric-specific polygenic risk score (PRS). Outcomes included consumption of all snacks (total EAH) and gummy candy only (gummy candy EAH). Linear mixed-effects models tested whether genetic exposures related to EAH outcomes. We tested for effect modification by food cues using multiplicative interaction terms. Among 177 children, each FTO risk allele was associated with a 30% increase in gummy candy EAH (p = 0.025) in adjusted models. Food cue exposure exacerbated associations between the FTO variant with gummy candy EAH (p = 0.046). No statistically significant associations were found between MC4R and EAH. The results suggest children with the FTO rs9939609 risk allele may be predisposed to excess consumption of candy and that this association may be exacerbated by food cues.

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

BackgroundCocaine 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.MethodsFifty-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.DiscussionThis 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 registrationNCT05833529 [clinicaltrials.gov]. Prospectively registered on April 17, 2023.

Study on the efficiency of virtual reality in the treatment of alcohol use disorder: study protocol for a randomized controlled trial

ContextAccording to the World Health Organization, alcohol is a major global public health problem, leading to a significant increase in illness and death. To treat alcohol use disorders, new therapeutic tools are being promoted, among which virtual reality (VR) shows promise. Previous research has demonstrated the efficacy of VR in reducing alcohol cravings in patients, but there is a lack of data on its effectiveness in maintaining abstinence or reducing consumption in recently abstinent individuals.The E-Reva study aims to compare the efficacy of a treatment strategy combining virtual reality cue exposure therapy (VR-CET) and cognitive behavioral therapy (CBT) with conventional CBT in reducing alcohol consumption and craving in patients with alcohol use disorder (AUD). In addition to this primary objective, the study will compare the effects of VR-CET combined with CBT on anxiety, depression, rumination, and feelings of self-efficacy versus conventional CBT.MethodsThis prospective randomized controlled trial will be conducted over 8 months in four addiction departments in France. It includes two parallel groups: i) the VR-CET + CBT group, and ii) the CBT-only group, which serves as a control group.Participants will be recruited by the investigating doctor in the addiction centers. The sample will consist of 156 patients diagnosed with AUD and abstinent for at least 15 days.Both treatment groups will participate in four group CBT sessions followed by four individual sessions: i) the VR-CET group will be exposed to virtual environments associated with alcohol-related stimuli, ii) the CBT-only group will receive traditional CBT sessions. After completion of the 8 sessions, patients will be followed up for 6 months. The primary outcome is the cumulative number of standard drinks consumed at 8 months, assessed using the TLFB method.DiscussionDespite the promise of VR-CET to reduce the desire to drink, the effect on alcohol consumption remains uncertain in the existing literature. Our protocol aims to address the limitations of previous research by increasing sample size, targeting consumption reduction, and incorporating neutral environments. E-Reva aims to enrich the literature on the use of VR in the treatment of AUD and open new perspectives for future interventions.Trial registrationClinicalTrials.gov ID NCT06104176, Registered 2023/11/13 (https://clinicaltrials.gov/study/NCT06104176?id=NCT06104176&rank=1).N° IDRCB: 2022-A02797-36.Protocol version 1.0, 12/05/2023.

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

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. 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. 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. 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. 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.

Momentary mechanisms of binge-eating symptoms using ecological momentary assessment: The moderating role of food addiction.

Food addiction (FA) shows phenotypic and diagnostic overlap with eating disorders characterised by binge eating, though it is unknown how momentary processes driving binge-eating symptoms differ by FA. The present study examined the possible moderating influence of FA severity on momentary mechanisms underlying binge-eating symptomatology using ecological momentary assessment (EMA). Adults (N=49, mean age=34.9±12.1, cis-gender female=77.1%) who met criteria for FA and/or binge-eating disorder completed baseline measures including the Yale Food Addiction Scale (YFAS) followed by a 10-day EMA protocol. Generalised linear mixed models assessed main effects of YFAS, momentary antecedents (affect, impulsivity, food cue exposure, appetite, and eating expectancies) and two-way interactions between YFAS and within-person antecedents. FA severity moderated momentary associations between food cue exposure and subsequent binge-eating symptoms: the association was stronger among participants with lower but not higher YFAS scores. No other interactions were significant. Some functional associations underlying binge-eating symptoms vary based on individuals' level of FA symptoms. Future research to further understand how observed associations may differ amongst diverse populations and over course of illness may also inform future prevention and interventions.

Isradipine augmentation of virtual reality cue exposure therapy for tobacco craving: a triple-blind randomized controlled trial.

Preclinical research with rodents suggests that the L-type calcium channel blocker isradipine can enhance long-term extinction of conditioned place preference for addictive substances when it is administered in conjunction with extinction training. Although isradipine alone, which is FDA-approved for hypertension, has not shown a direct effect on craving in human drug users, its potential to augment behavioral treatments designed to reduce craving remains unknown. We conducted a triple-blind, randomized placebo-controlled pilot clinical trial of isradipine combined with a novel virtual reality cue exposure therapy (VR-CET) approach with multimodal cues that targeted craving. After 24 hours of abstinence, 78 adults with an ongoing history of daily cigarette use received isradipine (n = 40) or placebo (n = 38) and reported craving levels after each of 10 trials of VR-CET. Consistent with pre-registered hypotheses, the isradipine group had significantly lower mean craving across cue exposure trials at the medication-free 24-hour follow-up (d = -0.42, p = 0.046). There were no serious adverse events; however, side effects such as headache and dizziness occurred more frequently in the isradipine group. The findings of the current study support follow-up clinical trials that specifically test the efficacy of isradipine-augmented VR-CET for reducing smoking relapse rates after an initial quit attempt. clinicaltrials.gov: NCT03083353.

Effects of Trauma Cue Exposure and Posttraumatic Stress Disorder (PTSD) on Affect and Cannabis Craving in Cannabis Users With Trauma Histories: Use of Expressive Writing as an Online Cue-Reactivity Paradigm: Effets de l'exposition aux signaux traumatiques et du SSPT sur l'affect et le besoin de cannabis chez les consommateurs de cannabis ayant des antécédents de traumatismes : utilisation de l'écriture

Posttraumatic stress disorder (PTSD) and cannabis use disorder (CUD) commonly co-occur. Conditioned associations between psychological trauma cues, distress, cannabis use, and desired relief outcomes may contribute to the comorbidity. These conditioned associations can be studied experimentally by manipulating trauma cue exposure in a cue-reactivity paradigm (CRP) and examining effects on affective and cognitive outcomes in participants with and without PTSD. However, traditional CRPs take place in-lab limiting recruitment/power. We aimed to examine the effects of CRP condition (trauma and neutral) and PTSD group (likely PTSD+ and PTSD-) on affective and craving outcomes using a stand-alone online expressive writing CRP. Participants (n = 202; 43.6% male; Mage = 42.94 years, SD = 14.71) with psychological trauma histories and past-month cannabis use completed a measure of PTSD symptoms (PTSD Checklist-5 for DSM-5 [PCL-5]) and were randomized to complete either a trauma or neutral expressive writing task. Then they completed validated measures of affect (Positive and Negative Affect Schedule-Short Form [PANAS-SF]) and cannabis craving (Marijuana Craving Questionnaire-Short Form [MCQ-SF]). Linear mixed models tested the hypothesized main and interactive effects of CRP condition (trauma and neutral) and PTSD group (likely PTSD+ and PTSD-) on negative and positive affect (PANAS-SF) and cannabis craving dimensions (MCQ-SF). The hypothesized main effects of trauma versus neutral expressive writing were found for negative affect and the expectancy dimension of cannabis craving and of PTSD group for negative affect and all cannabis craving dimensions; no interactions were observed. Expressive writing appears a useful online CRP. Interventions focused on reducing negative affect and expectancy craving to trauma cues may prevent/treat CUD among cannabis users with PTSD. The Use of an Online Expressive Writing as a Trauma Cue Exposure: Effects on Craving and Emotions.

Neural Correlates of Stress and Alcohol Cue-Induced Alcohol Craving and of Future Heavy Drinking: Evidence of Sex Differences.

Stress and alcohol cue reactivity are associated with poor treatment outcomes in alcohol use disorder (AUD), but sex-specific neural correlates of stress and alcohol cue-induced craving compared with neutral cue-induced craving and of heavy drinking outcomes in AUD have not been examined. Thus, this study prospectively examined these associations and assessed sex differences. Treatment-seeking adults with AUD (N=77; 46 men and 31 women) completed a functional MRI task involving stress, alcohol, and neutral cue exposure with repeated assessments of alcohol craving. Most of these participants (N=72; 43 men and 29 women) then participated in an 8-week standardized behavioral AUD treatment program, during which the percentage of heavy drinking days was assessed. Significant increases in both stress and alcohol cue-induced craving relative to neutral cue-induced craving were observed, with a greater alcohol-neutral contrast in craving relative to the stress-neutral contrast among men and equivalent stress-neutral and alcohol-neutral contrasts in craving among women. Whole-brain voxel-based regression analyses showed craving-associated hyperactivation in the neutral condition, but hypoactive prefrontal (ventromedial and lateral prefrontal, supplementary motor, and anterior cingulate regions) and striatal responses during exposure to stressful images (stress-neutral contrast) and alcohol cues (alcohol-neutral contrast), with significant sex differences. Additionally, a higher percentage of heavy drinking days was associated with hypoactivation of the subgenual anterior cingulate cortex and the bed nucleus of the stria terminalis in the stress-neutral contrast among women, hyperactivation of the hypothalamus in the stress-neutral contrast among men, and hyperactivation of the hippocampus in the alcohol-neutral contrast among men. Sex differences in stress- and alcohol cue-induced responses in the cortico-striatal-limbic network related to subjective alcohol craving and to heavy drinking indicated that distinct brain circuits underlie alcohol use outcomes in women and men. These findings underscore the need for sex-specific therapeutics to address this neural dysfunction effectively.

Leveraging meta-regression to test if medication effects on cue-induced craving are associated with clinical efficacy.

The alcohol cue exposure paradigm is a common method for evaluating new treatments for alcohol use disorder (AUD); however, it is unclear if medication-related reductions in cue-induced craving in the human laboratory can predict the clinical success of those medications in reducing alcohol consumption during clinical trials. To use a novel meta-analytic approach to test whether medication effect sizes on cue-induced alcohol craving are associated with clinical efficacy in clinical trials. We searched the literature for medications tested for AUD treatment using both the alcohol cue-reactivity paradigm and randomized clinical trials (RCTs). For alcohol cue-reactivity studies, we computed medication effect sizes for cue-induced alcohol craving (k = 36 studies, 15 medications). For RCTs, we calculated medication effect sizes for heavy drinking and abstinence (k = 139 studies, 19 medications). Using medication as the unit of analysis, we applied the Williamson-York bivariate weighted least squares estimation to account for errors in both independent and dependent variables. We also conducted leave-one-out cross validation simulations to examine the predictive utility of cue-craving medication effect sizes on RCT heavy drinking and abstinence endpoints. There was no significant relationship between medication effects on cue-induced alcohol craving in the human laboratory and medication effects on heavy drinking ( = 0.253, SE = 0.189,p = 0.090) and abstinence ( = 0.829, SE = 0.747,p = 0.133) in RCTs. The preliminary results of the current study challenge the assumption that alcohol cue-reactivity alone can be used as an early efficacy indicator for AUD pharmacotherapy development. These findings suggest that a wider range of early efficacy indicators and experimental paradigms be considered for Phase II testing of novel compounds.

Cigarette craving in virtual reality cue exposure in abstainers and relapsed smokers

Cue exposure therapy (CET) in substance-use disorders aims to reduce craving and ultimately relapse rates. Applying CET in virtual reality (VR) was proposed to increase its efficacy, as VR enables the presentation of social and environmental cues along with substance-related stimuli. However, limited success has been reported so far when applying VR-CET for smoking cessation. Understanding if effects of VR-CET differ between future abstainers and relapsing smokers may help to improve VR-CET. Data from 102 participants allocated to the intervention arm (VR-CET) of a recent RCT comparing VR-CET to relaxation in the context of smoking cessation was analyzed with respect to tolerability, presence, and craving during VR-CET. Cue exposure was conducted in four VR contexts (Loneliness/Rumination, Party, Stress, Café), each presented twice. Relapsed smokers compared to abstainers experienced higher craving during VR-CET and stronger craving responses especially during the Stress scenario. Furthermore, lower mean craving during VR-CET positively predicted abstinence at 6-month follow-up. Attempts to improve smoking cessation outcomes of VR-CET should aim to identify smokers who are more at risk of relapse based on high craving levels during VR-CET. Specifically measuring craving responses during social stress seems to be well suited to mark relapse. We propose to investigate individualized treatment approaches accordingly.

Can scent-detection dogs detect the stress associated with trauma cue exposure in people with trauma histories? A proof-of-concept study.

Post-traumatic stress disorder (PTSD) is an impairing mental health condition with high prevalence among military and general populations alike. PTSD service dogs are a complementary and alternative intervention needing scientific validation. We investigated whether dogs can detect putative stress-related volatile organic compounds (VOCs) in the breath of people with trauma histories (54% with PTSD) exposed to personalized trauma cues. Breath samples were collected from 26 humans over 40 experimental sessions during a calm (control breath sample) and stressed state induced by trauma cue exposure (target breath sample). Two scent detection canines were presented with the samples in a two alternative forced choice (2AFC) discrimination and yes/no detection task. The 2AFC task assessed the dogs' ability to discriminate between the two states within the breath samples of one individual. The detection task determined their ability to generalize the target odour across different individuals and different stressful events of one individual. Signal Detection Theory was applied to assess dogs' sensitivity, specificity, precision, and response bias. The dogs performed at ∼90% accuracy across all sample sets in the discrimination experiment, and at 74% and 81% accuracy, respectively, in the detection experiment. Further analysis of dog olfactory performance in relation to human donor self-reported emotional responses to trauma cue exposure suggested the dogs may have been detecting distinct endocrine stress markers. One dog's performance correlated with the human donors' self-reported fear responses and the other dog's performance correlated with the human donors' self-reported shame responses. Based on these correlations between dog performance and donor self-report measures, we speculate that the VOCs each dog was detecting likely originated from the sympathetico-adreno-medullary axis (SAM; adrenaline, noradrenaline) in the case of the first dog and the hypothalamo-pituitary-adrenal axis (HPA; glucocorticoids) in the case of the second dog. Our proof-of-concept study is the first to demonstrate that some dogs can detect putative VOCs emitted by people with trauma histories when experiencing distress theoretically associated with the intrusion and arousal/reactivity symptoms of PTSD. Results have potential to improve the effectiveness and training protocol of PTSD service dogs with a focus on enhancing their alert function.

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.

Termination of convulsion seizures by destabilizing and perturbing seizure memory engrams.

Epileptogenesis, arising from alterations in synaptic strength, shares mechanistic and phenotypic parallels with memory formation. However, direct evidence supporting the existence of seizure memory remains scarce. Leveraging a conditioned seizure memory (CSM) paradigm, we found that CSM enabled the environmental cue to trigger seizure repetitively, and activating cue-responding engram cells could generate CSM artificially. Moreover, cue exposure initiated an analogous process of memory reconsolidation driven by mammalian target of rapamycin-brain-derived neurotrophic factor signaling. Pharmacological targeting of the mammalian target of rapamycin pathway within a limited time window reduced seizures in animals and interictal epileptiform discharges in patients with refractory seizures. Our findings reveal a causal link between seizure memory engrams and seizures, which leads us to a deeper understanding of epileptogenesis and points to a promising direction for epilepsy treatment.

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

RationaleCue-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.ObjectivesThis 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).MethodsIn 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.ResultsOur 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.ConclusionsThese 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.

Bioassay complexities—exploring challenges in aquatic chemosensory research

Chemosensory science, the study of how organisms produce and assess olfactory information, is central to our understanding of how organisms interact and gain information about their environment. Signaling cue identification in aquatic systems lags behind our knowledge in terrestrial insects due to analytical challenges in aqueous environments. Unambiguous, reliable, and fast behavioral assays to evaluate the biological activity and function of a chemosensory cue are critical to understand aquatic signaling systems and enable research into their ecology, evolution, and threats in a changing environment. Yet, a range of anthropomorphic assumptions made in this research field create additional challenges to interpret data generated. Here, we evaluate common challenges including assumed readiness of individuals to respond, lack of information on the animals’ physiological and social status, their pre-experimental cue exposure, the innate or learned character of the responses, the animals’ acclimation and habituation status, and the impact of the animals upon their own environment. These factors lead to significant variability in animals’ responses in bioassays, both in the field and in laboratory setups. In the light of our limited knowledge of aquatic chemosensory cues’ chemical structure, active concentrations in samples, and undetermined response thresholds, we evaluate methods of mitigation to minimize differences between studies. We conclude that currently it is nearly impossible to compare results from chemosensory behavioral studies undertaken in different ecosystems, laboratories, and time points. There is an urgent need for the standardization of behavioral methods, recording of environmental conditions, and individuals’ physiology, physical, and social status, to avoid conflicting and contradicting results when comparing studies. Including these parameters in experimental design and data interpretation will provide a deeper understanding of chemosensory communication, reduce unconscious bias in studies, and can help to explain the substantial individuality in animals’ responses to chemosensory cues and their acclimation to environmental stress.

Molecular mechanisms underlying sex and treatment-dependent differences in an animal model of cue-exposure therapy for cocaine relapse prevention.

Environmental enrichment combined with the glycine transporter-1 inhibitor Org24598 (EE+ORG) during cocaine-cue extinction (EXT) inhibited reacquisition of 1.0 mg/kg cocaine self-administration in male but not female rats in a previous investigation. In this investigation, we determined if this treatment benefit in males required EXT training and ascertained the molecular basis for the observed sex difference in treatment efficacy. Nine groups of male rats trained to self-administer 1.0 mg/kg cocaine or receiving yoked-saline underwent EXT or NoEXT with or without EE and/or ORG. Next, they underwent reacquisition of cocaine self-administration or were sacrificed for molecular analysis of 9 protein targets indicative of neuroplasticity in four brain regions. Two groups of female rats trained to self-administer 1.0 mg/kg cocaine also underwent EXT with or without EE + ORG and were sacrificed for molecular analysis, as above. EE + ORG facilitated the rate of EXT learning in both sexes, and importantly, the therapeutic benefit of EE + ORG for inhibiting cocaine relapse required EXT training. Males were more sensitive than females to neuroplasticity-inducing effects of EE + ORG, which prevented reductions in total GluA1 and PSD95 proteins selectively in basolateral amygdala of male rats trained to self-administer cocaine and receiving EXT. Females were deficient in expression of multiple protein targets, especially after EE + ORG. These included total GluA1 and PSD95 proteins in basolateral amygdala, and total TrkB protein in basolateral amygdala, dorsal hippocampus, and ventromedial prefrontal cortex. Together, these results support the clinical view that sex-specific pharmacological and behavioral treatment approaches may be needed during cue exposure therapy to inhibit cocaine relapse.

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

BackgroundCue 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.MethodsForty-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.ResultsAfter 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).ConclusionVirtual 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 registrationThe study protocol was registered at the China Clinical Trial Registry on 26/02/2021 (www.chictr.org.cn; ChiCTR ID: ChiCTR2100043680).

Daily exposure to combat-related cues and posttraumatic stress symptoms among veterans: Moderating effects of peri- and postdeployment experiences.

One of the central symptoms of posttraumatic stress disorder (PTSD) is a heightened reactivity to trauma cues. The current study used experience sampling to investigate the associations between exposure to combat-related cues and PTSD symptoms in 93 U.S. veterans who served in support of recent military operations in Afghanistan and Iraq. We also examined the effects of peri- and postdeployment factors, including exposure to combat, unit support during deployment, and postdeployment social support on PTSD. Participants completed eight brief random surveys daily for 2 weeks using palmtop computers. The results indicated that more daytime exposure to trauma cues was associated with experiencing more PTSD symptoms at the within-person level, B = 3.18. At the between-person level, combat exposure, B = 4.20, was associated with more PTSD symptoms, whereas unit support, B = -0.89, was associated with experiencing fewer symptoms. At the cross-level interaction, unit support, B = -0.80, moderated the association between trauma cue exposure and PTSD symptom count. Contrary to our hypothesis, postdeployment social support, B = -0.59, was not associated with PTSD symptoms. These findings suggest a functional association between exposure to trauma cues and PTSD symptoms among recent-era U.S. veterans and underscore the importance of unit support during deployment.

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

BackgroundAlcohol 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.MethodsA 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.DiscussionResults 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 registrationThis study was approved by the Charité—Universitätsmedizin Berlin Institutional Review Board (EA1/190/22, 23.05.2023). It was registered on ClinicalTrials.gov (NCT05861843).