Effects of lockdowns on neurobiological and psychometric parameters in unipolar depression during the COVID-19 pandemic.

Defying the COVID-19 pandemic required restriction measures of unprecedented scale, that may induce and exacerbate psychiatric symptoms across the population. We aimed to assess in vivo dynamic effects of mitigation strategies on human brain neurobiology, neuroplastic as well as psychometric parameters. Three structural magnetic resonance imaging measurements, serum brain-derived neurotrophic factor (sBDNF) analyses, and psychometric assessments (Beck Depression Inventory-II and Perceived Stress Questionnaire-20) were performed in healthy individuals and patients with a recurrent major depressive disorder in the period from September 2020 to July 2021. Group differences and changes over time in structural imaging, neuroplastic and psychometric parameters were assessed with linear mixed models. Analysis of data from 18 patients with a recurrent major depressive disorder and 28 healthy individuals showed clinically relevant scores for depression and stress in the patient group as well as significant cross-sectional differences in depression scores (F = 30.89, p < 0.001) and three subscales of the Perceived Stress Questionnaire (Worries: F = 19.19, p < 0.001, Tension: F = 34.44, p < 0.001, Joy: F = 12.05, p = 0.001). Linear mixed models revealed no significant changes over time in cortical thickness of the prefrontal cortex, anterior cingulate cortex, hippocampus, and amygdala (F = 0.29, p > 0.1) and no interaction with group (F = 0.28, p > 0.1). Further, analysis revealed no main effect of time and no interaction of time x group in depressive symptoms, perceived stress subscales, and sBDNF (all p > 0.1). Despite the limited sample size, the strength of this investigation lies in the multimodal assessment of peri-pandemic lockdown effects. Nine months of varying restrictions measures did not result in observable changes in brain morphology nor impact depressive symptoms in either psychiatric patients with a recurrent major depressive disorder or healthy individuals. While these neurobiological and psychometric data stand in contrast to initial expectations about the effects of restriction measures, they might inform future investigations of longitudinal effects of restriction measures on mental health.

Effects of facial biofeedback on hypomimia, emotion recognition, and affect in Parkinson's disease.

OBJECTIVES: Facial expressions are a core component of emotions and nonverbal social communication. Therefore, hypomimia as secondary symptom of Parkinson's disease (PD) has adverse effects like social impairment, stigmatization, under-diagnosis and under-treatment of depression, and a generally lower quality of life. Beside unspecific dopaminergic treatment, specific treatment options for hypomimia in PD are rarely investigated. This quasi-randomized controlled trial evaluated the short-term effects of facial electromyogram (EMG) based biofeedback to enhance facial expression and emotion recognition as nonverbal social communication skills in PD patients. Furthermore effects on affect are examined. METHOD: A sample of 34 in-patients with PD were allocated either to facial EMG-biofeedback as experimental group or non-facial exercises as control group. Facial expression during posing of emotions (measured via EMG), facial emotion recognition, and positive and negative affect were assessed before and after treatment. Stronger improvements were expected in the EMG-biofeedback in comparison to the control group. RESULTS: The facial EMG-biofeedback group showed significantly greater improvements in overall facial expression, and especially for happiness and disgust. Also, overall facial emotion recognition abilities improved significantly stronger in the experimental group. Positive affect was significantly increased in both groups with no significant differences between them, while negative affect did not change within both groups. CONCLUSIONS: The study provides promising evidence for facial EMG-biofeedback as a tool to improve facial expression and emotion recognition in PD. Embodiment theories are discussed as working mechanism.

Looking fear in the eye: Gamified virtual reality exposure towards spiders for children using attention based feedback.

Many children around the globe suffer from spider phobia. Virtual reality exposure therapy is an effective phobia treatment, but so far predominantly tailored for adults. A gamified approach utilizing gaze interaction would allow for a more child-friendly and engaging experience, and provide the possibility to foster working mechanisms of exposure therapy. We developed an application in which children make spiders change in positively connoted ways (e.g., make them dance or shrink) if sufficient visual attention towards them is captured via eye tracking. Thereby, motivation for and positive affects during exposure towards spiders are aspired. In this pilot study on 21 children without (n = 11) and with fear of spiders (n = 10), we examined positive and negative affect during exposure to a virtual spider and to different gaze-related transformations of the spider within a quasi-experimental design. Within a one-group design, we additionally examined fear of spiders in spider fearful children before and one week after the intervention. We found that significantly more positive than negative affect was induced by the spiders' transformations in children without and with fear of spiders. Fear of spiders was furthermore significantly reduced in spider-fearful children, showing large effect sizes (d > .80). Findings indicate eligibility for future clinical use and evaluation in children with spider phobia.

Fear, psychophysiological arousal, and cognitions during a virtual social skills training in social anxiety disorder while manipulating gaze duration.

The use of virtual reality (VR) is an option for social skills training and exposure in Social Anxiety Disorder (SAD). In addition, virtual social situations are an ideal tool to study the influence of a counterpart's social behavior, e. g. eye contact. We developed two scenarios in VR that enable users to practice to assert their rights. The participants' tasks were to ask a passenger to release their reserved seat in a virtual train and to cancel a trip in a virtual travel agency. In a randomized, crossover design, we compared the effect of a large (during 80% of the conversation time) and a small (20%) amount of direct gaze by the virtual conversational partners in 41 patients with SAD and 21 healthy controls (HCs). We expected fear and psychophysiological arousal to be higher in patients than in HCs and higher in the 80% eye contact condition. The scenarios provoked an increase of fear and psychophysiological arousal over baseline in patients and in HCs. Gaze duration of the virtual agent had no influence on fear and psychophysiological arousal, but affected the experience of presence. Our results suggest a suitability of our scenarios for social skills training and exposure therapy in SAD. The lack of influence of gaze duration on parameters of fear might be explained by the fact that participants did not consciously detect the differences in gaze duration. However, the impact on some parameters (e. g. presence) suggests that participants noticed differences in gaze duration on a subliminal level.

Individual changes in stress, depression, anxiety, pathological worry, posttraumatic stress, and health anxiety from before to during the COVID-19 pandemic in adults from Southeastern Germany.

BACKGROUND: Many studies have previously compared the prevalence or sample means of distress and mental health problems from before to during the COVID-19 pandemic, while results on changes at the individual-level, and regarding multiple outcome measures are demanded. METHODS: This online study investigated individual changes in stress and mental health from before the COVID-19 pandemic to the first lockdown in adults from Southeastern Germany. This region was selected as it was where SARS-CoV-2 was first documented in Germany, and also due to the implementation of strict stay-at-home orders and social contact prohibitions. From April 10-27, 2020, we collected state measures and their clinical relevance for the subareas of perceived stress: worries, tension, joy, and demands. We also collected information regarding the following mental health problems: depression, anxiety, pathological worry, posttraumatic stress disorder (PTSD), and health anxiety; as well as retrospective measures of how participants felt they have changed in comparison to before the pandemic, ranging from worse to better. RESULTS: The analytical sample comprised 396 adult participants. On average, participants experienced increases in worries, tension, and lack of joy, and increases in mental health problems, but a decrease in demands. Perceived increases in symptoms of depression (26.0%) and PTSD (25.5%) were significantly more frequent than in symptoms of anxiety (particularly acute fear and panic) (5.6%), pathological worry (9.8%), and health anxiety (7.3%) (ps<.001). One per 10 participants (10.4%) reported an increase in depressive symptoms, and nearly two per 10 (18.4%) an increase in PTSD symptoms and additionally showed a clinically relevant symptom strain during lockdown. Interestingly, mainly non-specific PTSD symptoms associated with a general stress reaction were experienced to be increased. CONCLUSION: The findings suggest a dissociation of perceived changes in subareas of stress and mental health with a particular experience of increases in depressive and general stress symptoms and a decrease in external demands. This points to a need for a more differentiated view on the impact of the COVID-19 pandemic on stress and mental health, and for targeted interventions for mental health problems arising frequently during the pandemic.

Inhibition of the Translation Initiation Factor eIF4A Enhances Tumor Cell Radiosensitivity.

A fundamental component of cellular radioresponse is the translational control of gene expression. Because a critical regulator of translational control is the eukaryotic translation initiation factor 4F (eIF4F) cap binding complex, we investigated whether eIF4A, the RNA helicase component of eIF4F, can serve as a target for radiosensitization. Knockdown of eIF4A using siRNA reduced translational efficiency, as determined from polysome profiles, and enhanced tumor cell radiosensitivity as determined by clonogenic survival. The increased radiosensitivity was accompanied by a delayed dispersion of radiation-induced γH2AX foci, suggestive of an inhibition of DNA double-strand break repair. Studies were then extended to (-)-SDS-1-021, a pharmacologic inhibitor of eIF4A. Treatment of cells with the rocaglate (-)-SDS-1-021 resulted in a decrease in translational efficiency as well as protein synthesis. (-)-SDS-1-021 treatment also enhanced the radiosensitivity of tumor cell lines. This (-)-SDS-1-021-induced radiosensitization was accompanied by a delay in radiation-induced γH2AX foci dispersal, consistent with a causative role for the inhibition of double-strand break repair. In contrast, although (-)-SDS-1-021 inhibited translation and protein synthesis in a normal fibroblast cell line, it had no effect on radiosensitivity of normal cells. Subcutaneous xenografts were then used to evaluate the in vivo response to (-)-SDS-1-021 and radiation. Treatment of mice bearing subcutaneous xenografts with (-)-SDS-1-021 decreased tumor translational efficiency as determined by polysome profiles. Although (-)-SDS-1-021 treatment alone had no effect on tumor growth, it significantly enhanced the radiation-induced growth delay. These results suggest that eIF4A is a tumor-selective target for radiosensitization.

Look at the Audience? A Randomized Controlled Study of Shifting Attention From Self-Focus to Nonsocial vs. Social External Stimuli During Virtual Reality Exposure to Public Speaking in Social Anxiety.

Background: Enhanced self-focused attention plays a central role in the maintenance and treatment of Social Anxiety and is targeted in contemporary cognitive behavioral therapy. Actual developments use Virtual Reality (VR) for behavioral training. However, no VR attention training combining exposure to public speaking with shifting attention from self-focus to external focus has been investigated, and no experimental evidence exists on different kinds of external cues as targets of attention. Therefore, we investigated the effects of an attention training during public speaking in VR and examined differential effects of an external focus on nonsocial vs. social stimuli. Methods: In this randomized controlled study, highly socially anxious participants were instructed to focus on either objects or the audience within a virtual speech task. We assessed the pre-post effects on affective reactions, self-perception, and attentional processes during public speaking as well as general Social Anxiety using subjective, physiological, and eye-tracking measures. Repeated-measures analyses of variance (ANOVAs) were calculated to detect changes from pretest to posttest over both groups, and time × group interaction effects. Results: Within the analysis sample (n = 41), anxiety during public speaking and fear of negative evaluation significantly decreased, with no significant differences between groups. No significant time effect, but a significant time × group effect, was found for the looking time proportion on the audience members' heads. Follow-up tests confirmed a significant increase in the social-focus group and a significant decrease in the nonsocial-focus group. For all other variables, except external focus and fear of public speaking, significant improvements were found over both groups. Further significant time x group effects were found for positive affect during public speaking, with a significant increase in the social focus, and no significant change in the nonsocial-focus group. Conclusion: Our findings suggest that attention training to reduce self-focus can be successfully conducted in VR. Both training versions showed positive short-term effects in the highly socially anxious, with particular advantages of an external social focus concerning eye contact to the audience and positive affect. Further research should investigate whether social focus is even more advantageous long term and if reinterpretations of dysfunctional beliefs could be achieved by not avoiding social cues.

Widespread Recommendations Can Change Our Habits of Hand-Washing and Physical Distance During the COVID-19 Pandemic.

Background: Habits and behaviors in everyday life currently need to be modified as quickly as possible due to the COVID-19 pandemic. Two of the most effective tools to prevent infection seem to be regular and thorough hand-washing and physical distancing during interpersonal interactions. Method: Two hundred and eighty-four participants completed a short survey to investigate how previous habits regarding hand-washing and physical distancing have changed in the general population as a function of the current pandemic and the thereby increased information and constant recommendations regarding these behaviors. Results: Participants aged 51 and older reported a greater change in everyday hand-washing behavior than younger participants. In addition, participants aged 31 and older selected significantly greater distances to have a conversation than younger participants. However, that was not the case if participants had to actively stop their conversational partner from approaching. Conclusion: Participants aged 51 years and older seem to be well aware of their at-risk status during the current pandemic and might therefore be willing to change their behavior more strongly than younger survey participants. Nevertheless, they seem to struggle with enforcing the current rules towards others. The group aged between 31 and 50 years, however, reports a comparable level of fear, but no corresponding change in hand-washing behavior. Future surveys should try to provide more insight into why this might be the case.

Dissociation of endocrine responses to the Trier Social Stress Test in Virtual Reality (VR-TSST) by the benzodiazepine alprazolam and the translocator protein 18 kDa (TSPO) ligand etifoxine.

BACKGROUND: Activity of the two major stress systems, the hypothalamic-pituitary-adrenal (HPA) and the sympathetic-adrenal-medullary (SAM) axis, has already been shown to be modulated by different compounds that bind to the central benzodiazepine receptor. Less is known about ligands that modulate the peripheral benzodiazepine receptor - meanwhile known as the translocator protein 18 kDa (TSPO) - which constitute promising candidates in the search of novel anxiolytics. To close this gap, the present study compared the effects of the benzodiazepine alprazolam and the TSPO ligand etifoxine on responses of the HPA and SAM axes to the Trier Social Stress Test, a standardized paradigm to induce acute psychosocial stress in humans, performed in Virtual Reality (VR-TSST). METHODS: Sixty healthy males, aged between 18 and 55 years, were randomly assigned to receive either a daily dose of 1.5 mg alprazolam, 150 mg etifoxine, or placebo over five days. On the last day of intake, they were exposed to the VR-TSST. We assessed changes of salivary cortisol, allopregnanolone, (nor-) epinephrine in serum, TSPO expression in platelets as well as heart rate (HR), skin conductance level (SCL) and self-reports in response to the stress task. Repeated measures ANOVAs were conducted to examine treatment effects on these stress response variables during the course of VR-TSST. RESULTS: The response of salivary cortisol to the VR-TSST was significantly blunted in participants pre-treated with alprazolam but was not affected by etifoxine. While levels of allopregnanolone, epinephrine and norepinephrine increased in response to stress, TSPO expression decreased. None of those endocrine stress markers was affected by the active treatments, whereas TSPO expression increased after etifoxine administration over all study days. There were no effects of the two anxiolytics on HR, SCL or any self-report measurement. CONCLUSION: The current study confirmed the attenuating effects of benzodiazepines on stress-induced HPA axis activity but did not reveal a comparable effect of the TSPO ligand etifoxine. The long-term consequences of a pharmacologically blunted response of the HPA axis to an acute stressor should be further elucidated. Due to the missing effects of etifoxine on stress-related parameters in our sample of healthy subjects, it might be concluded that the therapeutic effects of this TSPO ligand are restricted to stronger or pathological stress responses, respectively.

Linking Personality Traits to Individual Differences in Affective Spaces.

Different individuals respond differently to emotional stimuli in their environment. Therefore, to understand how emotions are represented mentally will ultimately require investigations into individual-level information. Here we tasked participants with freely arranging emotionally charged images on a computer screen according to their subjective emotional similarity (yielding a unique affective space for each participant) and subsequently sought external validity of the layout of the individuals' affective spaces through the five-factor personality model (Neuroticism, Extraversion, Openness to Experience, Agreeableness, Conscientiousness) assessed via the NEO Five-Factor Inventory. Applying agglomerative hierarchical clustering to the group-level affective space revealed a set of underlying affective clusters whose within-cluster dissimilarity, per individual, was then correlated with individuals' personality scores. These cluster-based analyses predominantly revealed that the dispersion of the negative cluster showed a positive relationship with Neuroticism and a negative relationship with Conscientiousness, a finding that would be predicted by prior work. Such results demonstrate the non-spurious structure of individualized emotion information revealed by data-driven analyses of a behavioral task (and validated by incorporating psychological measures of personality) and corroborate prior knowledge of the interaction between affect and personality. Future investigations can similarly combine hypothesis- and data-driven methods to extend such findings, potentially yielding new perspectives on underlying cognitive processes, disease susceptibility, or even diagnostic/prognostic markers for mental disorders involving emotion dysregulation.

Inferiority or Even Superiority of Virtual Reality Exposure Therapy in Phobias?-A Systematic Review and Quantitative Meta-Analysis on Randomized Controlled Trials Specifically Comparing the Efficacy of Virtual Reality Exposure to Gold Standard in vivo Exposure in Agoraphobia, Specific Phobia, and Social Phobia.

Background: Convincing evidence on Virtual Reality (VR) exposure for phobic anxiety disorders has been reported, however, the benchmark and golden standard for phobia treatment is in vivo exposure. For direct treatment comparisons, the control of confounding variables is essential. Therefore, the comparison of VR and in vivo exposure in studies applying an equivalent amount of exposure in both treatments is necessary. Methods: We conducted a systematic search of reports published until June 2019. Inclusion criteria covered the diagnosis of Specific Phobia, Social Phobia, or Agoraphobia, and a randomized-controlled design with an equivalent amount of exposure in VR and in vivo. We qualitatively reviewed participants' characteristics, materials, and the treatment procedures of all included studies. For quantitative synthesis, we calculated Hedges' g effect sizes for the treatment effects of VR exposure, in vivo exposure, and the comparison of VR to in vivo exposure in all studies and separately for studies on each diagnosis. Results: Nine studies (n = 371) were included, four on Specific Phobia, three on Social Phobia, and two on Agoraphobia. VR and in vivo exposure both showed large, significant effect sizes. The comparison of VR to in vivo exposure revealed a small, but non-significant effect size favoring in vivo (g = -0.20). Specifically, effect sizes for Specific Phobia (g = -0.15) and Agoraphobia (g = -0.01) were non-significant, only for Social Phobia we found a significant effect size favoring in vivo (g = -0.50). Except for Agoraphobia, effect sizes varied across studies from favoring VR to favoring in vivo exposure. Conclusions: We found no evidence that VR exposure is significantly less efficacious than in vivo exposure in Specific Phobia and Agoraphobia. The wide range of study specific effect sizes, especially in Social Phobia, indicates a high potential of VR, but also points to the need for a deeper investigation and empirical examination of relevant working mechanisms. In Social Phobia, a combination of VR exposure with cognitive interventions and the realization of virtual social interactions targeting central fears might be advantageous. Considering the advantages of VR exposure, its dissemination should be emphasized. Improvements in technology and procedures might even yield superior effects in the future.