Fear attenuation collaborations to optimize translation.

Here, we describe the efforts we dedicated to the challenge of modifying entrenched emotionally laden memories. In recent years, through a number of collaborations and using a combination of behavioral, molecular, and computational approaches, we: (a) developed novel approaches to fear attenuation that engage mechanisms that differ from those engaged during extinction (Monfils), (b) examined whether our approaches can generalize to other reinforcers (Lee, Gonzales, Chaudhri, Cofresi, and Monfils), (c) derived principled explanations for the differential outcomes of our approaches (Niv, Gershman, Song, and Monfils), (d) developed better assessment metrics to evaluate outcome success (Shumake and Monfils), (e) identified biomarkers that can explain significant variance in our outcomes of interest (Shumake and Monfils), and (f) developed better basic research assays and translated efforts to the clinic (Smits, Telch, Otto, Shumake, and Monfils). We briefly highlight each of these milestones and conclude with final remarks and extracted principles. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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.

Improving Exposure Therapy: Rationale and Design of an International Consortium.

The Exposure Therapy Consortium (ETC) was established to advance the science and practice of exposure therapy. To encourage participation from researchers and clinicians, this article describes the organizational structure and activities of the ETC. Initial research working group experiences and a proof-of-principle study underscore the potential of team science and larger-scale collaborative research in this area. Clinical working groups have begun to identify opportunities to enhance access to helpful resources for implementing exposure therapy effectively. This article discusses directions for expanding the consortium's activities and its impact on a global scale.

Efficacy and implementation of exercise-based smoking cessation treatment for adults with high anxiety sensitivity (STEP): Study protocol for a randomized controlled trial.

Anxiety sensitivity (AS), reflecting the fear of bodily sensations, is a transdiagnostic vulnerability factor that underpins both affective psychopathology and smoking. Phase II research supports the efficacy of a 15-week community-based intervention (STEP) that combines high-intensity exercise offered by the YMCA with standard smoking cessation treatment (tobacco quitline and nicotine replacement therapy) for sedentary smokers with elevated AS. This Phase III study aims to enroll 360 adults to evaluate whether STEP efficacy for achieving smoking abstinence generalizes to Black and Hispanic smokers with elevated AS.

Carbon Dioxide Reactivity Differentially Predicts Fear Expression After Extinction and Retrieval-Extinction in Rats.

Background: Cues present during a traumatic event may result in persistent fear responses. These responses can be attenuated through extinction learning, a core component of exposure therapy. Exposure/extinction is effective for some people, but not all. We recently demonstrated that carbon dioxide (CO2) reactivity predicts fear extinction memory and orexin activation and that orexin activation predicts fear extinction memory, which suggests that a CO2 challenge may enable identification of whether an individual is a good candidate for an extinction-based approach. Another method to attenuate conditioned responses, retrieval-extinction, renders the original associative memory labile via distinct neural mechanisms. The purpose of the current study was to examine whether we could replicate previous findings that retrieval-extinction is more effective than extinction at preventing the return of fear and that CO2 reactivity predicts fear memory after extinction. We also examined whether CO2 reactivity predicts fear memory after retrieval-extinction. Methods: Male rats first underwent a CO2 challenge and fear conditioning and were assigned to receive either standard extinction (n = 28) or retrieval-extinction (n = 28). Then, they underwent a long-term memory (LTM) test and a reinstatement test. Results: We found that retrieval-extinction resulted in lower freezing during extinction, LTM, and reinstatement than standard extinction. Using the best subset approach to linear regression, we found that CO2 reactivity predicted LTM after extinction and also predicted LTM after retrieval-extinction, although to a lesser degree. Conclusions: CO2 reactivity could be used as a screening tool to determine whether an individual may be a good candidate for an extinction-based therapeutic approach.

Extinction learning underlies exposure therapy, a treatment for anxiety disorders. However, not everyone benefits from exposure therapy, highlighting the need in developing approaches that may help predict which individuals will respond. We tested whether extinction or an alternative treatment called retrieval-extinction would be more effective at reducing conditioned fear responses in rats and whether the response to a carbon dioxide (CO₂) challenge would predict treatment response. We found that retrieval-extinction was more effective at reducing fear, and CO₂ reactivity was better at predicting the response to extinction. These findings could help improve treatment strategies for anxiety disorders.

Low reliability when determining criterion a for posttraumatic stress disorder from self-report descriptions of traumatic events: The need for transparent methods.

OBJECTIVE: Exposure to a traumatic event is a primary criterion (Criterion A) for meeting Posttraumatic Stress Disorder (PTSD). Using self-report to establish diagnostic criteria in research has become more common, especially with internet-based research. However, some individuals may construe events as traumatic when they do not meet Criterion A. There has yet to be a test of interrater reliability (IRR) from self-report of traumatic events. METHOD: Three graduate students in clinical psychology and three licensed psychologists rated Criterion A using the life events checklist (LEC), as well as the three modified LEC versions (specification of up to three index traumas; extension of part 2 of the LEC) aimed to increase IRR. One hundred participants completed each of the four versions of the LEC (N = 400). Bootstrapped permutation tests were used to estimate differences in IRR and to generate 95% confidence intervals (CIs). RESULTS: Overall, findings indicated fair-moderate IRR (Fleiss's kappa) κ = 0.428, 95% CI [0.379, 0.477]. The other versions of the LEC (including additional clarifying questions in part 2 of the LEC and/or opportunities to describe up to three traumas) did not meaningfully increase IRR. CONCLUSIONS: Findings indicate that relying on self-report from the LEC alone and/or single-rater assessment of open-text trauma descriptions is not recommended for determining whether a traumatic event meets Criterion A. We conclude that it is critical when collecting self-reported PTSD symptoms to provide a clear description of how Criterion A was assessed, initial agreement between raters, and how disagreements were resolved. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

What good are positive emotions for treatment? A replication test of whether trait positive emotionality predicts response to exposure therapy for social anxiety disorder.

BACKGROUND: Positive valence emotions serve functions that may facilitate response to exposure therapy - they encourage approach behavior, diminish perceived threat reactivity, and enhance assimilation of new information in memory. Few studies have examined whether positive emotions predict exposure therapy success and extant findings are mixed. METHODS: We conducted a secondary analysis of an exposure therapy trial for social anxiety disorder to test the hypothesis that patients endorsing higher trait positive emotions at baseline would display the greatest treatment response. N = 152 participants enrolled in a randomized controlled trial of d-cycloserine augmentation completed five sessions of group exposure therapy. Pre-treatment positive emotionality was assessed using the NEO Five-Factor Inventory. Social anxiety symptoms were assessed throughout treatment by blinded evaluators using the Liebowitz Social Anxiety Scale. RESULTS: Accounting for baseline symptom severity, multilevel growth curve models revealed that patients with higher pre-treatment positive emotionality displayed faster social anxiety symptom reductions and lower scores at 3-month follow-up. This predictive effect remained significant after controlling for baseline depression and extraversion (without the positive emotionality facet). CONCLUSIONS: These findings add to emerging evidence suggesting that explicitly targeting and enhancing positive emotions during exposure to perceived threat may improve treatment outcomes for anxiety and fear-based disorders. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02066792https://clinicaltrials.gov/ct2/show/NCT02066792.

Social avoidance and testosterone enhanced exposure efficacy in women with social anxiety disorder: A pilot investigation.

Social avoidance has been associated with more persistent social anxiety disorder (SAD) symptoms and low testosterone levels in individuals with SAD. We tested whether pre-treatment avoidance tendencies moderate the efficacy of testosterone-augmented exposure therapy. Fifty-five females with SAD received two exposure sessions during which fear levels were assessed. Session 1 was augmented with testosterone (0.50 mg) or placebo. Avoidance tendencies and symptom severity were assessed pre- and post-exposure. Participants showed stronger avoidance for social versus non-social stimuli and this tendency remained stable over time. Stronger pretreatment avoidance tendencies were associated with larger fear reduction in the testosterone but not the placebo condition. This effect did not transfer to the second non-enhanced session or symptom severity. The findings support the hypothesis that individuals suffering from SAD with relatively stronger pretreatment avoidance tendencies benefit more from testosterone-augmentation, pointing to a potential behavioral marker for testosterone enhancement of exposure therapy.

Using pre-treatment de novo threat conditioning outcomes to predict treatment response to DCS augmentation of exposure-based CBT.

BACKGROUND: Over a decade and a half of research has resulted in inconsistent evidence for the efficacy of d-cycloserine (DCS), a partial glutamatergic N-methyl-D-aspartate agonist, for augmenting exposure-based cognitive behavioral therapy (CBT) for anxiety- and fear-based disorders. These variable findings have motivated the search for moderators of DCS augmentation efficacy. METHODS: In this secondary analysis of a previous randomized clinical trial, we evaluated the value of de novo threat conditioning outcomes-degree of threat acquisition, extinction, and extinction retention-for predicting treatment response to exposure-based CBT for social anxiety disorder, applied with and without DCS augmentation in a sample of 59 outpatients. RESULTS: We found that average differential skin conductance response (SCR) during extinction and extinction retention significantly moderated the prediction of clinical response to DCS: participants with poorer extinction and extinction retention showed relatively improved treatment response with DCS. No such effects were found for expectancy ratings, consistent with accounts of DCS selectively aiding lower-order but not higher-order extinction learning. CONCLUSIONS: These findings provide support for extinction and extinction retention outcomes from threat conditioning as potential pre-treatment biomarkers for DCS augmentation benefits. Independent of DCS augmentation, the current study did not support threat conditioning outcomes as useful for predicting response to exposure-based CBT.

The Relationship Between Cigarette Dependence and Cessation Methods: Implications for Smoking Cessation Among People With HIV.

OBJECTIVE: These analyses investigate how dependence may be related to cessation method choice and how this relationship may vary by subpopulation among people with HIV (PWH) who smoke cigarettes. METHOD: PWH who smoke (N = 71) were recruited from clinics in Boston, MA. The Fagerström Test for Nicotine Dependence (FTND) and Smoking History Questionnaire (SHQ) were completed to assess for cigarette dependence, past-week cigarettes per day (CPD), and past cessation method use. Logistic regression examined the association between dependence and previous cessation methods for the whole sample, and moderation analyses assessed this relationship by age and race. RESULTS: Higher FTND was associated with less use of behavioral modification methods (odds ratio [OR] = 0.658, 95% CI [0.435, 0.994], p = .047). Higher past-week CPD was associated with use of the American Cancer Society/American Lung Association (ACS/ALA) programs (OR = 1.159, 95% CI [1.011, 1.328], p = .035) and telephone counselling (OR = 1.142, 95% CI [1.006, 1.295], p = .040]). Older participants with more past-week CPD were more likely to have used the ACS/ALA programs (B = 0.0169, 95% CI [0.0008, 0.0331], p = .0401), and White participants with more past-week CPD were less likely to have tried to quit "cold turkey" (B = 0.1676, 95% CI [0.0027, 0.3326], p = .0464). CONCLUSIONS: These preliminary results suggest that there is likely not a "one-size-fits-all" approach to cessation for PWH who smoke, especially within subpopulations (i.e., age and race). Implications include ensuring access to multiple cessation methods, identifying methods that could be culturally appropriate outside of the clinical intervention setting, and providing education and support on cessation methods offered.

CO2 reactivity is associated with individual differences in appetitive extinction memory.

Pavlovian conditioning can underly the maladaptive behaviors seen in psychiatric disorders such as anxiety and addiction. In both the lab and the clinic, these responses can be attenuated through extinction learning, but often return with the passage of time, stress, or a change in context. Extinction to fear and reward cues are both subject to these return of behavior phenomena and have overlap in neurocircuitry, yet it is unknown whether they share any common predictors. The orexin system has been implicated in both fear and appetitive extinction and can be activated through a CO2 challenge. We previously found that behavioral CO2 reactivity predicts fear extinction and orexin activation. Here, we sought to extend our previous findings to determine whether CO2 reactivity might also predict extinction memory for appetitive light-food conditioning. We find that the same subcomponent of behavioral CO2 reactivity that predicted fear extinction also predicts appetitive extinction, but in the opposite direction. We show evidence that this subcomponent remains stable across two CO2 challenges, suggesting it may be a stable trait of both behavioral CO2 reactivity and appetitive extinction phenotype. Our findings further the possibility for CO2 reactivity to be used as a transdiagnostic screening tool to determine whether an individual would be a good candidate for exposure therapy.

Study protocol for approach bias retraining for nicotine addiction among dual combustible and electronic cigarette users.

BACKGROUND: Electronic cigarette (ECIG) use has become a popular method for nicotine delivery. Combustible cigarette (CC) cessation or reduction are the primary reasons for ECIG uptake among adults. Yet, most CC smokers who initiate ECIG use do not fully transition from CC to ECIG, despite intending to quit CC completely. Retraining approach bias, or the approach action tendency toward stimuli related to the substance of interest, has been effective in alcohol and CC use treatments. However, approach bias retraining for both CC and (ECIG) users has not been explored. Therefore, the objective of the study is to evaluate the initial efficacy of approach bias retraining among dual CC and ECIG users. METHODS: Eligible dual CC/ECIG using adults (N = 90) will complete a phone-screener, baseline assessment, 4 treatment sessions over 2 weeks, ecological momentary assessments (EMAs) post-intervention, and follow-ups at 4- and 6-week post-intervention. Participants will be assigned to one of three conditions at baseline: (1) CC + ECIG retraining; (2) CC only retraining; and (3) sham retraining. Participants will engage in a self-guided quit attempt to abstain from all nicotine products starting at treatment session 4. CONCLUSIONS: The study may lead to a more effective treatment for at-risk nicotine users while simultaneously isolating explanatory mechanisms. The findings should guide advances in the theoretical conceptualization of nicotine addiction for dual users and mechanisms involved in maintaining and abstaining from CC and ECIG, and provide initial effect size data for a brief intervention, thus providing necessary data for a large-scale follow-up trial. Clinical Trials ID: NCT05306158.

Working it out: can an acute exercise bout alleviate memory bias, rumination and negative mood?

Although it is well known that exercise reduces depressive symptoms, the underlying psychological mechanisms remain unclear. This experimental study examined the acute effect of exercise on mood, and depressotypic memory bias and state rumination. Trait rumination was tested as a possible moderator. A sample of non-regular exercisers (N = 100) was randomized to exercise or rest. After a negative mood induction, the exercise condition cycled for 24 min at moderate intensity, while the rest condition rested. Negative and overgeneral memory bias, as well as positive and negative affect were assessed after exercise/rest. To capture the lingering of negative mood and state rumination, both were assessed multiple times throughout the study. The exercise (as compared to rest) condition reported more positive affect. However, no differences were found on overgeneral memory bias, as well as depression-specific mood or state rumination measured throughout the study. Interestingly, the exercise condition showed more negative memory bias at higher levels of rumination. Individual differences in trait rumination moderated the exercise-memory bias relation, such that exercise increased negative memory bias at higher levels of rumination. It is possible that long-term exercise protocols are necessary to change cognitive processes related to depression.

Applications of isradipine in human addiction studies: A systematic literature review.

Given the personal and public health burden of addictive disorders, innovative approaches to treatment are sorely needed. This systematic review examined the use of the pharmacological agent isradipine in the context of potential applications for addiction treatment. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guided a comprehensive search of PubMed, Cochrane Library, and PsycINFO between the years 1985 to July 2022. Studies were included if isradipine was administered to adults with a current Diagnostic and Statistical Manual of Mental Disorders-5th edition diagnosis of a substance use disorder and/or to healthy volunteers alone and in conjunction with a substance (i.e, cocaine, methamphetamine, alcohol). A total of 16 studies with 252 participants were included in this review. Substantial variability was identified with study designs, isradipine dosages/dosing, and addictive substance of interest. Outcomes clustered in four categories: (a) cerebral blood flow (CBF), (b) hemodynamic effects, (c) subjective effects, and (d) cognitive effects. Isradipine was found to improve CBF in individuals with cocaine-induced hypoperfusion and in several studies was found to reduce parameters of blood pressure elevation after stimulant use. There were no significant findings on isradipine's effect on subjective reporting (i.e., craving, mood, drug affect) or cognition/attention. Given the limited number of studies identified in this review, there is insufficient data to draw clear conclusions. The direct effects of isradipine as a pharmacologic agent for addictive disorder treatment appear minimal, however, future work may benefit from examining the impact of isradipine as an augmentative agent within existing cue exposure paradigms for preventing cue-induced drug relapse. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

CO2 reactivity as a biomarker of exposure-based therapy non-response: study protocol.

BACKGROUND: Exposure-based therapy is an effective first-line treatment for anxiety-, obsessive-compulsive, and trauma- and stressor-related disorders; however, many patients do not improve, resulting in prolonged suffering and poorly used resources. Basic research on fear extinction may inform the development of a biomarker for the selection of exposure-based therapy. Growing evidence links orexin system activity to deficits in fear extinction and we have demonstrated that reactivity to an inhaled carbon dioxide (CO2) challenge-a safe, affordable, and easy-to-implement procedure-can serve as a proxy for orexin system activity and predicts fear extinction deficits in rodents. Building upon this basic research, the goal for the proposed study is to validate CO2 reactivity as a biomarker of exposure-based therapy non-response. METHODS: We will assess CO2 reactivity in 600 adults meeting criteria for one or more fear- or anxiety-related disorders prior to providing open exposure-based therapy. By incorporating CO2 reactivity into a multivariate model predicting treatment non-response that also includes reactivity to hyperventilation as well as a number of related predictor variables, we will establish the mechanistic specificity and the additive predictive utility of the potential CO2 reactivity biomarker. By developing models independently within two study sites (University of Texas at Austin and Boston University) and predicting the other site's data, we will validate that the results are likely to generalize to future clinical samples. DISCUSSION: Representing a necessary stage in translating basic research, this investigation addresses an important public health issue by testing an accessible clinical assessment strategy that may lead to a more effective treatment selection (personalized medicine) for patients with anxiety- and fear-related disorders, and enhanced understanding of the mechanisms governing exposure-based therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05467683 (20/07/2022).

Approach bias retraining to augment smoking cessation: A pilot randomized controlled trial.

BACKGROUND: Approach tendency to smoking-related cues has been associated with greater cravings, nicotine dependence, and the likelihood of relapse. In this pilot randomized clinical trial, we examined the efficacy of approach bias retraining (ABR; i.e., increasing avoidance tendency) for enhancing standard smoking cessation treatment (ST). METHODS: Adult smokers (N = 96) motivated to quit were randomly assigned to 7 weekly in-person treatment sessions consisting of either (1) cognitive-behavioral therapy for smoking cessation (ST) and ABR (ST+ABR) or ST and sham retraining (ST+Sham). All participants also received optional nicotine replacement therapy for up to 8 weeks following the scheduled quit date (week 6). We measured avoidance tendency from weeks 1-7. Point prevalence abstinence (PPA) and prolonged abstinence (PA) were measured up to 3 months following the quit attempt (week 18 follow-up). RESULTS: Consistent with our hypothesis, participants in ST+ABR evidenced higher abstinence rates than those in ST+Sham at the final follow-up (b=0.71, 95 % CI: [0.14, 1.27], t[1721]=2.46, p = 0.014, OR=2.03, 95 % CI: [1.15, 3.57]). Specifically, PPA and PA rates were 50 % and 66 % in ST+ABR compared to 31 % and 47 % in ST+Sham. As expected, participants assigned to the ST+ABR condition also showed a greater training-compatible increase in avoidance tendency scores relative to those assigned to the ST+Sham condition (b=248.06, 95 % CI: [148.51, 347,62], t[84]=4.96, p < .001). CONCLUSIONS: The current pilot randomized clinical trial provides initial evidence for the efficacy of integrating standard smoking cessation with ABR. These findings encourage the testing of the long-term efficacy and mechanisms of action of this integrated intervention.

Corrigendum to "Approach bias retraining to augment smoking cessation: Study protocol for a randomized controlled trial" [Contemp. Clin. Trials Commun. 14 (2019) 100340].

[This corrects the article DOI: 10.1016/j.conctc.2019.100340.].

Change in negative attention bias mediates the association between attention bias modification training and depression symptom improvement.

OBJECTIVE: Attention bias modification training (ABMT) is purported to reduce depression by targeting and modifying an attentional bias for sadness-related stimuli. However, few tests of this hypothesis have been completed. METHOD: The present study examined whether change in attentional bias mediated a previously reported association between ABMT condition (active ABMT, sham ABMT, assessments only; N = 145) and depression symptom change among depressed adults. The preregistered, primary measure of attention bias was a discretized eye-tracking metric that quantified the proportion of trials where gaze time was greater for sad stimuli than neutral stimuli. RESULTS: Contemporaneous longitudinal simplex mediation indicated that change in attentional bias early in treatment partially mediated the effect of ABMT on depression symptoms. Specificity analyses indicated that in contrast to the eye-tracking mediator, reaction time assessments of attentional bias for sad stimuli (mean bias and trial level variability) and lapses in sustained attention did not mediate the association between ABMT and depression change. Results also suggested that mediation effects were limited to a degree by suboptimal measurement of attentional bias for sad stimuli. CONCLUSION: When effective, ABMT may improve depression in part by reducing an attentional bias for sad stimuli, particularly early on during ABMT. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Exploratory and Confirmatory Bayesian Networks Identify the Central Role of Non-judging in Symptoms of Depression.

OBJECTIVES: Depression is a highly heterogeneous disorder, and meta-analyses of mindfulness-based interventions show moderate efficacy for reducing depressive symptoms. However, the mechanisms governing their efficacy remain unclear, highlighting the need for hypothesis-generating analyses to guide future research. METHODS: We used Bayesian network analysis in three cross-sectional samples (N = 1135) of undergraduates and participants from the community to identify links between individual symptoms of depression and specific facets of mindfulness. In two exploratory studies, we assessed depression using the Patient Health Questionnaire (n = 384) or the Depression Anxiety and Stress Scale (n = 350) and mindfulness using the Five-Facet Mindfulness Scale. RESULTS: Across these samples and measures, exploratory analyses indicated that non-judging was a central bridge between facets of mindfulness and symptoms of depression. We confirmed this finding in a pre-registered replication (n = 401) using a recently developed confirmatory testing framework for network analysis. Non-judging was consistently a central bridge in the networks and specifically linked to the symptoms of depression related to feelings of failure and worthlessness. CONCLUSIONS: These findings provide strong evidence that non-judging is an essential feature of mindfulness in the context of depression and provides direction for future research testing mindfulness-oriented treatment prescriptions for depression. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12671-021-01726-1.