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The experience of threat was found to result—mostly—in increased pain, however it is still unclear whether the exact opposite, namely the feeling of safety may lead to a reduction of pain. To test this hypothesis, we conducted two between-subject experiments (N = 94; N = 87), investigating whether learned safety relative to a neutral control condition can reduce pain, while threat should lead to increased pain compared to a neutral condition. Therefore, participants first underwent either threat or safety conditioning, before entering an identical test phase, where the previously conditioned threat or safety cue and a newly introduced visual cue were presented simultaneously with heat pain stimuli. Methodological changes were performed in experiment 2 to prevent safety extinction and to facilitate conditioning in the first place: We included additional verbal instructions, increased the maximum length of the ISI and raised CS-US contingency in the threat group from 50% to 75%. In addition to pain ratings and ratings of the visual cues (threat, safety, arousal, valence, and contingency), in both experiments, we collected heart rate and skin conductance. Analysis of the cue ratings during acquisition indicate successful threat and safety induction, however results of the test phase, when also heat pain was administered, demonstrate rapid safety extinction in both experiments. Results suggest rather small modulation of subjective and physiological pain responses following threat or safety cues relative to the neutral condition. However, exploratory analysis revealed reduced pain ratings in later trials of the experiment in the safety group compared to the threat group in both studies, suggesting different temporal dynamics for threat and safety learning and extinction, respectively.
Perspective: The present results demonstrate the challenge to maintain safety in the presence of acute pain and suggest more research on the interaction of affective learning mechanism and pain processing.
Rationale: Social factors are considered important for the initiation and maintenance of drug abuse. Virtual reality (VR) research on cue reactivity and exposure frequently incorporates social stimuli as part of complex drug-intake scenarios. Attempts are rarely made to dissect the impact of the different components and their interactive effects. The present study critically extends this line of research by investigating the modulatory effects of social context on the reactivity evoked by proximal smoking cues.
Methods: Thirty-two smokers and 33 never-smokers were presented in VR with proximal cues and neutral stimuli, embedded in a social context or a neutral context. A virtual hand model was used to translate real hand movements into VR. Each trial started with the presentation of the different stimulus–context combinations. Discrete stimuli were presented on the table in front of the participants, and contextual stimuli were presented at the end of the table. Afterward, participants were instructed to grasp the target stimulus (a cigarette vs. a pencil) in front of them. After successful contact, the stimulus appeared in the virtual hand. Modulation of cue reactivity by social context was assessed by self-report, physiological measures, and overt approach behavior.
Results: The results revealed modulatory effects of social context on the responses to proximal smoking cues in smokers. In contrast to never-smokers, smoking cues evoked craving in smokers, which was attenuated in a social context. Furthermore, social context increased the latency to approach and contact the cigarette in the group of smokers but did not affect behavioral approach responses in never-smokers. Other data provided indications for interactive, but also main effects of cues and contexts. Interestingly, cue-evoked craving was increased after contact with the virtual cigarette.
Conclusion: The present study critically extends previous research by providing evidence for the modulation of cue reactivity by social context. The results are particularly important given the well-established role of drug-associated environmental contexts in the stimulus control of addictive behaviors. Our results emphasize the need to address social context effects on cue reactivity in basic research and treatment and further suggest that changes in the perceived availability of smoking might enhance or inhibit cue-evoked reactivity.
Pain-associated approach and avoidance behaviours are critically involved in the development and maintenance of chronic pain. Empirical research suggests a key role of operant learning mechanisms, and first experimental paradigms were developed for their investigation within a controlled laboratory setting. We introduce a new Virtual Reality paradigm to the study of pain-related behaviour and investigate pain experiences on multiple dimensions. The paradigm evaluates the effects of three-tiered heat-pain stimuli applied contingent versus non-contingent with three types of arm movements in naturalistic virtual sceneries. Behaviour, self-reported pain-related fear, pain expectancy and electrodermal activity were assessed in 42 healthy participants during an acquisition phase (contingent movement-pain association) and a modification phase (no contingent movement-pain association). Pain-associated approach behaviour, as measured by arm movements followed by a severe heat stimulus, quickly decreased in-line with the arm movement-pain contingency. Slower effects were observed in fear of movement-related pain and pain expectancy ratings. During the subsequent modification phase, the removal of the pain contingencies modified all three indices. In both phases, skin conductance responses resemble the pattern observed for approach behaviour, while skin conductance levels equal the pattern observed for the self-ratings. Our findings highlight a fast reduction in approach behaviour in the face of acute pain and inform about accompanying psychological and physiological processes. We discuss strength and limitations of our paradigm for future investigations with the ultimate goal of gaining a comprehensive understanding of the mechanisms involved in chronic pain development, maintenance, and its therapy.
Traditionally, adversity was defined as the accumulation of environmental events (allostatic load). Recently however, a mismatch between the early and the later (adult) environment (mismatch) has been hypothesized to be critical for disease development, a hypothesis that has not yet been tested explicitly in humans. We explored the impact of timing of life adversity (childhood and past year) on anxiety and depression levels (N = 833) and brain morphology (N = 129). Both remote (childhood) and proximal (recent) adversities were differentially mirrored in morphometric changes in areas critically involved in emotional processing (i.e. amygdala/hippocampus, dorsal anterior cingulate cortex, respectively). The effect of adversity on affect acted in an additive way with no evidence for interactions (mismatch). Structural equation modeling demonstrated a direct effect of adversity on morphometric estimates and anxiety/depression without evidence of brain morphology functioning as a mediator. Our results highlight that adversity manifests as pronounced changes in brain morphometric and affective temperament even though these seem to represent distinct mechanistic pathways. A major goal of future studies should be to define critical time periods for the impact of adversity and strategies for intervening to prevent or reverse the effects of adverse childhood life experiences.
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.
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.
Immersive virtual reality is a powerful method to modify the environment and thereby influence experience. The present study used a virtual hand illusion and context manipulation in immersive virtual reality to examine top-down modulation of pain. Participants received painful heat stimuli on their forearm and placed an embodied virtual hand (co-located with their real one) under a virtual water tap, which dispensed virtual water under different experimental conditions. We aimed to induce a temperature illusion by a red, blue or white light suggesting warm, cold or no virtual water. In addition, the sense of agency was manipulated by allowing participants to have high or low control over the virtual hand’s movements. Most participants experienced a thermal sensation in response to the virtual water and associated the blue and red light with cool/cold or warm/hot temperatures, respectively. Importantly, the blue light condition reduced and the red light condition increased pain intensity and unpleasantness, both compared to the control condition. The control manipulation influenced the sense of agency, but did not influence pain ratings. The large effects revealed in our study suggest that context effects within an embodied setting in an immersive virtual environment should be considered within VR based pain therapy.
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.
No abstract available.
Background: Although there is solid evidence for the efficacy of in vivo and virtual reality (VR) exposure therapy for a specific phobia, there is a significant debate over whether techniques promoting distraction or relaxation have impairing or enhancing effects on treatment outcome. In the present pilot study, we investigated the effect of diaphragmatic breathing (DB) as a relaxation technique during VR exposure treatment.
Method: Twenty-nine patients with aviophobia were randomly assigned to VR exposure treatment either with or without diaphragmatic breathing (six cycles per minute). Subjective fear ratings, heart rate and skin conductance were assessed as indicators of fear during both the exposure and the test session one week later.
Results: The group that experienced VR exposure combined with diaphragmatic breathing showed a higher tendency to effectively overcome the fear of flying. Psychophysiological measures of fear decreased and self-efficacy increased in both groups with no significant difference between the groups.
Conclusions: Our findings indicate that diaphragmatic breathing during VR exposure does not interfere with the treatment outcome and may even enhance treatment effects of VR exposure therapy for aviophobic patients.
Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction.
In classical conditioning, an initially neutral stimulus (conditioned stimulus, CS) becomes associated with a biologically salient event (unconditioned stimulus, US), which might be pain (aversive conditioning) or food (appetitive conditioning). After a few associations, the CS is able to initiate either defensive or consummatory responses, respectively. Contrary to aversive conditioning, appetitive conditioning is rarely investigated in humans, although its importance for normal and pathological behaviors (e.g., obesity, addiction) is undeniable. The present study intents to translate animal findings on appetitive conditioning to humans using food as an US. Thirty-three participants were investigated between 8 and 10 am without breakfast in order to assure that they felt hungry. During two acquisition phases, one geometrical shape (avCS+) predicted an aversive US (painful electric shock), another shape (appCS+) predicted an appetitive US (chocolate or salty pretzel according to the participants' preference), and a third shape (CS) predicted neither US. In a extinction phase, these three shapes plus a novel shape (NEW) were presented again without US delivery. Valence and arousal ratings as well as startle and skin conductance (SCR) responses were collected as learning indices. We found successful aversive and appetitive conditioning. On the one hand, the avCS+ was rated as more negative and more arousing than the CS and induced startle potentiation and enhanced SCR. On the other hand, the appCS+ was rated more positive than the CS and induced startle attenuation and larger SCR. In summary, we successfully confirmed animal findings in (hungry) humans by demonstrating appetitive learning and normal aversive learning.
Anxiety patients over-generalize fear, possibly because of an incapacity to discriminate threat and safety signals. Discrimination trainings are promising approaches for reducing such fear over-generalization. Here we investigated the efficacy of a fear-relevant vs. a fear-irrelevant discrimination training on fear generalization and whether the effects are increased with feedback during training. Eighty participants underwent two fear acquisition blocks, during which one face (conditioned stimulus, CS+), but not another face (CS−), was associated with a female scream (unconditioned stimulus, US). During two generalization blocks, both CSs plus four morphs (generalization stimuli, GS1–GS4) were presented. Between these generalization blocks, half of the participants underwent a fear-relevant discrimination training (discrimination between CS+ and the other faces) with or without feedback and the other half a fear-irrelevant discrimination training (discrimination between the width of lines) with or without feedback. US expectancy, arousal, valence ratings, and skin conductance responses (SCR) indicated successful fear acquisition. Importantly, fear-relevant vs. fear-irrelevant discrimination trainings and feedback vs. no feedback reduced generalization as reflected in US expectancy ratings independently from one another. No effects of training condition were found for arousal and valence ratings or SCR. In summary, this is a first indication that fear-relevant discrimination training and feedback can improve the discrimination between threat and safety signals in healthy individuals, at least for learning-related evaluations, but not evaluations of valence or (physiological) arousal.
Acrophobia is characterized by intense fear in height situations. Virtual reality (VR) can be used to trigger such phobic fear, and VR exposure therapy (VRET) has proven effective for treatment of phobias, although it remains important to further elucidate factors that modulate and mediate the fear responses triggered in VR. The present study assessed verbal and behavioral fear responses triggered by a height simulation in a 5-sided cave automatic virtual environment (CAVE) with visual and acoustic simulation and further investigated how fear responses are modulated by immersion, i.e., an additional wind simulation, and presence, i.e., the feeling to be present in the VE. Results revealed a high validity for the CAVE and VE in provoking height related self-reported fear and avoidance behavior in accordance with a trait measure of acrophobic fear. Increasing immersion significantly increased fear responses in high height anxious (HHA) participants, but did not affect presence. Nevertheless, presence was found to be an important predictor of fear responses. We conclude that a CAVE system can be used to elicit valid fear responses, which might be further enhanced by immersion manipulations independent from presence. These results may help to improve VRET efficacy and its transfer to real situations.
BACKGROUND:
Thigmotaxis refers to a specific behavior of animals (i.e., to stay close to walls when exploring an open space). Such behavior can be assessed with the open field test (OFT), which is a well-established indicator of animal fear. The detection of similar open field behavior in humans may verify the translational validity of this paradigm. Enhanced thigmotaxis related to anxiety may suggest the relevance of such behavior for anxiety disorders, especially agoraphobia.
METHODS:
A global positioning system was used to analyze the behavior of 16 patients with agoraphobia and 18 healthy individuals with a risk for agoraphobia (i.e., high anxiety sensitivity) during a human OFT and compare it with appropriate control groups (n = 16 and n = 19). We also tracked 17 patients with agoraphobia and 17 control participants during a city walk that involved walking through an open market square. RESULTS: Our human OFT triggered thigmotaxis in participants; patients with agoraphobia and participants with high anxiety sensitivity exhibited enhanced thigmotaxis. This behavior was evident in increased movement lengths along the wall of the natural open field and fewer entries into the center of the field despite normal movement speed and length. Furthermore, participants avoided passing through the market square during the city walk, indicating again that thigmotaxis is related to agoraphobia.
CONCLUSIONS:
This study is the first to our knowledge to verify the translational validity of the OFT and to reveal that thigmotaxis, an evolutionarily adaptive behavior shown by most species, is related to agoraphobia, a pathologic fear of open spaces, and anxiety sensitivity, a risk factor for agoraphobia.
Approach and avoidance of positive and negative social cues are fundamental to prevent isolation and ensure survival. High trait social anxiety is characterized by an avoidance of social situations and extensive avoidance is a risk factor for the development of social anxiety disorder (SAD). Therefore, experimental methods to assess social avoidance behavior in humans are essential. The social conditioned place preference (SCPP) paradigm is a well-established experimental paradigm in animal research that is used to objectively investigate social approach–avoidance mechanisms. We retranslated this paradigm for human research using virtual reality. To this end, 58 healthy adults were exposed to either a happy- or angry-looking virtual agent in a specific room, and the effects of this encounter on dwell time as well as evaluation of this room in a later test without an agent were examined. We did not observe a general SCPP effect on dwell time or ratings but discovered a moderation by trait social anxiety, in which participants with higher trait social anxiety spent less time in the room in which the angry agent was present before, suggesting that higher levels of trait social anxiety foster conditioned social avoidance. However, further studies are needed to verify this observation and substantiate an association with social anxiety disorder. We discussed the strengths, limitations, and technical implications of our paradigm for future investigations to more comprehensively understand the mechanisms involved in social anxiety and facilitate the development of new personalized treatment approaches by using virtual reality.
Analysis of structural brain asymmetries in attention‐deficit/hyperactivity disorder in 39 datasets
(2021)
Objective
Some studies have suggested alterations of structural brain asymmetry in attention‐deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left‐right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium.
Methods
We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries.
Results
There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from −0.18 to 0.18) and would not survive study‐wide correction for multiple testing.
Conclusion
Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.
Expectation and previous experience are both well established key mediators of placebo and nocebo effects. However, the investigation of their respective contribution to placebo and nocebo responses is rather difficult because most placebo and nocebo manipulations are contaminated by pre-existing treatment expectancies resulting from a learning history of previous medical interventions. To circumvent any resemblance to classical treatments, a purely psychological placebonocebo manipulation was established, namely, the "visual stripe pattern induced modulation of pain." To this end, experience and expectation regarding the effects of different visual cues (stripe patterns) on pain were varied across 3 different groups, with either only placebo instruction (expectation), placebo conditioning (experience), or both (expectation + experience) applied. Only the combined manipulation (expectation + experience) revealed significant behavioral and physiological placebo nocebo effects on pain. Two subsequent experiments, which, in addition to placebo and nocebo cues, included a neutral control condition further showed that especially nocebo responses were more easily induced by this psychological placebo and nocebo manipulation. The results emphasize the great effect of psychological processes on placebo and nocebo effects. Particularly, nocebo effects should be addressed more thoroughly and carefully considered in clinical practice to prevent the accidental induction of side effects.