Elemental and configural representation of a conditioned context.

A context can be conceptualized as a stable arrangement of elements or as the sum of single elements. Both configural and elemental representations play a role in associative processes. This study aimed to explore the respective contributions of these two representations of a context in the acquisition of conditioned anxiety in humans. Virtual reality (VR) can be an ecologically valid tool to investigate context-related mechanisms, yet the influence of the sense of presence within the virtual environment remains unclear. Forty-eight healthy individuals participated in a VR-based context conditioning wherein electric shocks (unconditioned stimulus, US) were unpredictably delivered in one virtual office (CTX+), but not in the other (CTX-). During the test phase, nine elements from each context were presented singularly. We found a cluster of participants, who exhibited heightened anticipation of the US for anxiety-related elements as compared to the other group. In contrast to their clear elemental representation, these individuals showed diminished discriminative responses between the two context's configurations. Discriminative responses to the contexts were boosted in those individuals, who had a weaker elemental representation. Importantly, the individual sense of presence significantly influenced the conditioned responses. These findings align with the dual-representation view of context and provide insights into the role of presence in eliciting (conditioned) anxiety responses.

Trauma history and course of therapy in a naturalistic cognitive behavior therapy outpatient sample: An archive data study.

OBJECTIVE: Cognitive Behavior Therapy (CBT) is an effective treatment for anxiety and depression disorders. Nonetheless, nearly 50% of all patients do not respond. Besides other factors, nonresponse may be linked to traumatic life events. This study aims to assess the relationship between trauma history, applied therapy interventions, and therapy outcomes. METHODS: We analyzed data from 340 CBT outpatients diagnosed with a depression or anxiety disorder and possibly a trauma history treated under naturalistic conditions. Based on their therapy files, we collected information on trauma history, diagnoses, applied interventions, and severity of depression and anxiety symptoms at the start and end of therapy. The relationship between trauma, diagnoses, and intervention use and the development of depression and anxiety symptoms was analyzed using Linear Mixed Models. RESULTS: Patients with a trauma history reported higher pre- and posttreatment symptom severity than those without trauma. No differences in applied interventions or decrease in symptom severity were found between patients with and without a trauma history. Specialized interventions were seldom applied. CONCLUSION: Although no differences between patients with and without a trauma history were found in therapy response, patients with a trauma history maintained higher levels of symptom severity. These results indicate a need for more personalized interventions and evidence-based guidelines to personalize CBT for patients with a trauma history and high symptom severity.

Context-Dependent Responses to the Spread of COVID-19 Among National and International Students During the First Lockdown: An Online Survey.

BACKGROUND: Restrictions to minimize social contact was necessary to prevent the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus but may have impacted individuals' mental well-being. Emotional responses are modulated by contextual information. Living abroad during the coronavirus disease 2019 (COVID-19) pandemic may have boosted the feeling of isolation as the context is unfamiliar. OBJECTIVES: This study compared the psychological impact of social distancing in national students (living in a familiar context) versus international students (living in an unfamiliar context). METHODS: During March/April 2020 (first lockdown in the Netherlands), 850 university students completed an online survey. Structural equation modeling (SEM) was conducted to compare how students' responses to the virus were predicted by health anxiety, emotional distress, and personal traits. RESULTS: Compared with national students, international students showed higher levels in 4 identified factors (COVID-19-related worry, perceived risk of infection, distance from possibly contaminated objects, distance from social situations). The factors were mainly predicted by health anxiety across international students, while emotional distress and individual traits (eg, intolerance of uncertainty) played a role across national students. CONCLUSIONS: In the familiar context, individual characteristics (traits) predicted the responses to the virus, while the unfamiliar context drove individuals' health-focused responses. Living in a foreign country is associated with psychological burdens and this should be considered by universities for more pronounced social support and clear references to health-related institutions.

Examining the impact of cue similarity and fear learning on perceptual tuning.

Past research on the effects of associative aversive learning on discrimination acuity has shown mixed results, including increases, decreases, and no changes in discrimination ability. An animal study found that the type of learning experience determined the direction and extent of learning-induced changes. The current preregistered web-based study aimed to translate these findings to humans. Experiment 1 (N = 245) compared changes in stimulus discrimination between simple learning (only one oriented grating cue), coarse differential conditioning (physically distinct cues), and fine differential conditioning (physically similar cues) as well as to their three respective control groups. The discrimination task consisted of a two-alternative-forced-choice task with oriented grating stimuli. During learning, a specific orientation was paired with unpleasant pictures. Our analysis using generative modeling demonstrated weak to moderate evidence that aversive learning did not alter discrimination acuity in any of the groups. In a follow-up experiment (N = 121), we replicated these findings despite successful learning trajectories in all three groups and a more detailed assessment of discrimination acuity. Contrary to prior assumptions, our findings indicate that aversive learning does not enhance perceptual discrimination, and the presence of additional safety cues does not appear to moderate this effect.

VR for Studying the Neuroscience of Emotional Responses.

Emotions are frequently considered as the driving force of behavior, and psychopathology is often characterized by aberrant emotional responding. Emotional states are reflected on a cognitive-verbal, physiological-humoral, and motor-behavioral level but to date, human research lacks an experimental protocol for a comprehensive and ecologically valid characterization of such emotional states. Virtual reality (VR) might help to overcome this situation by allowing researchers to study mental processes and behavior in highly controlled but reality-like laboratory settings. In this chapter, we first elucidate the role of presence and immersion as requirements for eliciting emotional states in a virtual environment and discuss different VR methods for emotion induction. We then consider the organization of emotional states on a valence continuum (i.e., from negative to positive) and on this basis discuss the use of VR to study threat processing and avoidance as well as reward processing and approach behavior. Although the potential of VR has not been fully realized in laboratory and clinical settings yet, this technological tool can open up new avenues to better understand the neurobiological mechanisms of emotional responding in healthy and pathological conditions.

Investigating sustained attention in contextual threat using steady-state VEPs evoked by flickering video stimuli.

Anxiety is characterized by anxious anticipation and heightened vigilance to uncertain threat. However, if threat is not reliably indicated by a specific cue, the context in which threat was previously experienced becomes its best predictor, leading to anxiety. A suitable means to induce anxiety experimentally is context conditioning: In one context (CTX+), an unpredictable aversive stimulus (US) is repeatedly presented, in contrast to a second context (CTX-), in which no US is ever presented. In this EEG study, we investigated attentional mechanisms during acquisition and extinction learning in 38 participants, who underwent a context conditioning protocol. Flickering video stimuli (32 s clips depicting virtual offices representing CTX+/-) were used to evoke steady-state visual evoked potentials (ssVEPs) as an index of visuocortical engagement with the contexts. Analyses of the electrocortical responses suggest a successful induction of the ssVEP signal by video presentation in flicker mode. Furthermore, we found clear indices of context conditioning and extinction learning on a subjective level, while cortical processing of the CTX+ was unexpectedly reduced during video presentation. The differences between CTX+ and CTX- diminished during extinction learning. Together, these results indicate that the dynamic sensory input of the video presentation leads to disruptions in the ssVEP signal, which is greater for motivationally significant, threatening contexts.

The effect of inherently threatening contexts on visuocortical engagement to conditioned threat.

Fear and anxiety are crucial for adaptive responding in life-threatening situations. Whereas fear is a phasic response to an acute threat accompanied by selective attention, anxiety is characterized by a sustained feeling of apprehension and hypervigilance during situations of potential threat. In the current literature, fear and anxiety are usually considered mutually exclusive, with partially separated neural underpinnings. However, there is accumulating evidence that challenges this distinction between fear and anxiety, and simultaneous activation of fear and anxiety networks has been reported. Therefore, the current study experimentally tested potential interactions between fear and anxiety. Fifty-two healthy participants completed a differential fear conditioning paradigm followed by a test phase in which the conditioned stimuli were presented in front of threatening or neutral contextual images. To capture defense system activation, we recorded subjective (threat, US-expectancy), physiological (skin conductance, heart rate) and visuocortical (steady-state visual evoked potentials) responses to the conditioned stimuli as a function of contextual threat. Results demonstrated successful fear conditioning in all measures. In addition, threat and US-expectancy ratings, cardiac deceleration, and visuocortical activity were enhanced for fear cues presented in threatening compared with neutral contexts. These results are in line with an additive or interactive rather than an exclusive model of fear and anxiety, indicating facilitated defensive behavior to imminent danger in situations of potential threat.

Responsivity of the Striatal Dopamine System to Methylphenidate-A Within-Subject I-123-ß-CIT-SPECT Study in Male Children and Adolescents With Attention-Deficit/Hyperactivity Disorder.

Background: Methylphenidate (MPH) is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). MPH binds to the dopamine (DA) transporter (DAT), which has high density in the striatum. Assessments of the striatal dopamine transporter by single positron emission computed tomography (SPECT) in childhood and adolescent patients are rare but can provide insight on how the effects of MPH affect DAT availability. The aim of our within-subject study was to investigate the effect of MPH on DAT availability and how responsivity to MPH in DAT availability is linked to clinical symptoms and cognitive functioning. Methods: Thirteen adolescent male patients (9-16 years) with a diagnosis of ADHD according to the DSM-IV and long-term stimulant medication (for at least 6 months) with MPH were assessed twice within 7 days using SPECT after application of I-123-ß-CIT to examine DAT binding potential (DAT BP). SPECT measures took place in an on- and off-MPH status balanced for order across participants. A virtual reality continuous performance test was performed at each time point. Further clinical symptoms were assessed for baseline off-MPH. Results: On-MPH status was associated with a highly significant change (-29.9%) of striatal DAT BP as compared to off-MPH (t = -4.12, p = 0.002). A more pronounced change in striatal DAT BP was associated with higher off-MPH attentional and externalizing symptom ratings (Pearson r = 0.68, p = 0.01). Striatal DAT BP off-MPH, but not on-MPH, was associated with higher symptom ratings (Pearson r = 0.56, p = 0.04). Conclusion: Our findings corroborate previous reports from mainly adult samples that MPH changes striatal DAT BP availability and suggest higher off-MPH DAT BP, likely reflecting low baseline DA levels, as a marker of symptom severity.

The skin conductance response indicating pain relief is independent of self or social influence on pain.

Pain relief is defined as the ease of pain and is thus highly relevant for clinical applications and everyday life. Given that pain relief is based on the cessation of an aversive pain experience, it is reasonable to assume that pain relief learning would also be shaped by factors that alter subjective and physiological pain responses, such as social presence or a feeling of control. To date, it remains unclear whether and how factors that shape autonomic pain responses might affect pain relief learning. Here, we investigated how pain relief learning is shaped by two important factors known to modulate pain responses, i.e. social influence and controllability of pain. Skin conductance responses (SCRs) were recorded while participants learned to associate a formerly neutral stimulus with pain relief under three different pain conditions. In the social-influence condition (N = 34), the pain stimulation could be influenced by another person's decisions. In the self-influence condition (N = 31), the participants themselves could influence the pain stimulation. Finally, in the no-influence condition (N = 32), pain stimulation was simply delivered without any influence. According to our results, the SCRs elicited by the stimulus that was associated with pain relief were significantly smaller compared to the SCRs elicited by a neutral control stimulus, indicating pain relief learning. However, there was no significant difference in the pain relief learning effect across the groups. These results suggest that physiological pain relief learning in humans is not significantly influenced by social influence and pain controllability.

Fear conditioning and stimulus generalization in association with age in children and adolescents.

The aim of the study was to investigate age-related differences in fear learning and generalization in healthy children and adolescents (n = 133), aged 8-17 years, using an aversive discriminative fear conditioning and generalization paradigm adapted from Lau et al. (2008). In the current task, participants underwent 24 trials of discriminative conditioning of two female faces with neutral facial expressions, with (CS+) or without (CS-) a 95-dB loud female scream, presented simultaneously with a fearful facial expression (US). The discriminative conditioning was followed by 72 generalization trials (12 CS+, 12 GS1, 12 GS2, 12 GS3, 12 GS4, and 12 CS-): four generalization stimuli depicting gradual morphs from CS+ to CS- in 20%-steps were created for the generalization phases. We hypothesized that generalization in children and adolescents is negatively correlated with age. The subjective ratings of valence, arousal, and US expectancy (the probability of an aversive noise following each stimulus), as well as skin conductance responses (SCRs) were measured. Repeated-measures ANOVAs on ratings and SCR amplitudes were calculated with the within-subject factors stimulus type (CS+, CS-, GS1-4) and phase (Pre-Acquisition, Acquisition 1, Acquisition 2, Generalization 1, Generalization 2). To analyze the modulatory role of age, we additionally calculated ANCOVAs considering age as covariate. Results indicated that (1) subjective and physiological responses were generally lower with increasing age irrespective to the stimulus quality, and (2) stimulus discrimination improved with increasing age paralleled by reduced overgeneralization in older individuals. Longitudinal follow-up studies are required to analyze fear generalization with regard to brain maturational aspects and clarify whether overgeneralization of conditioned fear promotes the development of anxiety disorders or vice versa.

Contextual modulation of conditioned responses in humans: A review on virtual reality studies.

Conditioned response (CRs) triggered by stimuli predicting aversive consequences have been confirmed across various species including humans, and were found to be exaggerated in anxious individuals and anxiety disorder patients. Importantly, contextual information may strongly modulate such conditioned responses (CR), however, there are several methodological boundaries in the translation of animal findings to humans, and from healthy individuals to patients. Virtual Reality (VR) is a useful technological tool for overcoming such boundaries. In this review, we summarize and evaluate human VR conditioning studies exploring the role of the context as conditioned stimulus or occasion setter for CRs. We observe that VR allows successful acquisition of conditioned anxiety and conditioned fear in response to virtual contexts and virtual cues, respectively. VR studies also revealed that spatial or temporal contextual information determine whether conditioned anxiety and conditioned fear become extinguished and/or return. Novel contexts resembling the threatening context foster conditioned fear but not conditioned anxiety, suggesting distinct context-related generalization processes. We conclude VR contexts are able to strongly modulate CRs and therefore allow a comprehensive investigation of the modulatory role of the context over CR in humans leading to conclusions relevant for non-VR and clinical studies.

Social cognitive factors outweigh negative emotionality in predicting COVID-19 related safety behaviors.

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.

Associative learning shapes visual discrimination in a web-based classical conditioning task.

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.

Reducing Generalization of Conditioned Fear: Beneficial Impact of Fear Relevance and Feedback in Discrimination Training.

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.

The role of intolerance of uncertainty in the acquisition and extinction of reward.

Individuals, who score high in self-reported intolerance of uncertainty (IU), tend to find uncertainty anxiety-provoking. IU has been reliably associated with disrupted threat extinction. However, it is unclear whether IU would be related to disrupted extinction to other arousing stimuli that are not threatening (i.e., rewarding). We addressed this question by conducting a Pavlovian reward conditioning task with acquisition and extinction training phases (n = 58). In the Pavlovian reward conditioning task, we recorded liking ratings, skin conductance response (SCR), and corrugator supercilii activity (i.e., brow muscle indicative or negative and positive affect) to learned reward (CS+) and neutral (CS-) cues. Typical patterns of reward acquisition and extinction training were observed for liking ratings. There was evidence for conditioning in SCR during the extinction training phase but not the acquisition training phase. However, no evidence of conditioning in either the acquisition or extinction training phase was observed for the corrugator supercilii. IU was not related to any measures during the acquisition or extinction training phases. Taken together, these results suggest that the current Pavlovian reward conditioning task was not sufficient for eliciting a reliable conditioned reward response, and therefore, further research with optimized reward conditioning designs are required to test whether IU-related deficits occur during the extinction of reward.

Brain-Derived Neurotrophic Factor/Tropomyosin Receptor Kinase B Signaling Controls Excitability and Long-Term Depression in Oval Nucleus of the BNST.

Dysregulation of proteins involved in synaptic plasticity is associated with pathologies in the CNS, including psychiatric disorders. The bed nucleus of the stria terminalis (BNST), a brain region of the extended amygdala circuit, has been identified as the critical hub responsible for fear responses related to stress coping and pathologic systems states. Here, we report that one particular nucleus, the oval nucleus of the BNST (ovBNST), is rich in brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) receptor. Whole-cell patch-clamp recordings of neurons from male mouse ovBNST in vitro showed that the BDNF/TrkB interaction causes a hyperpolarizing shift of the membrane potential from resting value, mediated by an inwardly rectifying potassium current, resulting in reduced neuronal excitability in all major types of ovBNST neurons. Furthermore, BDNF/TrkB signaling mediated long-term depression (LTD) at postsynaptic sites in ovBNST neurons. LTD of ovBNST neurons was prevented by a BDNF scavenger or in the presence of TrkB inhibitors, indicating the contribution to LTD induction. Our data identify BDNF/TrkB signaling as a critical regulator of synaptic activity in ovBNST, which acts at postsynaptic sites to dampen excitability at short and long time scales. Given the central role of ovBNST in mediating maladaptive behaviors associated with stress exposure, our findings suggest a synaptic entry point of the BDNF/TrkB system for adaptation to stressful environmental encounters.

Context-dependent generalization of conditioned responses to threat and safety signals.

Contextual information can modulate the conditioned response to a threat signal (conditioned stimulus, CS+): fear responses are either potentiated or attenuated depending on whether the context is threatening or safe. In this study, we investigated the influence of context on conditioned fear as well as on generalization of conditioned fear. Thirty-two participants underwent a cue-in-context learning protocol in virtual reality (VR). On Day 1 (acquisition), participants received a mild painful electric shock (unconditioned stimulus, US) in one virtual room (fear context, CTX+) at the offset of one colored light (CS+), but never at the offset of another colored light (CS-). In a second room (safety context, CTX-), the two lights were also presented, but not the US. Successful cue conditioning was indicated by aversive ratings and startle potentiation but not skin conductance responses (SCR) to CS+ versus CS- in CTX+ and not in CTX-. On Day 2 (generalization), participants re-visited both fear and safety contexts plus a generalization context (G-CTX), which was an equal mix of CTX+ and CTX-. The two CSs were shown again in all three contexts. Generalization of conditioned fear was revealed in affective ratings (CS+ was rated more aversive than CS- in G-CTX), but not in physiological measures (equal startle potentiation to CS+ versus CS- in all contexts). In sum, contextual information modulates the responses to a threat signal such that a safety context can inhibit conditioned fear. Interestingly, generalization processes also depend on contextual information.

Conjunctive and Elemental Representations of a Context in Humans.

The dual-process theory assumes that contexts are encoded in an elemental and in a conjunctive representation. However, this theory was developed from animal studies, and we still have to explore if and how elemental and conjunctive representations contribute to, for example, contextual anxiety in humans. Therefore, 28 participants underwent differential context conditioning in a newly developed flip-book paradigm. Virtual rooms were presented similar to a flip-book, that is, as a stream of 49 consecutive screenshots creating the impression of walking through the rooms. This allowed registration of event-related brain potentials triggered by specific screenshots. During two acquisition phases, two rooms were shown in this way for six times each. In one room, the anxiety context (CTX+), mildly painful electric stimuli (unconditioned stimuli [USs]) were administered unpredictably after 12 distinct screenshots, which became threat elements, whereas 12 selected comparable screenshots became nonthreat elements (elemental representation); all screenshots represented the anxiety context (conjunctive representation). In the second room, the safety context (CTX-), no USs were applied; thus, all screenshots created the safety context whereby 12 preselected screenshots represented safety elements. Increased US expectancy ratings for threat versus nonthreat or safety elements reflected elemental representation. Conjunctive representation was evident in differential ratings (arousal and contingency) and increased P100 and early posterior negativity amplitudes for threat and nonthreat CTX+ versus safety CTX- screenshots. These differences disappeared during two test phases without US delivery indicating successful extinction. In summary, we revealed the first piece of evidence for the simultaneous contributions of elemental and conjunctive representation during context conditioning in humans.

Generalization of Conditioned Contextual Anxiety and the Modulatory Effects of Anxiety Sensitivity.

Anxiety patients overgeneralize fear responses, possibly because they cannot distinguish between cues never been associated with a threat (i.e., safe) and threat-associated cues. However, as contexts and not cues are discussed as the relevant triggers for prolonged anxiety responses characterizing many anxiety disorders, we speculated that it is rather overgeneralization of contextual anxiety, which constitutes a risk factor for anxiety disorders. To this end, we investigated generalization of conditioned contextual anxiety and explored modulatory effects of anxiety sensitivity, a risk factor for anxiety disorders. Fifty-five participants underwent context conditioning in a virtual reality paradigm. On Day 1 (acquisition), participants received unpredictable mildly painful electric stimuli (unconditioned stimulus, US) in one virtual office (anxiety context, CTX+), but never in a second office (safety context, CTX-). Successful acquisition of conditioned anxiety was indicated by aversive ratings and defensive physiological responses (i.e., SCR) to CTX+ vs CTX-. On Day 2 (generalization), participants re-visited both the anxiety and the safety contexts plus three generalization contexts (G-CTX), which were gradually dissimilar to CTX+ (from 75 to 25%). Generalization of conditioned anxiety was evident for ratings, but less clear for physiological responses. The observed dissociation between generalization of verbal and physiological responses suggests that these responses depend on two distinct context representations, likely elemental and contextual representations. Importantly, anxiety sensitivity was positively correlated with the generalization of reported contextual anxiety. Thus, this study demonstrates generalization gradients for conditioned contextual anxiety and that anxiety sensitivity facilitates such generalization processes suggesting the importance of generalization of contextual anxiety for the development of anxiety disorders.

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020).

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice.