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Sleep benefits memory consolidation. Here, we tested the beneficial effect of sleep on memory consolidation following exposure psychotherapy of phobic anxiety. A total of 40 individuals afflicted with spider phobia according to DSM-IV underwent a one-session virtual reality exposure treatment and either slept for 90 min or stayed awake afterwards. Sleep following exposure therapy compared with wakefulness led to better reductions in self-reported fear (p = 0.045, d = 0.47) and catastrophic spider-related cognitions (p = 0.026, d = 0.53) during approaching a live spider, both tested after 1 week. Both reductions were associated with greater percentages of stage 2 sleep. Our results indicate that sleep following successful psychotherapy, such as exposure therapy, improves therapeutic effectiveness, possibly by strengthening new non-fearful memory traces established during therapy. These findings offer an important non-invasive alternative to recent attempts to facilitate therapeutic memory extinction and consolidation processes with pharmacological or behavioral interventions.

•Multiscale entropy is a measure of neural information production and complexity.•First study to asses 7T MRI complexity.•Spider phobia shows increased multiscale entropy in fear and anxiety networks.•The bed nucleus of the stria terminalis shows most entropy changes in spider phobia.•Multiscale entropy correlates with phobia severity but not trait anxiety. Resting-state functional connectivity is limited in assessing the temporal dynamics of brain networks and, due to an insufficient signal-to-noise ratio, in detecting subtle changes at 3T MRI. Nonetheless, measures of complexity, which capitalize on temporal dynamics, have revealed alterations for some affective disorders at this field strength. Anxiety disorders have received only scant attention in this regard, despite indications of altered functional brain architecture in spider-fearful participants (SP). To address this gap, we probed resting-state complexity using 7T MRI, comparing 28 adults with SP with 45 healthy controls (HC). We computed multiscale entropy (MSE) on ten scales (1 – 0.1 Hz) for brain regions of the fear and anxiety networks in HC and SP. The MSE scales interacted with group (HC, SP) and brain area, revealing MSE increments in limbic regions in SP (versus HC). Whilst most MSE changes related to SP ranged between 1 and 0.33 Hz, the MSE of the bed nucleus of the stria terminalis (BNST), a nucleus involved in anxiety and the hormonal system, exhibited increases on all scales bar two for SP (i.e., for 0.5 – 0.125, and 0.1 Hz). MSE was also positively associated with SP severity (but not trait anxiety) in the BNST. Altogether, 7T fMRI detected elevated MSE in SP, indicating excessive intra-regional processing in brain regions key to fear and anxiety. The most pronounced effects were found in the BNST, corroborating its central role in the anxiety circuit. [Display omitted]

Return of fear after successful exposure therapy for a phobia is a common clinical challenge. A previous study on mice demonstrated that the persistent attenuation of remote fear memories can be achieved by combining histone deacetylase inhibitors (HDACis) with fear-memory retrieval prior to extinction training. To evaluate the translational potential of this approach, we conducted a randomized, double-blind, placebo-controlled trial. Forty-eight individuals with DSM-IV spider phobia received either HDACi valproic acid (VPA, 500 mg) or a placebo prior to the retrieval of fear memory, followed by exposure therapy in virtual reality. No significant group difference was found in terms of behavioral change on the behavioral approach test at 3 months follow-up and baseline (primary outcome). However, the VPA group displayed significantly reduced fear in two self-report questionnaires related to spider phobia (Fear of Spiders Questionnaire; Spider Phobia Beliefs Questionnaire) as compared to the placebo group. No group differences were observed for psychophysiological indicators of fear. The favorable impact of a single administration of VPA in combination with fear-memory retrieval prior to exposure therapy suggests that it might be an effective way to enhance symptom improvement at the subjective level in the treatment of phobias. Further studies need to investigate the conditions under which an improvement on the psychophysiological and behavioral levels can be achieved as well.

Persons with specific phobias typically generalize the dangerousness of the phobic animal to all members of its species, possibly as a result of malfunctioning brain circuitry normally providing quick and dirty identification of evolutionary-relevant stimuli. An objective assessment of which perceptual features make an animal more or less scary to phobic and non-phobic people would help overcome the limitations of the few studies available so far, based on self-reports. To achieve this aim, we built an augmented reality setting where volunteers with different levels of fear of spiders were asked to make holographic spiders that look either dangerous or harmless. To reach this goal, a computerized interface allowed participants to modify the spider's perceptual features (hairiness, body/leg size, and locomotion) in real time. On average, the dangerous spiders were made hairy, thick, and moving according to spider-like locomotion; coherently, the harmless spiders were made hairless, slim, and moving according to a butterfly-like locomotion. However, these averaged preferences could not fully describe the complex relationship between perceptual preferences with each other and with arachnophobia symptoms. An example of a key finding revealed by cluster analysis is the similarity in perceptual preferences among participants with little or no fear of spiders, whereas participants with more arachnophobia symptoms expressed more varying preferences. Perceptual preferences toward the spider's features were behaviorally assessed through an observational study, objectively confirming a generalization effect characterizing spider-fearful participants. These results advance our knowledge of phobic preferences and could be used to improve the acceptability of exposure therapies.

Specific phobias are the most common anxiety disorder and are characterized by avoidance behavior. Avoidance behavior impacts daily function and is proposed to impair extinction learning. However, despite its prevalence, its objective assessment remains a challenge. To this end, we developed a fully automated experimental procedure using immersive virtual reality. The procedure contained a behavioral search, forced-choice, and an approach task with varying degrees of freedom and task relevance of the stimuli. In this study, we examined the sensitivity and feasibility of these tasks to assess avoidance behavior in patients with specific phobia. We adapted the tasks by replacing the originally conditioned stimuli with a spider and a neutral animal and investigated 31 female participants composed of 15 spider-phobic and 16 non-phobic participants. As the non-phobics were quite heterogeneous in terms of their Fear of Spiders Questionnaire (FSQ) scores, we subdivided them into 6 ‘fearfuls’ that had elevated FSQ scores, and 10 ‘non-fearfuls’ that had no fear of spiders. The phobics successfully managed to complete the procedure and showed consistent avoidance behavior across all behavioral tasks. Compared to the non-fearfuls, which did not show any avoidance behavior at all, the phobics looked at the spider much more often and clearly directed their body towards it in the search task. In the approach task, they hesitated most when they were close to the spider, and their difficulty to touch the spider was reflected in a strong increase in right hand acceleration changes. The fearfuls showed avoidance behavior depending on the tasks: strongest in the search task and weakest in the approach task. Additionally, we identified subjective valence ratings of the spider as the main influence on both objective avoidance behavior and subjective well-being after exposure, mediating the effect of the FSQ. In summary, the behavioral tasks are well suited to assess avoidance behavior in phobic participants and provide detailed insights into the process of avoidance.

Specific phobias are characterized by excessive fear of an object or situation and its avoidance. In research, avoidance behavior is often assessed via the behavioral avoidance test (BAT) which employs real fear-eliciting stimuli. While its feasibility and standardization can be improved by using virtual reality, these two setups have not been compared yet. This study aims to validate a BAT in virtual reality, regarding fear and avoidance, and compare different approach behaviors, utilized in BATs. Individuals with spider phobia ( N  = 25) completed four BATs, two in virtuo and two in vivo in a randomized order. The BATs involved approaching a (virtual) spider by either walking towards it or sliding it towards oneself. The final distance between the patient and the spider in each BAT indicated the avoidance behavior. The study was preregistered with the Open Science Framework (osf.io/xmf62). The results showed large associations between the BATs in virtuo and the BATs in vivo, but also between the two approach behaviors. Correlations with a psychometric measure of spider phobia revealed large associations. Overall, the BAT in virtuo offers a feasible and reliable alternative to traditional BAT procedures and provides valuable insights into the manifestations of avoidance behavior in a controlled virtual environment.

Spider phobics show an exaggerated fear response when encountering spiders. This fear response is aggravated by negative and irrational beliefs about the feared object. Cognitive reappraisal can target these beliefs, and therefore has a fear regulating effect. The presented study investigated if neurofeedback derived from functional magnetic resonance imaging (fMRI) would facilitate anxiety regulation by cognitive reappraisal, using spider phobia as a model of anxiety disorders. Feedback was provided based on activation in left dorsolateral prefrontal cortex and right insula, as indicators of engagement and regulation success, respectively. Eighteen female spider phobics participated in a randomized, controlled, single-blinded study. All participants completed a training session in the MRI scanner. Participants assigned to the neurofeedback condition were instructed to shape their regulatory strategy based on the provided feedback. Participants assigned to the control condition were asked to adapt their strategy intuitively. Neurofeedback participants exhibited lower anxiety levels than the control group at the end of the training. In addition, only neurofeedback participants achieved down-regulation of insula activation levels by cognitive reappraisal. Group differences became more pronounced over time, supporting learning as a mechanism behind this effect. Importantly, within the neurofeedback group, achieved changes in insula activation levels during training predicted long-term anxiety reduction. The conducted study provides first evidence that fMRI neurofeedback has a facilitating effect on anxiety regulation in spider phobia.

Exposure therapy is the treatment of choice for specific phobias but prolonged exposure to feared stimuli is strenuous and may lead to treatment dropout. Previous research showed that repeated exposure to masked spiders was effective in reducing psychophysiological and behavioural fear responses, but appeared ineffective in changing subjective feelings towards spiders. This study investigated in an unselected female sample if masked counterconditioning would be more effective in reducing spider dislike compared to masked exposure, and if masked counterconditioning would also be more effective than non-masked counterconditioning. Women with varying levels of spider aversion (N = 272) were randomly assigned to one of four conditions. Three spider pictures were always (counterconditioning) or never (exposure) followed by smiling faces. For half of the participants in each condition the spiders were masked. Results indicated that participants rated the spider more positively after both masked counterconditioning and masked exposure. However, the increase in valence after masked counterconditioning was not significantly larger than after mere masked exposure, or after non-masked counterconditioning. Thus, our findings show that repeated exposure to masked spider pictures is effective in reducing spider aversion, but they provided no support for the anticipated added benefit of pairing the spider with positive stimuli.

Background Specific phobias are among the most common anxiety disorders. Exposure therapy is the treatment of choice for specific phobias. However, not all patients respond equally well to it. Hence, current research focuses on therapeutic add-ons to increase and consolidate the effects of exposure therapy. One potential therapeutic add-on is biofeedback to increase heart rate variability (HRV). A recent meta-analysis shows beneficial effects of HRV biofeedback interventions on stress and anxiety symptoms. Therefore, the purpose of the current trial is to evaluate the effects of HRV biofeedback, which is practiced before and utilized during exposure, in spider-fearful individuals. Further, this trial is the first to differentiate between the effects of a HRV biofeedback intervention and those of a low-load working memory (WM) task. Methods Eighty spider-fearful individuals participate in the study. All participants receive a training session in which they practice two tasks (HRV biofeedback and a motor pseudo-biofeedback task or two motor pseudo-biofeedback tasks). Afterwards, they train both tasks at home for 6 days. One week later, during the exposure session, they watch 16 1-min spider video clips. Participants are divided into four groups: group 1 practices the HRV biofeedback and one motor pseudo-task before exposure and utilizes HRV biofeedback during exposure. Group 2 receives the same training, but continues the pseudo-biofeedback task during exposure. Group 3 practices two pseudo-biofeedback tasks and continues one of them during exposure. Group 4 trains in two pseudo-biofeedback tasks and has no additional task during exposure. The primary outcome is fear of spiders (measured by the Fear of Spiders Questionnaire and the Behavioral Approach Test). Secondary outcomes are physiological measures based on electrodermal activity, electrocardiogram and respiration. Discussion This RCT is the first one to investigate the effects of using a pre-trained HRV biofeedback during exposure in spider-fearful individuals. The study critically contrasts the effects of the biofeedback intervention with those of pseudo-tasks, which also require WM capacity, but which do not have a physiological base. If HRV biofeedback is effective in reducing fear of spiders, it would represent an easy-to-use tool to improve exposure-therapy outcomes. Trial registration Deutsches Register Klinischer Studien, DRKS00012278 . Registered on 23 May 2017, amendment on 5 October 2017.

Background: While exposure therapy effectively reduces anxiety associated with specific phobias, not all individuals respond to treatment and some will experience a return of fear after treatment ceases. Aims: This study aimed to test the potential benefit of increasing the intensity of exposure therapy by adding an extra step that challenged uncontrollability (Step 15: allowing a spider to walk freely over one's body) to the standard fear hierarchy. Method: Fifty-one participants who had a severe fear of spiders completed two 60-min exposure sessions 1 week apart in a context that was either the same or different from the baseline and follow-up assessment context. Participants were categorized into groups based on the last hierarchy step they completed during treatment (Step 14 or fewer, or Step 15). Results: Those who completed Step 15 had greater reductions in fear and beliefs about the probability of harm from baseline to post-treatment than those who completed fewer steps. Although completing Step 15 did not prevent fear from returning after a context change, it allowed people to maintain their ability to tolerate their fear, which earlier steps did not. Despite some fear returning after a context change, individuals who completed Step 15 tended to report greater reductions in fear from baseline to the follow-up assessment than participants who completed 14 or fewer steps. Conclusions: Overall, these results suggest that more intensive exposure that directly challenges harm beliefs may lead to greater changes in fear and fear beliefs than less intensive exposure.