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.
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: 1. 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. 2. Neural correlates of approach-avoidance (phenotyping) A subset of participants (high anxiety, high anhedonia, combined, and healthy controls (STICSA \< 40 and/or 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. 3. 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: 1. 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. 2. 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. 3. A hungry state will reduce anxiety-like behavior and increase the approach of rewards. 4. 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. 5. 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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
SINGLE
Enrollment
104
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.
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.
University Hospital Bonn, Bonn, Germany
Bonn, Germany
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).
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: During each stimulation session (tVNS and sham) throughout study completion (approximately 3 weeks)
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.
Time frame: 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.
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
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.
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
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.
Time frame: 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.
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
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.
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
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.
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)
The primary outcome is the comparison of time spent foraging (seconds) during the VR foraging task between stimulation conditions (tVNS vs. sham).
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)
The primary outcome is the comparison of escape latency (seconds) during the VR foraging task between stimulation conditions (tVNS vs. sham).
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)
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.
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)
The primary outcome is the comparison of heart rate recovery following threat response during the VR foraging task between stimulation conditions (tVNS vs. sham).
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)
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.
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)
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.
Time frame: 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.
Time frame: 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.
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)
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.
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)
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.
Time frame: 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).
Time frame: 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).
Time frame: 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.
Time frame: 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.
Time frame: 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).
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
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).
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
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.
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
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.
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
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.
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
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.
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
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.
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
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.
Time frame: 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.
Time frame: 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).
Time frame: Assessed online before lab-visits (approximately 10 days)
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