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Preclinical research suggests that enhancing CB1 receptor agonism may improve fear extinction. In order to translate this knowledge into a clinical application we examined whether cannabidiol (CBD), a hydrolysis inhibitor of the endogenous CB1 receptor agonist anandamide (AEA), would enhance the effects of exposure therapy in treatment refractory patients with anxiety disorders. Patients with panic disorder with agoraphobia or social anxiety disorder were recruited for a double-blind parallel randomised controlled trial at three mental health care centres in the Netherlands. Eight therapist-assisted exposure in vivo sessions (weekly, outpatient) were augmented with 300 mg oral CBD (n = 39) or placebo (n = 41). The Fear Questionnaire (FQ) was assessed at baseline, mid-and post-treatment, and at 3 and 6 months follow-up. Primary analyses were on an intent-to-treat basis. No differences were found in treatment outcome over time between CBD and placebo on FQ scores, neither across (beta = 0.32, 95% CI [-0.60; 1.25]) nor within diagnosis groups (beta = -0.11, 95% CI [-1.62; 1.40]). In contrast to our hypotheses, CBD augmentation did not enhance early treatment response, within-session fear extinction or extinction learning. Incidence of adverse effects was equal in the CBD (n = 4, 10.3%) and placebo condition (n = 6, 15.4%). In this first clinical trial examining CBD as an adjunctive therapy in anxiety disorders, CBD did not improve treatment outcome. Future clinical trials may investigate different dosage regimens. (c) 2022 Published by Elsevier B.V.

Conditioned fear can substantially reduce the likelihood that an individual will engage in reward-related behavior––a phenomenon coined conditioned suppression. Despite the unmistakable relevance of conditioned suppression for excessive fears and their adverse consequences, the phenomenon has primarily been observed in animal models and is not yet well understood. Here, we aimed to develop a conditioned suppression paradigm that enables a robust quantification of the effect of Pavlovian fear on subsequent reward-related behavior in humans and assess its potential relation to physiological measures of fear. In phase 1, an instrumental response was incentivized with monetary rewards. In phase 2, one of two conditioned stimuli (CS+) was reinforced with an aversive unconditioned stimulus (US, i.e., electric stimulus). During Pavlovian fear learning we assessed differential skin conductance (SCR) and fear- potentiated startle responses (FPS). Lastly, we tested the effect of the fear conditioned CS+ on the response rate of the instrumental response in a transfer phase. Despite strong Pavlovian fear conditioning, as indicated by large effect sizes in differential SCR and FPS, we did not find any evidence for conditioned suppression: that is, there was no significant reduction of instrumental responding in the presence of the CS+ compared to a new control stimulus. This lack of conditioned suppression is in line with previous studies that reported difficulties inducing conditioned suppression and points toward a general challenge in investigating conditioned suppression in humans. Implications and directions for future research on the highly relevant behavioral effects of fear and anxiety are discussed.

The impact of the COVID-19 pandemic on mental health, well-being, and behavior is likely influenced by individual characteristics that determine one's capacity for resilience. In this exploratory study, we examined whether individual differences in working memory (WM) capacity and habit propensity (HP), measured before the outbreak, could predict variation in subsequent psychological coping efficacy (as operationalized by measures of depression, mental well-being, perceived stress, and loneliness) and behavioral adjustment (by evaluating compliance and self-reported automaticity of four COVID-19 guidelines) among Dutch older adults (n = 36) during the pandemic (measured April 25 to May 6, 2020). While we found elevated levels of depression and emotional loneliness, overall mental well-being, and perceived stress were not affected by the pandemic. Contrary to our expectations, we found no robust evidence for a protective role of WM in predicting these outcomes, although our findings hint at a positive relationship with perceived change in mental well-being. Interestingly, WM and HP were found to affect the self-reported automaticity levels of adherence to behavioral COVID-19 guidelines (i.e., washing hands, physical distancing), where a strong HP appeared beneficial when deliberate resources were less available (e.g., low WM capacity). These novel and preliminary findings offer new potential avenues for investigating individual differences in resilience in times of major life events or challenges.Supplementary Information: The online version contains supplementary material available at 10.1007/s10804-022-09404-9.

Although reconsolidation-based interventions constitute a promising new avenue to treating fear and anxieties disorders, the success of the intervention is not guaranteed. The initiation of memory reconsolidation is dependent on whether a mismatch between the experienced and predicted outcome-a prediction error (PE)-occurs during fear memory reactivation. It remains, however, elusive whether any type of PE renders fear memories susceptible to reconsolidation disruption. Here, we investigated whether a value PE, elicited by an outcome that is better or worse than expected, is necessary to make fear memories susceptible to reconsolidation disruption or whether a model-based identity PE, i.e., a PE elicited by an outcome equally aversive but different than expected, would be sufficient. Blocking beta-adrenergic receptors with propranolol HCl after reactivation did, however, not reduce the expression of fear after either type of PE. Instead, we observed intact fear memory expression 24 h after reactivation in the value-, identity- and a no-PE control group. The present results do not corroborate our earlier findings of reconsolidation disruption and point towards challenges that the field is currently facing in observing evidence for memory reconsolidation at all. We provide potential explanations for the unexpected failure of replicating reconsolidation disruption and discuss future directions.

Raw data are typically required to be processed to be ready for statistical analyses, and processing pipelines are often characterized by substantial heterogeneity. Here, we applied seven different approaches (trough-to-peak scoring by two different raters, script-based baseline correction, Ledalab as well as four different models implemented in the software PsPM) to two fear conditioning data sets. Selection of the approaches included was guided by a systematic literature search by using fear conditioning research as a case example. Our approach can be viewed as a set of robustness analyses (i.e., same data subjected to different processing pipelines) aiming to investigate if and to what extent these different quantification approaches yield comparable results given the same data. To our knowledge, no formal framework for the evaluation of robustness analyses exists to date, but we may borrow some criteria from a framework suggested for the evaluation of "replicability" in general. Our results from seven different SCR quantification approaches applied to two data sets with different paradigms suggest that there may be no single approach that consistently yields larger effect sizes and could be universally considered "best." Yet, at least some of the approaches employed show consistent effect sizes within each data set indicating comparability. Finally, we highlight substantial heterogeneity also within most quantification approaches and discuss implications and potential remedies.

There is heterogeneity in and a lack of consensus on the preferred statistical analyses foranalyzing fear conditioning effects in light of a multitude of potentially equally justifiablestatistical approaches. Here, we introduce the concept of multiverse analysis for fearconditioning research. We also present a model multiverse approach specifically tailored tofear conditioning research and introduce the novel and easy to use R package ‘multifear’ thatallows to run all the models though a single line of code. Model specifications and datareduction approaches employed in the ‘multifear’ package were identified through arepresentative systematic literature search. The heterogeneity of statistical models identifiedincluded Bayesian ANOVA and t-tests as well as frequentist ANOVA, t-test as well as mixedmodels with a variety of data reduction approaches (i.e., number of trials, trial blocks,averages) as input. We illustrate the power of a multiverse analysis for fear conditioning databased on two pre-existing data sets with partial (data set 1) and 100% reinforcement rate(data set 2) by using CS discrimination in skin conductance responses (SCRs) during fearacquisition and extinction training as case examples. Both the effect size and the direction ofeffect was impacted by choice of the model and data reduction techniques. We anticipatethat an increase in multiverse-type of studies in the field of fear conditioning research andtheir extension to other outcome measures as well as data and design multiverse analyseswill aid the development of formal theories through the accumulation of empirical evidence.This may contribute to facilitated and more successful clinical translation.

BackgroundThe use of oral contraceptives (OCs) has been associated with increased incidences of anxiety and depression, for which adolescents seem to be particularly vulnerable. Rather than looking at singular outcomes, we examined whether OC use is associated with depressive and anxiety symptom trajectories from early adolescence into early adulthood.Materials and MethodsData from 178 girls were drawn from the Research on Adolescent Development and Relationships (RADAR-Y) younger cohort study. We used assessments on 9 waves from age 13 until 24. Developmental trajectories of ratings on the Reynolds Adolescent Depression Scale (RADS-2) and the Screen for Child Anxiety Related Emotional Disorders (SCARED) were compared between never and ever users of OCs.ResultsNever users showed increases in depressive and anxiety symptoms in late adolescence, whereas OC users showed a stable level of symptoms throughout adolescence. This effect remained after adjusting for baseline differences between groups in romantic relationships, sexual debut, educational level, smoking, drinking, and drug use. Age of OC use onset did not significantly predict symptom development.ConclusionsOC use in adolescence was related to an altered developmental trajectory of internalizing symptoms, in which OC users did not show an increase in depressive and anxiety symptoms in late adolescence, whereas never users did. The question remains whether this altered symptom trajectory can be considered a protective effect of OC use on psychopathology. Additional research is needed to improve our understanding of the long-term consequences of OC use on mental health.

Previous studies have not clearly demonstrated whether motivational tendencies during reward feedback are mainly characterized by appetitive responses to a gain or mainly by aversive consequences of reward omission. In the current study this issue was addressed employing a passive head or tails game and using the startle reflex as an index of the appetitive-aversive continuum. A second aim of the current study was to use startle-reflex modulation as a means to compare the subjective value of monetary rewards of varying magnitude. Startle responses after receiving feedback that a potential reward was won or not won were compared with a baseline condition without a potential gain. Furthermore, startle responses during anticipation of no versus potential gain were compared. Consistent with previous studies, startle-reflex magnitudes were significantly potentiated when participants anticipated a reward compared to no reward, which may reflect anticipatory arousal. Specifically for the largest reward (20-cents) startle magnitudes were potentiated when a reward was at stake but not won, compared to a neutral baseline without potential gain. In contrast, startle was not inhibited relative to baseline when a reward was won. This suggests that startle modulation during feedback is better characterized in terms of potentiation when missing out on reward rather than in terms of inhibition as a result of winning. However, neither of these effects were replicated in a more targeted second experiment. The discrepancy between these experiments may be due to differences in motivation to obtain rewards or differences in task engagement. From these experiments it may be concluded that the nature of the processing of reward feedback and reward cues is very sensitive to experimental parameters and settings. These studies show how apparently modest changes in these parameters and settings may lead to quite different modulations of appetitive/aversive motivation. A future experiment may shed more light on the question whether startle-reflex modulation after feedback is indeed mainly characterized by the aversive consequences of reward omission for relatively large rewards.

Background: Preclinical research suggests that cannabidiol (CBD) may have therapeutic potential in pathological anxiety. Dosing guidelines to inform future human studies are however lacking. Aim: We aimed to predict the therapeutic window for anxiety-reducing effects of CBD in humans based on preclinical models. Methods: We conducted two systematic searches in PubMed and Embase up to August 2021, into pharmacokinetic (PK) and pharmacodynamic (PD) data of systemic CBD exposure in humans and animals, which includes anxiety-reducing and potential side effects. Risk of bias was assessed with SYRCLE’s RoB tool and Cochrane RoB 2.0. A control group was an inclusion criterion in outcome studies. In human outcome studies, randomisation was required. We excluded studies that co-administered other substances. We used the IB-de-risk tool for a translational integration of outcomes. Results: We synthesised data from 87 studies. For most observations (70.3%), CBD had no effect on anxiety outcomes. There was no identifiable relation between anxiety outcomes and drug levels across species. In all species (humans, mice, rats), anxiety-reducing effects seemed to be clustered in certain concentration ranges, which differed between species. Discussion: A straightforward dosing recommendation was not possible, given variable concentration–effect relations across species, and no consistent linear effect of CBD on anxiety reduction. Currently, these results raise questions about the broad use as a drug for anxiety. Meta-analytic studies are needed to quantitatively investigate drug efficacy, including aspects of anxiety symptomatology. Acute and (sub)chronic dosing studies with integrated PK and PD outcomes are required for substantiated dose recommendations.

Recent meta-analyses indicated differences in fear acquisition and extinction between patients with anxiety related disorders and comparison subjects. However, these effects are small and may hold for only a subsample of patients. To investigate individual trajectories in fear acquisition and extinction across patients with anxiety-related disorders (N = 104; before treatment) and comparison subjects (N = 93), data from a previous study (Duits et al., 2017) were re-analyzed using data-driven latent class growth analyses. In this explorative study, subjective fear ratings, shock expectancy ratings and startle responses were used as outcome measures. Fear and expectancy ratings, but not startle data, yielded distinct fear conditioning trajectories across participants. Patients were, compared to controls, overrepresented in two distinct dysfunctional fear conditioning trajectories: impaired safety learning and poor fear extinction to danger cues. The profiling of individual patterns allowed to determine that whereas a subset of patients showed trajectories of dysfunctional fear conditioning, a significant proportion of patients (?50 %) did not. The strength of trajectory analyses as opposed to group analyses is that it allows the identification of individuals with dysfunctional fear conditioning. Results suggested that dysfunctional fear learning may also be associated with poor treatment outcome, but further research in larger samples is needed to address this question.

Optimal decision-making requires humans to predict the value and probability of prospective (rewarding) outcomes. The aim of the present study was to evaluate and dissociate the cortical mechanisms activated by information on an upcoming potentially rewarded target stimulus with varying probabilities. Electro-cortical activity was recorded during a cued Go/NoGo experiment, during which cue letters signaled upcoming target letters to which participants had to respond. The probability of target letter appearance after the cue letter and the amount of money that could be won for correct and fast responses were orthogonally manipulated across four task blocks. As expected, reward availability affected a prefrontally distributed reward-related positivity, and a centrally distributed P300-like event-related potential (ERP). Moreover, a late prefrontally distributed ERP was affected by probability information. These results show that information on value and probability, respectively, activates separate mechanisms in the cortex. These results contribute to a further understanding of the neural underpinnings of normal and abnormal reward processing.

Humans (as well as animals) have an inherent tendency to seek out rewards and to avoid punishments. This tendency is crucially important in daily life. The brain selects those behavioral actions that have high probabilities of leading to highly valuable outcomes. Therefore, the brain should compute the value as well as the probability of future rewards in order to make optimal decisions. One of the main questions of this thesis was: how does the human brain assess the value and probability of potential future rewards? Other questions that I addressed in this thesis are: How can the subjective value of monetary rewards be assessed? Are there individual differences in reward sensitivity as reflected in learning style? And as reflected in spontaneous fluctuations in brain activity? In Chapter 2 the startle reflex was used as a readout measure of motivational state during the anticipation, obtainment and omission of rewards with varying magnitudes in order to compare the value of these rewards. However, no evidence was found for systematic increases in startle modulation with increased reward magnitude at stake. The aim of Chapter 3 and 4 was to investigate whether there are individual differences in reward sensitivity as reflected in the extent to which subjects learn from reward and punishment feedback as assessed by the probabilistic selection task (PST) and as reflected in the ratio between spontaneous slow-wave theta and fast-wave beta oscillations in the electro-encephalogram. The results indicate that neither of these two methods could be used as a reliable index of individual differences in reward sensitivity. The results of Chapter 3 show that categorization as being reward/punishment sensitive may not solely reflect motivational style, but also the perceptual discriminability or salience of stimulus characters in the PST. The results of Chapter 4 show that high theta/beta EEG ratio is not related to high reward sensitivity, but rather to poor behavioral adaptation in a context with changing reward-punishment contingencies. This may indicate that subjects with a high theta/beta EEG ratio are less able to learn to make optimal decisions based on reward and punishment feedback. In Chapter 5 and 6 it is shown that cortical processes related to the anticipation of reward value and probability are dissociable, statistically, in terms of timing, and neurochemically. More specifically, the results demonstrate that the anticipation of reward involves at least three distinct neural processes specifically related to either the coding of value (reward-related positivity (RRP) and reward P300) or the coding of probability (probability-positivity (PRP)). The value-related processes were found to be under control of dopamine, whereas the probability-related process was found to be under control of noradrenaline. The results described in this thesis may contribute to a better understanding of various mental disorders associated with abnormal valuation of reward or motivational deficits, such as in depression and ADHD.

The present study aimed to replicate the findings of Blakey, Abramowitz, Reuman, Leonard, and Riemann (2017) that higher anxiety sensitivity (AS) predicted worse treatment outcome in 187 patients with obsessive-compulsive disorder (OCD), treated with cognitive-behavioral therapy. We also tested whether this finding is observed in other anxiety (related) disorders and if AS would predict treatment length. Assuming that exposure assignments would be more difficult for high AS individuals, we hypothesized that higher AS would predict worse treatment outcome and longer treatment length. Controlling for the presence and severity of pretreatment symptoms, these hypotheses were tested in 110 OCD patients and in 285 patients with mixed anxiety disorders. We failed to replicate the earlier findings. Hierarchical linear regressions revealed that AS did not contribute to the prediction of treatment outcome or treatment length; neither in OCD or in the other disorders. Findings are critically discussed.

The endocannabinoid system is a promising candidate for anxiolytic therapy, but translation to the clinic has been lagging. We meta-analyzed the evidence for anxiety-reduction by compounds that facilitate endocannabinoid signaling in humans and animals. To identify areas of specific potential, effects of moderators were assessed. Literature was searched in Pubmed and Embase up to May 2021. A placebo/vehicle-control group was required and in human studies, randomization. We excluded studies that co-administered other substances. Risk of bias was assessed with SYRCLE's RoB tool and Cochrane RoB 2.0. We conducted three-level random effects meta-analyses and explored sources of heterogeneity using Bayesian regularized meta-regression (BRMA). The systematic review yielded 134 studies. We analyzed 120 studies (114 animal, 6 human) that investigated cannabidiol (CBD, 61), URB597 (39), PF-3845 (6) and AM404 (14). Pooled effects on conditioned and unconditioned anxiety in animals (with the exception of URB597 on unconditioned anxiety) and on experimentally induced anxiety in humans favored the investigational drugs over placebo/vehicle. Publication year was negatively associated with effects of CBD on unconditioned anxiety. Compared to approach avoidance tests, tests of repetitive-compulsive behavior were associated with larger effects of CBD and URB597, and the social interaction test with smaller effects of URB597. Larger effects of CBD on unconditioned anxiety were observed when anxiety pre-existed. Studies reported few side effects at therapeutic doses. The evidence quality was low with indications of publication bias. More clinical trials are needed to translate the overall positive results to clinical applications.

Objectives\ud We aimed to examine differences in fear conditioning between anxious and nonanxious participants in a single large sample.\ud \ud Materials and methods\ud We employed a remote fear conditioning task (FLARe) to collect data from participants from the Twins Early Development Study (n = 1,146; 41% anxious vs. 59% nonanxious). Differences between groups were estimated for their expectancy of an aversive outcome towards a reinforced conditional stimulus (CS+) and an unreinforced conditional stimulus (CS−) during acquisition and extinction phases.\ud \ud Results\ud During acquisition, the anxious group (vs. nonanxious group) showed greater expectancy towards the CS−. During extinction, the anxious group (vs. nonanxious group) showed greater expectancy to both CSs. These comparisons yielded effect size estimates (d = 0.26–0.34) similar to those identified in previous meta‐analyses.\ud \ud Conclusion\ud The current study demonstrates that remote fear conditioning can be used to detect differences between groups of anxious and nonanxious individuals, which appear to be consistent with previous meta‐analyses including in‐person studies.