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The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
Effects of Acrophobic Fear and Trait Anxiety on Human Behavior in a Virtual Elevated Plus-Maze
(2021)
The Elevated Plus-Maze (EPM) is a well-established apparatus to measure anxiety in rodents, i.e., animals exhibiting an increased relative time spent in the closed vs. the open arms are considered anxious. To examine whether such anxiety-modulated behaviors are conserved in humans, we re-translated this paradigm to a human setting using virtual reality in a Cave Automatic Virtual Environment (CAVE) system. In two studies, we examined whether the EPM exploration behavior of humans is modulated by their trait anxiety and also assessed the individuals’ levels of acrophobia (fear of height), claustrophobia (fear of confined spaces), sensation seeking, and the reported anxiety when on the maze. First, we constructed an exact virtual copy of the animal EPM adjusted to human proportions. In analogy to animal EPM studies, participants (N = 30) freely explored the EPM for 5 min. In the second study (N = 61), we redesigned the EPM to make it more human-adapted and to differentiate influences of trait anxiety and acrophobia by introducing various floor textures and lower walls of closed arms to the height of standard handrails. In the first experiment, hierarchical regression analyses of exploration behavior revealed the expected association between open arm avoidance and Trait Anxiety, an even stronger association with acrophobic fear. In the second study, results revealed that acrophobia was associated with avoidance of open arms with mesh-floor texture, whereas for trait anxiety, claustrophobia, and sensation seeking, no effect was detected. Also, subjects’ fear rating was moderated by all psychometrics but trait anxiety. In sum, both studies consistently indicate that humans show no general open arm avoidance analogous to rodents and that human EPM behavior is modulated strongest by acrophobic fear, whereas trait anxiety plays a subordinate role. Thus, we conclude that the criteria for cross-species validity are met insufficiently in this case. Despite the exploratory nature, our studies provide in-depth insights into human exploration behavior on the virtual EPM.
Emotion-motivation models propose that behaviors, including health behaviors, should be predicted by the same variables that also predict negative affect since emotional reactions should induce a motivation to avoid threatening situations. In contrast, social cognitive models propose that safety behaviors are predicted by a different set of variables that mainly reflect cognitive and socio-structural aspects. Here, we directly tested these opposing hypotheses in young adults (N = 4134) in the context of COVID-19-related safety behaviors to prevent infections. In each participant, we collected measures of negative affect as well as cognitive and socio-structural variables during the lockdown in the first infection wave in Germany. We found a negative effect of the pandemic on emotional responses. However, this was not the main predictor for young adults’ willingness to comply with COVID-19-related safety measures. Instead, individual differences in compliance were mainly predicted by cognitive and socio-structural variables. These results were confirmed in an independent data set. This study shows that individuals scoring high on negative affect during the pandemic are not necessarily more likely to comply with safety regulations. Instead, political measures should focus on cognitive interventions and the societal relevance of the health issue. These findings provide important insights into the basis of health-related concerns and feelings as well as behavioral adaptations.
Threat detection plays a vital role in adapting behavior to changing environments. A fundamental function to improve threat detection is learning to differentiate between stimuli predicting danger and safety. Accordingly, aversive learning should lead to enhanced sensory discrimination of danger and safety cues. However, studies investigating the psychophysics of visual and auditory perception after aversive learning show divergent findings, and both enhanced and impaired discrimination after aversive learning have been reported. Therefore, the aim of this web-based study is to examine the impact of aversive learning on a continuous measure of visual discrimination. To this end, 205 participants underwent a differential fear conditioning paradigm before and after completing a visual discrimination task using differently oriented grating stimuli. Participants saw either unpleasant or neutral pictures as unconditioned stimuli (US). Results demonstrated sharpened visual discrimination for the US-associated stimulus (CS+), but not for the unpaired conditioned stimuli (CS-). Importantly, this finding was irrespective of the US's valence. These findings suggest that associative learning results in increased stimulus salience, which facilitates perceptual discrimination in order to prioritize attentional deployment.
Catastrophizing thoughts may contribute to the development of anxiety, but functional emotion regulation may help to improve treatment. No study so far directly compared up- and down-regulation of fear by cognitive reappraisal. Here, healthy individuals took part in a cued fear experiment, in which multiple pictures of faces were paired twice with an unpleasant scream or presented as safety stimuli. Participants (N = 47) were asked (within-subjects) to down-regulate, to up-regulate and to maintain their natural emotional response. Valence and arousal ratings indicated successful up- and down-regulation of the emotional experience, while heart rate and pupil dilation increased during up-regulation, but showed no reduction in down-regulation. State and trait anxiety correlated with evaluations of safety but not threat stimuli, which supports the role of deficient safety learning in anxiety. Reappraisal did not modulate this effect. In conclusion, this study reveals evidence for up-regulation effects in fear, which might be even more efficient than down-regulation on a physiological level and highlights the importance of catastrophizing thoughts for the maintenance of fear and anxiety.
Background: The rehabilitation of gait disorders in patients with multiple sclerosis (MS) and stroke is often based on conventional treadmill training. Virtual reality (VR)-based treadmill training can increase motivation and improve therapy outcomes. The present study evaluated an immersive virtual reality application (using a head-mounted display, HMD) for gait rehabilitation with patients to (1) demonstrate its feasibility and acceptance and to (2) compare its short-term effects to a semi-immersive presentation (using a monitor) and a conventional treadmill training without VR to assess the usability of both systems and estimate the effects on walking speed and motivation. Methods: In a within-subjects study design, 36 healthy participants and 14 persons with MS or stroke participated in each of the three experimental conditions (VR via HMD, VR via monitor, treadmill training without VR). Results: For both groups, the walking speed in the HMD condition was higher than in treadmill training without VR and in the monitor condition. Healthy participants reported a higher motivation after the HMD condition as compared with the other conditions. Importantly, no side effects in the sense of simulator sickness occurred and usability ratings were high. No increases in heart rate were observed following the VR conditions. Presence ratings were higher for the HMD condition compared with the monitor condition for both user groups. Most of the healthy study participants (89%) and patients (71%) preferred the HMD-based training among the three conditions and most patients could imagine using it more frequently. Conclusions For the first time, the present study evaluated the usability of an immersive VR system for gait rehabilitation in a direct comparison with a semi-immersive system and a conventional training without VR with healthy participants and patients. The study demonstrated the feasibility of combining a treadmill training with immersive VR. Due to its high usability and low side effects, it might be particularly suited for patients to improve training motivation and training outcome e. g. the walking speed compared with treadmill training using no or only semi-immersive VR. Immersive VR systems still require specific technical setup procedures. This should be taken into account for specific clinical use-cases during a cost-benefit assessment.
Animal models are used to study neurobiological mechanisms in mental disorders. Although there has been significant progress in the understanding of neurobiological underpinnings of threat-related behaviors and anxiety, little progress was made with regard to new or improved treatments for mental disorders. A possible reason for this lack of success is the unknown predictive and cross-species translational validity of animal models used in preclinical studies. Re-translational approaches, therefore, seek to establish cross-species translational validity by identifying behavioral operations shared across species. To this end, we implemented a human open field test in virtual reality and measured behavioral indices derived from animal studies in three experiments (N=31, N=30, and N=80). In addition, we investigated the associations between anxious traits and such behaviors. Results indicated a strong similarity in behavior across species, i.e., participants in our study-like rodents in animal studies-preferred to stay in the outer region of the open field, as indexed by multiple behavioral parameters. However, correlational analyses did not clearly indicate that these behaviors were a function of anxious traits of participants. We conclude that the realized virtual open field test is able to elicit thigmotaxis and thus demonstrates cross-species validity of this aspect of the test. Modulatory effects of anxiety on human open field behavior should be examined further by incorporating possible threats in the virtual scenario and/or by examining participants with higher anxiety levels or anxiety disorder patients.
Acceptance-based regulation of pain, which focuses on the allowing of pain and pain related thoughts and emotions, was found to modulate pain. However, results so far are inconsistent regarding different pain modalities and indices. Moreover, studies so far often lack a suitable control condition, focus on behavioral pain measures rather than physiological correlates, and often use between-subject designs, which potentially impede the evaluation of the effectiveness of the strategies. Therefore, we investigated whether acceptance-based strategies can reduce subjective and physiological markers of acute pain in comparison to a control condition in a within-subject design. To this end, participants (N = 30) completed 24 trials comprising 10 s of heat pain stimulation. Each trial started with a cue instructing participants to welcome and experience pain (acceptance trials) or to react to the pain as it is without employing any regulation strategies (control trials). In addition to pain intensity and unpleasantness ratings, heart rate (HR) and skin conductance (SC) were recorded. Results showed significantly decreased pain intensity and unpleasantness ratings for acceptance compared to control trials. Additionally, HR was significantly lower during acceptance compared to control trials, whereas SC revealed no significant differences. These results demonstrate the effectiveness of acceptance-based strategies in reducing subjective and physiological pain responses relative to a control condition, even after short training. Therefore, the systematic investigation of acceptance in different pain modalities in healthy and chronic pain patients is warranted.
Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.
Context conditioning is characterized by unpredictable threat and its generalization may constitute risk factors for panic disorder (PD). Therefore, we examined differences between individuals with panic attacks (PA; N = 21) and healthy controls (HC, N = 22) in contextual learning and context generalization using a virtual reality (VR) paradigm. Successful context conditioning was indicated in both groups by higher arousal, anxiety and contingency ratings, and increased startle responses and skin conductance levels (SCLs) in an anxiety context (CTX+) where an aversive unconditioned stimulus (US) occurred unpredictably vs. a safety context (CTX−). PA compared to HC exhibited increased differential responding to CTX+ vs. CTX− and overgeneralization of contextual anxiety on an evaluative verbal level, but not on a physiological level. We conclude that increased contextual conditioning and contextual generalization may constitute risk factors for PD or agoraphobia contributing to the characteristic avoidance of anxiety contexts and withdrawal to safety contexts and that evaluative cognitive process may play a major role.