Healthy ParticipantsNCT07476469
tVNS and Approach-Avoidance Behavior in Anhedonia and Anxiety
A study testing tVNS in people with Healthy Participants and Anxiety Disorders (With High Anxiety Symptoms), run by Dr. Nils B. Kroemer at 1 site in Germany.
Trial summary
This study investigates if anhedonia and anxiety symptoms are associated with alterations in reinforcement learning, effort trade-offs for wins vs. punishments, and foraging behavior under threat. Read more about this study
- Who is it for?
- Ages 18 to 40 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy Participants, Anxiety Disorders (With High Anxiety Symptoms), Depressive Disorders (With High Anhedonia Symptoms)
- What is being tested?
- tVNS
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 104 participants
- Where
- 1 siteGermany
- Study dates
- 23 Mar 2026to 31 Dec 2028
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 40 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- BMI between 18,5 and 30,0 kg/m2,
- between 18 and 40 years of age, and
- be able and willing to provide informed consent.
Who cannot join
- have a high risk of suicide,
- have a lifetime diagnosis of severe neurological disorder (incl. ADHD), schizophrenia, bipolar disorder, or severe substance abuse, posttraumatic stress disorder, obsessive-compulsive disorder, diabetes, epilepsy, or coronary heart disease
- have fulfilled criteria for an eating disorder or somatic symptom disorder within the last 12-months,
- take medication (except psychopharmacological medication for MDD or anxiety), patients have to be on stable psychopharmacological medication for at least two months before study participation (minimizing confounding effects)
- contraindications for MRI (metal implants or claustrophobia)
- for female individuals if they are pregnant or nursing at the time,
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- impaired movement ability or hearing
- impaired, uncorrected vision (need contact lenses)
- contraindications for tVNS hearing aids or diseased skin on the right ear.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Germany1 site, 1 recruiting
- Recruiting
University Hospital Bonn, Bonn, Germany
Bonn, 53127
Prof. Dr. rer. nat. Nils Kroemer, +49 228 28719123, nkroemer@uni-bonn.de
About this study
Official title: Vagus Nerve Stimulation and Approach-Avoidance Behavior in Anhedonia and Anxiety
This study investigates if anhedonia and anxiety symptoms are associated with alterations in reinforcement learning, effort trade-offs for wins vs. punishments, and foraging behavior under threat. Moreover, it will investigate whether these processes can be influenced by a metabolic load and/or transcutaneous vagus nerve stimulation (tVNS). The project consists of (a) an online reinforcement learning study, used to characterize learning, reward sensitivity, and meta-cognition, and (b) a laboratory study in which participants first undergo fMRI while completing an effort-based decision-making task. Second, participants will complete two sessions in VR with randomized active or sham tVNS during a foraging task before and after a caloric load with concurrent physiological recordings.
Read the detailed description
The overarching goal of this project is to investigate the potential of modulating internal signals in patients with mood and anxiety disorders to improve the balance between approach and avoidance behavior. To this end, tVNS (vs. sham) will be used to alter foraging behavior under threat.
To address the inherent heterogeneity of symptoms, it is planned to recruit participants with anxiety symptoms (ANX), anhedonia symptoms (ANH), both anxiety and mood symptoms (ANX+ANH), and healthy control participants (HCP). The groups will be matched for the group-average and distribution of age, sex, and BMI (age: 18 to 40 years, BMI 18.5 - 30 kg/m²). After an online assessment, diagnostic visit, and MRl-based phenotyping, internal signals are targeted with tVNS and a caloric load to shift the approach-avoidance behavior. In a randomized crossover study, participants will receive stimulation (tVNS or sham) in a hungry state (>4 h after the last meal at a time when they would typically have their next meal) and complete a VR-based foraging task under threat. They will then receive a standardized caloric load (milkshake containing ~400 kcal) and repeat the task with the same stimulation in a different metabolic state (postprandial). Crucially, participants can move freely during the task so that behavioral adaptations in response to threats (e.g., escaping a panther) as well as physiological adaptations (e.g., heart rate) and their recovery can be measured.
The study is split into three parts:
- Online screening and behavioral characterization At least 250 participants (≥150 with clinically relevant symptoms; STICSA >= 43 and/or SHAPS > 29.5) will complete baseline questionnaires (anhedonia (SHAPS, TEPS, and DARS), anxiety (STICSA and STAI), depression (BDI), substance abuse) and an approx. two weeks online reinforcement learning task (10 runs). Behavioral indices (choices, response times) and computational modeling parameters (e.g., learning rates, reward sensitivity, decision noise) will be derived. At the end of each run, participants provide metacognitive performance ratings, enabling assessment of deviations between subjective and objective performance.
- Neural correlates of approach-avoidance (phenotyping) A subset of participants (high anxiety, high anhedonia, combined, and healthy controls (STICSA <= 40 and SHAPS < 23.5); ~26 per group) will undergo laboratory-based testing. Assessments include diagnostic interviews, fasting blood samples (glucose, insulin, triglycerides, cortisol), and fMRI during an effort trade-off task comparing the effort to gain rewards and to avoid punishments.
- tVNS intervention The same participants will then complete a randomized, sham-controlled crossover trial. Participants will perform a VR foraging task under threat in two metabolic states: hungry (>4 h fasted) and postprandial (following a standardized caloric load ~400kcal). During both states, participants will receive either active or sham tVNS. Behavioral outcomes will be combined with physiological measures (e.g., heart rate) to assess the effects of vagal stimulation on approach-avoidance trade-offs.
Hypotheses:
- Patients with more severe anxiety symptoms are more sensitive to punishments. Thus, they spend less time foraging under threat and gain fewer rewards. In contrast, patients with more severe anhedonia symptoms are less sensitive to rewards. Thus, their overall foraging rate will be lower, leading to fewer rewards independent of threat.
- Behavioral and self-rated differences in learning from rewards and punishments are reflected in altered brain responses when making effort-based choices to either approach rewards or avoid punishments.
- A hungry state will reduce anxiety-like behavior and increase the approach of rewards.
- tVNS will enhance the anxiolytic effects of hunger by increasing the weight on internal signals of metabolic demand, facilitating the approach of rewards. In contrast, it will facilitate avoidance in a postprandial state.
- Inter-individual differences in the balance between motivational and threat-related circuits during the effort trade off task will predict tVNS effects when foraging.
Enrollment:
In the online assessment, at least 250 participants will be included to investigate differences in learning from wins and losses and how well behavioral shifts align with self-evaluation of performance. The sample size allows detecting even small effects that are likely in psychiatric research (r = .20) with a high power (1-β = 0.89). If necessary, further participants will be recruited for the online sample until the planned sample of N=104 participants has completed the tVNS intervention. For the phenotyping and the subsequent intervention study, 104 participants from 4 groups combining low/high anxiety and low/high anhedonia will be reinvited. With this transdiagnostic approach, the effects of anhedonia and anxiety on approach-avoid behavior can be disentangled. Crucially, oversampling participants with either high or low symptoms will maximize the expected effect size. The sample allows for evaluation of medium correlations (r = .30) between symptoms and approach-avoid trade-offs with a power of 1-β = 0.89. For the tVNS intervention, a sample of 104 participants allows for the conclusive study of medium-sized effects (dz = .40) observed in previous work (Neuser et al., 2020) with very high power (1-β = 0.98) across the sample. Differences in the tVNS response between participants (medium effect size, r = .30) can be evaluated with a power of 1-β = 0.89.
- Conditions
- Healthy Participants, Anxiety Disorders (With High Anxiety Symptoms), Depressive Disorders (With High Anhedonia Symptoms), Comorbid Depression and Anxiety Disorder (With High Anhedonia and High Anxiety Symptoms)
- Being tested
- tVNS, Sham
- Keywords
- Depression, Anhedonia, Anxiety, Vagusnerv-Stimulation, tVNS, Virtual Reality, fMRI
- Medical subject headings
- Anxiety Disorders, Depressive Disorder, Depression, Anhedonia
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
tVNSDevice
The intervention consists of event-triggered tVNS in the form of short pulses (~1-5s; frequency: 25Hz). A non-CE-certified and non-medical device (tVNS® R tVNS technologies, for research purposes) will be used. Stimulation intensity will be individually calibrated to ensure perceptible (mild pricking) but non-painful stimulation for each participant. The protocol is the same for all groups.
ShamDevice
The sham condition similarly consists of event-triggered, closed-loop stimulation, but without vagus nerve activation (short pulses of 1-5s; frequency: 25Hz). A non-CE-certified and non-medical device (tVNS® R, for research purposes) will be used. The manufacturer is not involved in the study. Stimulation intensity will be individually calibrated to ensure perceptible (mild pricking) but non-painful stimulation for each participant. The protocol is the same for all groups.
| Study group | Role | What they receive |
|---|---|---|
| Healthy Controls | Experimental | The healthy control group will include participants without clinically relevant symptoms of anxiety or anhedonia. Inclusion criteria are a STICSA total score <= 40 and a SHAPS total score below 23.5. Participants in this group must not meet the criteria for a current psychiatric diagnosis defined in the exclusion criteria, as confirmed by the Structured Clinical Interview for DSM (SCID). Receives: Device: tVNS; Device: Sham |
| Anxiety | Experimental | The anxiety group will include participants with elevated anxiety symptoms, defined as a STICSA total score >= 43. All participants must meet diagnostic criteria for a current anxiety disorder or/and current depressive disorder, confirmed by the SCID. Receives: Device: tVNS; Device: Sham |
| Anhedonia | Experimental | The anhedonia group will include participants with elevated anhedonia symptoms, defined as a SHAPS total score greater than 29.5. All participants must meet diagnostic criteria for a current depressive disorder or/and current anxiety disorder, confirmed by the SCID. Receives: Device: tVNS; Device: Sham |
| Comorbid anhedonia and anxiety | Experimental | The combined group will include participants with both elevated anxiety and anhedonia symptoms, defined as STICSA >= 43 and SHAPS > 29.5, respectively. All participants must meet diagnostic criteria for a current anxiety disorder or/and a current depressive disorder, confirmed by the SCID. Receives: Device: tVNS; Device: Sham |
What is being measured
The primary outcome is the main question the study is designed to answer.
Stimulation-induced changes in the number of rewards collected under threat (VR foraging task)
The number of rewards collected during a VR foraging task will be compared between stimulation conditions (tVNS vs. sham).
Measured: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
BOLD response during the effort-trade-off task (offer-phase)
The outcome describes task-evoked neural activation (BOLD response) during the offer phase of the effort trade-off task.
Neural activation is measured as a task-evoked BOLD response during offer presentation.
Measured: Collected during fMRI session (single session throughout study completion ~35min per participant)
Reward learning
Reward learning is repeatedly measured during an online bandit task with fluctuating reward probabilities.
Reward learning behavior will be collected online in 10 runs spread over 5 to 10 days, each including 150 trials.
Measured: Online task performance assessed online before lab-visits (approximately 10 days)
Metabolic state x stimulation-induced changes in the number of rewards collected under threat (VR task)
The number of rewards collected during a VR foraging task will be compared between two different metabolic states (fasted vs. postprandial) and stimulation conditions (tVNS vs. sham).
Measured: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
Secondary outcomes (31)
BOLD response during the effort-trade-off task (feedback-phase)
The outcome describes task-evoked neural activation (BOLD response) during the feedback phase of the effort trade-off task.
Neural activation is measured as a task-evoked BOLD response during feedback presentation.
Measured: Collected during fMRI session (single session throughout study completion ~35min per participant)
Choices in the effort trade-off task
Choices in the effort trade-off task will be assessed as a binary outcome of accept vs. reject.
Measured: During a single fMRI session throughout study completion (approximately 3 weeks)
Association between BOLD response during the effort-trade-off task (offer-phase) and effort discounting
The primary outcome is the association (regression coefficient) quantifying the relationship between effort discounting and neural activation (BOLD response) during the offer-phase of an effort trade-off task.
Neural activation is measured as a task-evoked BOLD response during offer presentation. Effort discounting is estimated from behavioral choices in the effort trade-off task using computational modeling.
Measured: During a single fMRI session throughout study completion (approximately 3 weeks)
Association between BOLD response during the effort-trade-off task (feedback phase) and effort-discounting
The primary outcome is the association (regression coefficient) quantifying the relationship between effort-discounting and neural activation (BOLD response) during the feedback phase of an effort trade-off task.
Neural activation is measured as task-evoked BOLD response during feedback presentation.Effort-discounting is estimated from behavioral choices in the effort trade-off task using computational modeling.
Measured: During a single fMRI session throughout study completion (approximately 3 weeks)
Effort-discounting
The outcome describes effort-discounting derived from the effort trade-off task.
Effort-discounting is estimated from behavioral choices in the effort trade-off task using computational modeling.
Measured: During a single fMRI session throughout study completion (approximately 3 weeks)
Association between BOLD responses during effort trade-offs and number of rewards during VR
The primary outcome is the association (regression coefficient) quantifying the relationship between individual differences in foraging during VR and task-evoked neural connectivity.
Task-evoked BOLD responses during the effort trade-off task is measured using functional magnetic resonance imaging (fMRI). Foraging in the VR task is the number of rewards collected.
Measured: Neural data: During a single fMRI session throughout study completion (approximately 3 weeks); Behavioral data: During sham stimulation session throughout study completion (approximately 3 weeks)
Association between neural connectivity and number of rewards during VR
The primary outcome is the association (regression coefficient) quantifying the relationship between individual differences in effort-discounting and task-evoked neural connectivity.
Task-evoked neural connectivity during the effort trade-off task is measured using functional magnetic resonance imaging (fMRI). Neural connectivity is quantified as region-of-interest-level functional connectivity. The number of rewards is measured in the VR foraging task.
Measured: Neural data: During a single fMRI session throughout study completion (approximately 3 weeks); Behavioral data: During sham stimulation sessions throughout study completion (approximately 3 weeks)
Stimulation-induced changes in time spent foraging under threat (VR foraging task)
The primary outcome is the comparison of time spent foraging (seconds) during the VR foraging task between stimulation conditions (tVNS vs. sham).
Measured: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
Stimulation-induced changes in escape latency under threat (VR foraging task)
The primary outcome is the comparison of escape latency (seconds) during the VR foraging task between stimulation conditions (tVNS vs. sham).
Measured: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
Stimulation-induced changes in threat-evoked heart rate increase (VR foraging task)
The primary outcome is the comparison of heart rate increases following threat during the VR foraging task between active vs. sham tVNS.
Autonomic responses to threat are operationalized as the change in heart rate from a pre-threat baseline period (safety period preceding the trial) to the first minute following threat onset.
Measured: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
Stimulation-induced changes in heart rate recovery following threat (VR foraging task)
The primary outcome is the comparison of heart rate recovery following threat response during the VR foraging task between stimulation conditions (tVNS vs. sham).
Measured: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
Stimulation-induced changes in habituation of heart rate responses following threat (VR foraging task)
The primary outcome is the comparison of habituation of heart rate response following threat over trials during the VR foraging task between active vs. sham tVNS.
Measured: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
Stimulation-induced changes in subjective metabolic state (VR foraging task)
The primary outcome is the comparison of the change in subjective metabolic state after receiving a caloric load between stimulation conditions (tVNS vs. sham).
Subjective metabolic state assessed during a VR foraging task using 0-100 Visual Analog Scales (VAS) of hunger and satiety. A metabolic state score is calculated as the difference between hunger and satiety ratings, scaled from -1 to 1 ((hunger-satiety)/100). The difference will then be compared between stimulation conditions.
Measured: During each stimulation session (tVNS vs. sham) throughout study completion (approximately 3 weeks)
Stimulation-induced changes in affect (PANAS)
The primary outcome is the comparison of affect between stimulation conditions (tVNS vs. sham).
Affective state is assessed using the Positive and Negative Affect Schedule (PANAS), administered as Visual Analog Scales (0-100). A composite affect score (positive - negative affect) is calculated from positive and negative affect ratings.
Measured: During each stimulation session (tVNS vs. sham) throughout study completion (approximately 3 weeks)
Metabolic state x stimulation-induced changes in affect (PANAS)
The primary outcome is the comparison of affect between metabolic state (fasted vs. postprandial) and stimulation condition (tVNS vs. sham). The primary analysis examines the interaction between metabolic state and stimulation condition.
Affective state is assessed using the Positive and Negative Affect Schedule (PANAS), administered as Visual Analog Scales (0-100). A composite affect score (positive - negative affect) is calculated from positive and negative affect ratings.
Measured: During each stimulation session (tVNS vs. sham) throughout study completion (approximately 3 weeks)
Metabolic state x stimulation-induced changes in time spent foraging under threat (VR task)
The primary outcome is the comparison of time spent foraging (seconds) during a VR foraging task between metabolic state (fasted vs. postprandial) and stimulation condition (tVNS vs. sham). The primary analysis examines the interaction between metabolic state and stimulation condition.
Measured: During each stimulation session (active and sham) throughout study completion (approximately 3 weeks)
Metabolic state x stimulation-induced changes in escape latency under threat (VR task)
The primary outcome is the comparison of escape latency (seconds) during a VR foraging task between metabolic state (fasted vs. postprandial) and stimulation condition (tVNS vs. sham). The primary analysis examines the interaction between metabolic state and stimulation condition.
Measured: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
Response times in the online task
The outcome describes response times collected during the online task.
Response times (milliseconds) are collected in trials of the online reward learning task (10 runs with 150 each).
Measured: Assessed online before lab-visits (approximately 10 days)
Choice accuracy in the online task
Choice accuracy (binary correct vs. incorrect) is derived from trials of the online reward learning task (10 runs with 150 each).
Measured: Assessed online before lab-visits (approximately 10 days)
Metacognitive calibration (performance-rating coupling)
The outcome describes metacognitive calibration in a reward learning task.
Self-reported ratings are collected at the end of each run (10 runs) on a Visual Analog Scale (0-100 Visual Analog Scale) assessing subjective performance. Higher values represent better subjective performance. A metacognitive calibration score will be calculated as the difference between self-reported performance and objective task performance.
Measured: Assessed online before lab-visits (approximately 10 days)
Ecological Momentary Assessments (EMA) for mood
The outcome describes a mood state score calculated from data collected during the online reward learning task.
EMA questions (0-100 Visual Analog Scale) assessing mood state (happy and sad) will be asked before every run of the online task (10 runs). Mood state will be calculated as happy - sad.
Measured: Assessed online before lab-visits (approximately 10 days)
Ecological Momentary Assessments (EMA) for stress
The outcome describes the stress rating of participants collected during the online reward learning task.
EMA question (0-100 Visual Analog Scale) assessing subjective stress will be asked before every run of the online task (10 runs).
Measured: Assessed online before lab-visits (approximately 10 days); EMA data: Collected before every online session (x 10)
Association between Ecological Momentary Assessments (EMA) and response times in the online task
The primary outcome is the association (regression coefficient) quantifying the relationship between mood state and response times.
Response times (seconds) are derived from trials of the online reward learning task (10 runs with 150 trials each). EMA questions (0-100 Visual Analog Scale) assessing mood (happy - sad) are asked before every run of the online task (10 runs).
Measured: Assessed online before lab-visits (approximately 10 days)
Association between BOLD response during the effort-trade-off task and tVNS-induced changes in the number of rewards collected
The primary outcome is the association (regression coefficient) quantifying the relationship between neural activity and behavioral tVNS response.
tVNS response is defined as the within-subject change in the number of rewards collected during VR foraging under active vs sham tVNS. Neural activation is measured as task-evoked BOLD response.
Measured: Neural markers: Collected during fMRI session (single session, ~30 min per participant); Behavioral data: Collected during VR sessions with two visits per participant (throughout study completion, approx. 3 weeks)
Association between neural connectivity and tVNS-induced changes in number of rewards collected
The primary outcome is the association (regression coefficient) quantifying the relationship between neural connectivity and behavioral tVNS response.
Behavioral response is defined as the within-subject change in the number of rewards collected during VR foraging under tVNS vs sham. Neural connectivity markers derived from fMRI-testing will be used to assess how neural connectivity explains interindividual variability in behavioral tVNS response.
Measured: Neural markers: Collected during fMRI session (single session, ~30 min per participant); Behavioral data: Collected during VR sessions with two visits per participant (throughout study completion, approx. 3 weeks)
Associations between baseline cortisol and neural activation
The primary outcome is the association (regression coefficient) quantifying the relationship between cortisol and BOLD response during the effort-trade-off task.
Morning serum cortisol will be collected after an overnight fast at the laboratory visit immediately before the MRI session and quantified in nmol/L (expected range approx. 140-690nmol/L). Neural activation is measured as task-evoked BOLD response.
Measured: Blood draw: Collected before the MRI session; Neural activation: During a single MRI session throughout study completion (approx. 3 weeks)
Association between baseline cortisol and tVNS-induced changes in the number of rewards collected
The primary outcome is the association (regression coefficient) quantifying the relationship between cortisol and behavioral tVNS response.
Morning serum cortisol will be collected after an overnight fast at the laboratory visit immediately before the MRI session and quantified in nmol/L (expected range approx. 140-690nmol/L). Behavioral response is defined as the within-subject change in number of rewards collected during VR foraging under active vs sham tVNS.
Measured: Blood draw: Collected before the MRI session, Behavioral data: Collected during VR sessions with two visits per participant (throughout study completion, approx. 3 weeks)
Association between insulin resistance and BOLD response during the effort-trade-off task
The primary outcome is the association (regression coefficient) quantifying the relationship between the value of insulin resistance and neural activation (BOLD responses) during an effort-trade-off-task.
Neural activation is measured as task-evoked BOLD response.
Insulin resistance is assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), calculated from fasting plasma insulin and glucose concentrations obtained from morning blood samples.
Measured: Blood samples and neural activation assessed during a single MRI session throughout study completion (approximately 3 weeks)
Association between insulin resistance and tVNS-induced changes in number of rewards collected
The primary outcome is the association (regression coefficient) quantifying the relationship between insulin resistance and behavioral stimulation response during a VR foraging task.
Behavioral response to tVNS is measured as the change in the number of rewards collected under threat during a VR foraging task. Insulin resistance is assessed using the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), calculated from fasting plasma insulin and glucose concentrations obtained from morning blood samples.
Measured: Behavioral outcomes and biomarker measures assessed throughout study completion (approximately 3 weeks)
BMI (Body-Mass-Index)
Body mass index will be included as a covariate in analyses involving metabolic, neural, and behavioral outcomes.
Measured: Collected throughout study completion (approximately 3 weeks)
Association between Ecological Momentary Assessments (EMA) and reward learning in the online task
The primary outcome is the association (regression coefficient) quantifying the relationship between mood state and reward learning.
Reward learning is measured in the online reward learning task (10 runs with 150 trials each). EMA questions (0-100 Visual Analog Scale) assessing mood (happy - sad) are asked before every run of the online task (10 runs).
Measured: Assessed online before lab-visits (approximately 10 days)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Mar 2026
- Study start23 Mar 2026
- Primary completion31 Dec 2027 (estimated)
- Study completion31 Dec 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Healthy ParticipantsStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 104 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Dr. Nils B. Kroemer
- Sponsor type
- University, hospital or other
- Collaborators
- University of Bonn, Else Kröner Fresenius Foundation
- Responsible party
- Sponsor-investigator, Dr. Nils B. Kroemer, University of Bonn
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07476469
- Sponsor's protocol ID
- BON008
- Other IDs
- 2024_EKEA.149
- Status last verified
- Mar 2026
- First submitted
- 13 Feb 2026
- Last updated
- 23 Apr 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: After the publication of the key results of the study, anonymized data will be made publicly available (e.g., at osf.org)
Publications
Neuser MP, Teckentrup V, Kuhnel A, Hallschmid M, Walter M, Kroemer NB. Vagus nerve stimulation boosts the drive to work for rewards. Nat Commun. 2020 Jul 16;11(1):3555. doi: 10.1038/s41467-020-17344-9.
PubMed 32678082
Study at a glance
From the registry record, last updated by the sponsor on 23 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Vagus Nerve Stimulation and Approach-Avoidance Behavior in Anhedonia and Anxiety
- ClinicalTrials.gov ID
- NCT07476469
- Acronym / sponsor ID
- BON008
- Conditions
- Healthy Participants, Anxiety Disorders (With High Anxiety Symptoms), Depressive Disorders (With High Anhedonia Symptoms), Comorbid Depression and Anxiety Disorder (With High Anhedonia and High Anxiety Symptoms)
- Keywords
- Depression, Anhedonia, Anxiety, Vagusnerv-Stimulation, tVNS, Virtual Reality, fMRI
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 104 participants (estimated)
- Lead sponsor
- Dr. Nils B. KroemerUniversity, hospital or other
- Collaborators
- University of Bonn, Else Kröner Fresenius Foundation
- Study start
- 23 Mar 2026 (actual)
- Primary completion
- 31 Dec 2027 (estimated)
- Study completion
- 31 Dec 2028 (estimated)
- First posted
- 17 Mar 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This study investigates if anhedonia and anxiety symptoms are associated with alterations in reinforcement learning, effort trade-offs for wins vs. punishments, and foraging behavior under threat. Moreover, it will investigate whether these processes can be influenced by a metabolic load and/or transcutaneous vagus nerve stimulation (tVNS). The project consists of (a) an online reinforcement learning study, used to characterize learning, reward sensitivity, and meta-cognition, and (b) a laboratory study in which participants first undergo fMRI while completing an effort-based decision-making task. Second, participants will complete two sessions in VR with randomized active or sham tVNS during a foraging task before and after a caloric load with concurrent physiological recordings.
Detailed description
The overarching goal of this project is to investigate the potential of modulating internal signals in patients with mood and anxiety disorders to improve the balance between approach and avoidance behavior. To this end, tVNS (vs. sham) will be used to alter foraging behavior under threat.
To address the inherent heterogeneity of symptoms, it is planned to recruit participants with anxiety symptoms (ANX), anhedonia symptoms (ANH), both anxiety and mood symptoms (ANX+ANH), and healthy control participants (HCP). The groups will be matched for the group-average and distribution of age, sex, and BMI (age: 18 to 40 years, BMI 18.5 - 30 kg/m²). After an online assessment, diagnostic visit, and MRl-based phenotyping, internal signals are targeted with tVNS and a caloric load to shift the approach-avoidance behavior. In a randomized crossover study, participants will receive stimulation (tVNS or sham) in a hungry state (>4 h after the last meal at a time when they would typically have their next meal) and complete a VR-based foraging task under threat. They will then receive a standardized caloric load (milkshake containing ~400 kcal) and repeat the task with the same stimulation in a different metabolic state (postprandial). Crucially, participants can move freely during the task so that behavioral adaptations in response to threats (e.g., escaping a panther) as well as physiological adaptations (e.g., heart rate) and their recovery can be measured.
The study is split into three parts:
- Online screening and behavioral characterization At least 250 participants (≥150 with clinically relevant symptoms; STICSA >= 43 and/or SHAPS > 29.5) will complete baseline questionnaires (anhedonia (SHAPS, TEPS, and DARS), anxiety (STICSA and STAI), depression (BDI), substance abuse) and an approx. two weeks online reinforcement learning task (10 runs). Behavioral indices (choices, response times) and computational modeling parameters (e.g., learning rates, reward sensitivity, decision noise) will be derived. At the end of each run, participants provide metacognitive performance ratings, enabling assessment of deviations between subjective and objective performance.
- Neural correlates of approach-avoidance (phenotyping) A subset of participants (high anxiety, high anhedonia, combined, and healthy controls (STICSA <= 40 and SHAPS < 23.5); ~26 per group) will undergo laboratory-based testing. Assessments include diagnostic interviews, fasting blood samples (glucose, insulin, triglycerides, cortisol), and fMRI during an effort trade-off task comparing the effort to gain rewards and to avoid punishments.
- tVNS intervention The same participants will then complete a randomized, sham-controlled crossover trial. Participants will perform a VR foraging task under threat in two metabolic states: hungry (>4 h fasted) and postprandial (following a standardized caloric load ~400kcal). During both states, participants will receive either active or sham tVNS. Behavioral outcomes will be combined with physiological measures (e.g., heart rate) to assess the effects of vagal stimulation on approach-avoidance trade-offs.
Hypotheses:
- Patients with more severe anxiety symptoms are more sensitive to punishments. Thus, they spend less time foraging under threat and gain fewer rewards. In contrast, patients with more severe anhedonia symptoms are less sensitive to rewards. Thus, their overall foraging rate will be lower, leading to fewer rewards independent of threat.
- Behavioral and self-rated differences in learning from rewards and punishments are reflected in altered brain responses when making effort-based choices to either approach rewards or avoid punishments.
- A hungry state will reduce anxiety-like behavior and increase the approach of rewards.
- tVNS will enhance the anxiolytic effects of hunger by increasing the weight on internal signals of metabolic demand, facilitating the approach of rewards. In contrast, it will facilitate avoidance in a postprandial state.
- Inter-individual differences in the balance between motivational and threat-related circuits during the effort trade off task will predict tVNS effects when foraging.
Enrollment:
In the online assessment, at least 250 participants will be included to investigate differences in learning from wins and losses and how well behavioral shifts align with self-evaluation of performance. The sample size allows detecting even small effects that are likely in psychiatric research (r = .20) with a high power (1-β = 0.89). If necessary, further participants will be recruited for the online sample until the planned sample of N=104 participants has completed the tVNS intervention. For the phenotyping and the subsequent intervention study, 104 participants from 4 groups combining low/high anxiety and low/high anhedonia will be reinvited. With this transdiagnostic approach, the effects of anhedonia and anxiety on approach-avoid behavior can be disentangled. Crucially, oversampling participants with either high or low symptoms will maximize the expected effect size. The sample allows for evaluation of medium correlations (r = .30) between symptoms and approach-avoid trade-offs with a power of 1-β = 0.89. For the tVNS intervention, a sample of 104 participants allows for the conclusive study of medium-sized effects (dz = .40) observed in previous work (Neuser et al., 2020) with very high power (1-β = 0.98) across the sample. Differences in the tVNS response between participants (medium effect size, r = .30) can be evaluated with a power of 1-β = 0.89.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Single blind (participant)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Healthy Controls | Experimental | Device: tVNS, Device: ShamThe healthy control group will include participants without clinically relevant symptoms of anxiety or anhedonia. Inclusion criteria are a STICSA total score <= 40 and a SHAPS total score below 23.5. Participants in this group must not meet the criteria for a current psychiatric diagnosis defined in the exclusion criteria, as confirmed by the Structured Clinical Interview for DSM (SCID). |
| Anxiety | Experimental | Device: tVNS, Device: ShamThe anxiety group will include participants with elevated anxiety symptoms, defined as a STICSA total score >= 43. All participants must meet diagnostic criteria for a current anxiety disorder or/and current depressive disorder, confirmed by the SCID. |
| Anhedonia | Experimental | Device: tVNS, Device: ShamThe anhedonia group will include participants with elevated anhedonia symptoms, defined as a SHAPS total score greater than 29.5. All participants must meet diagnostic criteria for a current depressive disorder or/and current anxiety disorder, confirmed by the SCID. |
| Comorbid anhedonia and anxiety | Experimental | Device: tVNS, Device: ShamThe combined group will include participants with both elevated anxiety and anhedonia symptoms, defined as STICSA >= 43 and SHAPS > 29.5, respectively. All participants must meet diagnostic criteria for a current anxiety disorder or/and a current depressive disorder, confirmed by the SCID. |
Who may qualify
- Ages
- 18 to 40 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (3 listed)
- BMI between 18,5 and 30,0 kg/m2,
- between 18 and 40 years of age, and
- be able and willing to provide informed consent.
Key exclusion criteria (9 listed)
- have a high risk of suicide,
- have a lifetime diagnosis of severe neurological disorder (incl. ADHD), schizophrenia, bipolar disorder, or severe substance abuse, posttraumatic stress disorder, obsessive-compulsive disorder, diabetes, epilepsy, or coronary heart disease
- have fulfilled criteria for an eating disorder or somatic symptom disorder within the last 12-months,
- take medication (except psychopharmacological medication for MDD or anxiety), patients have to be on stable psychopharmacological medication for at least two months before study participation (minimizing confounding effects)
- contraindications for MRI (metal implants or claustrophobia)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| tVNSThe intervention consists of event-triggered tVNS in the form of short pulses (~1-5s; frequency: 25Hz). A non-CE-certified and non-medical device (tVNS® R tVNS technologies, for research purposes) will be used. Stimulation intensity will be individually calibrated to ensure perceptible (mild pricking) but non-painful stimulation for each participant. The protocol is the same for all groups. | Device | Anhedonia, Anxiety, Comorbid anhedonia and anxiety, Healthy Controls |
| ShamThe sham condition similarly consists of event-triggered, closed-loop stimulation, but without vagus nerve activation (short pulses of 1-5s; frequency: 25Hz). A non-CE-certified and non-medical device (tVNS® R, for research purposes) will be used. The manufacturer is not involved in the study. Stimulation intensity will be individually calibrated to ensure perceptible (mild pricking) but non-painful stimulation for each participant. The protocol is the same for all groups. | Device | Anhedonia, Anxiety, Comorbid anhedonia and anxiety, Healthy Controls |
Primary outcome
Stimulation-induced changes in the number of rewards collected under threat (VR foraging task)
Time frame: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
The number of rewards collected during a VR foraging task will be compared between stimulation conditions (tVNS vs. sham).
BOLD response during the effort-trade-off task (offer-phase)
Time frame: Collected during fMRI session (single session throughout study completion ~35min per participant)
The outcome describes task-evoked neural activation (BOLD response) during the offer phase of the effort trade-off task. Neural activation is measured as a task-evoked BOLD response during offer presentation.
Reward learning
Time frame: Online task performance assessed online before lab-visits (approximately 10 days)
Reward learning is repeatedly measured during an online bandit task with fluctuating reward probabilities. Reward learning behavior will be collected online in 10 runs spread over 5 to 10 days, each including 150 trials.
Metabolic state x stimulation-induced changes in the number of rewards collected under threat (VR task)
Time frame: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
The number of rewards collected during a VR foraging task will be compared between two different metabolic states (fasted vs. postprandial) and stimulation conditions (tVNS vs. sham).
31 secondary outcomes
BOLD response during the effort-trade-off task (feedback-phase)
Time frame: Collected during fMRI session (single session throughout study completion ~35min per participant)
Choices in the effort trade-off task
Time frame: During a single fMRI session throughout study completion (approximately 3 weeks)
Association between BOLD response during the effort-trade-off task (offer-phase) and effort discounting
Time frame: During a single fMRI session throughout study completion (approximately 3 weeks)
Association between BOLD response during the effort-trade-off task (feedback phase) and effort-discounting
Time frame: During a single fMRI session throughout study completion (approximately 3 weeks)
Effort-discounting
Time frame: During a single fMRI session throughout study completion (approximately 3 weeks)
Association between BOLD responses during effort trade-offs and number of rewards during VR
Time frame: Neural data: During a single fMRI session throughout study completion (approximately 3 weeks); Behavioral data: During sham stimulation session throughout study completion (approximately 3 weeks)
Association between neural connectivity and number of rewards during VR
Time frame: Neural data: During a single fMRI session throughout study completion (approximately 3 weeks); Behavioral data: During sham stimulation sessions throughout study completion (approximately 3 weeks)
Stimulation-induced changes in time spent foraging under threat (VR foraging task)
Time frame: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
Stimulation-induced changes in escape latency under threat (VR foraging task)
Time frame: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
Stimulation-induced changes in threat-evoked heart rate increase (VR foraging task)
Time frame: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
Stimulation-induced changes in heart rate recovery following threat (VR foraging task)
Time frame: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
Stimulation-induced changes in habituation of heart rate responses following threat (VR foraging task)
Time frame: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
Stimulation-induced changes in subjective metabolic state (VR foraging task)
Time frame: During each stimulation session (tVNS vs. sham) throughout study completion (approximately 3 weeks)
Stimulation-induced changes in affect (PANAS)
Time frame: During each stimulation session (tVNS vs. sham) throughout study completion (approximately 3 weeks)
Metabolic state x stimulation-induced changes in affect (PANAS)
Time frame: During each stimulation session (tVNS vs. sham) throughout study completion (approximately 3 weeks)
Metabolic state x stimulation-induced changes in time spent foraging under threat (VR task)
Time frame: During each stimulation session (active and sham) throughout study completion (approximately 3 weeks)
Metabolic state x stimulation-induced changes in escape latency under threat (VR task)
Time frame: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
Response times in the online task
Time frame: Assessed online before lab-visits (approximately 10 days)
Choice accuracy in the online task
Time frame: Assessed online before lab-visits (approximately 10 days)
Metacognitive calibration (performance-rating coupling)
Time frame: Assessed online before lab-visits (approximately 10 days)
Ecological Momentary Assessments (EMA) for mood
Time frame: Assessed online before lab-visits (approximately 10 days)
Ecological Momentary Assessments (EMA) for stress
Time frame: Assessed online before lab-visits (approximately 10 days); EMA data: Collected before every online session (x 10)
Association between Ecological Momentary Assessments (EMA) and response times in the online task
Time frame: Assessed online before lab-visits (approximately 10 days)
Association between BOLD response during the effort-trade-off task and tVNS-induced changes in the number of rewards collected
Time frame: Neural markers: Collected during fMRI session (single session, ~30 min per participant); Behavioral data: Collected during VR sessions with two visits per participant (throughout study completion, approx. 3 weeks)
Association between neural connectivity and tVNS-induced changes in number of rewards collected
Time frame: Neural markers: Collected during fMRI session (single session, ~30 min per participant); Behavioral data: Collected during VR sessions with two visits per participant (throughout study completion, approx. 3 weeks)
Associations between baseline cortisol and neural activation
Time frame: Blood draw: Collected before the MRI session; Neural activation: During a single MRI session throughout study completion (approx. 3 weeks)
Association between baseline cortisol and tVNS-induced changes in the number of rewards collected
Time frame: Blood draw: Collected before the MRI session, Behavioral data: Collected during VR sessions with two visits per participant (throughout study completion, approx. 3 weeks)
Association between insulin resistance and BOLD response during the effort-trade-off task
Time frame: Blood samples and neural activation assessed during a single MRI session throughout study completion (approximately 3 weeks)
Association between insulin resistance and tVNS-induced changes in number of rewards collected
Time frame: Behavioral outcomes and biomarker measures assessed throughout study completion (approximately 3 weeks)
BMI (Body-Mass-Index)
Time frame: Collected throughout study completion (approximately 3 weeks)
Association between Ecological Momentary Assessments (EMA) and reward learning in the online task
Time frame: Assessed online before lab-visits (approximately 10 days)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Apr 2026.
- Background: PubMed 32678082Neuser MP, Teckentrup V, Kuhnel A, Hallschmid M, Walter M, Kroemer NB. Vagus nerve stimulation boosts the drive to work for rewards. Nat Commun. 2020 Jul 16;11(1):3555. doi: 10.1038/s41467-020-17344-9.
- Individual participant dataSharing planned: Yes. After the publication of the key results of the study, anonymized data will be made publicly available (e.g., at osf.org)
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing tVNS in people with Healthy Participants and Anxiety Disorders (With High Anxiety Symptoms), run by Dr. Nils B. Kroemer at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 23 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Dr. Anne Kühnel (+49 228 28711519, akuehnel@uni-bonn.de), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Stimulation-induced changes in the number of rewards collected under threat (VR foraging task) (time frame: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT07476469, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Apr 2026.