Acute Effects of Non-invasive Vagus Nerve Stimulation on Motivation and Its Dependency on Insulin Sensitivity in Patients With Depression and Controls
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 120
- 试验地点
- 2
- 主要终点
- tVNS-induced behavioral changes in invigoration
研究概览
简要总结
Disturbances in energy metabolism significantly increase the risk of developing major depressive disorder (MDD), especially in individuals with type 2 diabetes. Insulin sensitivity may particularly impair reward anticipation and motivational processes, contributing to anhedonia, a core symptom of depression. Preclinical and clinical studies highlight the vagus nerve as a critical pathway mediating metabolic signals between the body and the brain, influencing motivational and affective states.
The present study aims to evaluate whether acute transcutaneous auricular vagus nerve stimulation (taVNS) improves motivation and mood and whether individual differences in insulin sensitivity modulate these improvements.
The investigators plan to recruit 60 patients with MDD and 60 control participants matched for age, sex, and body mass index (BMI), covering a wide BMI range (up to 40 kg/m²) and insulin sensitivity (including patients with type 2 diabetes). Participants will undergo comprehensive metabolic assessments, behavioral testing of reward anticipation, motivation, consummation, and learning, and ecological momentary assessments (EMA) coupled with continuous glucose monitoring to assess real-world motivational behavior and glucose dynamics. Furthermore, participants will undergo two neuroimaging sessions, involving both task-free and task-based functional MRI, during concurrent taVNS or sham stimulation, implemented in a randomized, single-blinded, crossover design.
This study hypothesizes that individuals with lower insulin sensitivity, particularly those with MDD and pronounced anhedonic symptoms, will show greater motivational and neural responsiveness to taVNS.
H1A. Individuals with depression (vs. controls) and higher anhedonia show greater deficits in reward-related behavior and lower insulin sensitivity.
H1B. Across all participants, reduced reward-related behavior and higher anhedonia are associated with lower insulin sensitivity.
H2A. tVNS (vs. sham) increases motivation for rewards, brain responses to rewards, and body-brain interactions across participants.
H2B. These tVNS-induced effects are particularly pronounced in individuals with depression and stronger anhedonia who show reductions in these domains.
H3A. Greater tVNS-induced effects (behavioral, neural, body-brain) are associated with lower insulin sensitivity.
详细描述
To assess where individual reward deficits manifest, participants will undergo an intake session that includes clinical interviews, a fasting blood draw, and a battery of reward tasks (Reward Rating, Effort Allocation, Taste Test, Go-Nogo-Learning). Changes in symptoms and glucose levels will be evaluated using a wearable glucose sensor and ecological momentary assessments (EMA) over 2 weeks. To assess insulin sensitivity, the investigators will perform an oral glucose tolerance test, with concurrent stimulation (tVNS vs. sham; i.e., two sessions, randomized). Finally, in two neuroimaging sessions, the investigators will assess the effect of acute tVNS (vs. sham; randomized) on motivation and stomach-brain coupling using concurrent functional magnetic resonance imaging (fMRI) and electrogastrography (EGG). Washout between tVNS/sham days will be a minimum of 2 days. Condition order will be randomized, and the design is single-blind (participant).
To characterize our sample, the investigators will also collect information using standardized questionnaires assessing personality traits, eating behavior, psychiatric symptoms, and physical activity. To further characterize our sample metabolically, the investigators will also collect blood samples to determine metabolic parameters (e.g., acyl-ghrelin, des-acyl ghrelin, insulin, glucose, triglycerides, HDL, LDL), and participants can opt in to collect data for genetic analyses as part of a Biobank. These measures will be used to describe the sample and will be explored as predictors to explain inter-individual intervention effects.
- Personality traits related to reward and motivation: Behavioral Inhibition/Activation System
- Eating behavior: Three Factor Eating Questionnaire
- Psychiatric symptoms: depressive symptoms and anhedonia (BDI-II; Snaith-Hamilton Pleasure Scale, German version, SHAPS-D; Temporal Experience of Pleasure Scale, TEPS; Dimensional Anhedonia Rating Scale, DARS).
- Physical activity: International Physical Activity Questionnaire (IPAQ).
During the EMA period, participants will measure changes in glucose using a continuous glucose monitor (CGM) using the Freestyle Libre 3 sensor. Participants will answer questions with respect to:
- state ratings (e.g. hunger, mood)
- anticipated rewarding activities (wanting, time planned)
- consummated rewarding activities (liking, time spent)
- as well as complete a food choice task.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Single (Participant)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Participants with depression (DSM-5 diagnosis) or participants without depression (no DSM-5 diagnosis, lifetime)
- •BMI between 18.5 and 40 kg/m²
- •Age between 18 and 60 years
- •Legally valid informed consent
排除标准
- •The following diagnoses in medical history:
- •Brain injury
- •Schizophrenia
- •Bipolar disorder
- •Severe substance use disorder
- •Coronary heart disease
- •Chronic inflammatory diseases (e.g., rheumatoid arthritis, Crohn's disease, etc.)
- •Type I diabetes
- •The following diagnoses within 12 months prior to the experiment:
- •Obsessive-compulsive disorder
- •Somatic symptom disorder
- •Eating disorder
- •The following diagnoses in medical history for control participants:
- •Depression
- •Anxiety disorders (except specific phobias)
- •Contraindications for MRI (e.g., metal implants, claustrophobia) or taVNS (e.g., piercings, sore or diseased skin on the outer right ear)
- •Pregnant and breastfeeding women will not be included
- •Unclear capacity to consent
- •Stomach surgeries affecting body weight (e.g., bypass surgeries)
结局指标
主要结局
tVNS-induced behavioral changes in invigoration
时间窗: During MRI scan of effort allocation task (20 minutes), tVNS vs. sham session
The primary outcome of interest is the invigoration related to monetary and food rewards, which will be operationalized via the relative effort exerted on a grip force device using the effort allocation task. Invigoration is captured by the slope of the initial approach (i.e., the increase of force until a first plateau is reached). Invigoration will be compared between groups (CP, MDD) and stimulation conditions (tVNS, sham), and will be associated with insulin sensitivity. We will also investigate how effects on invigoration compare to effects on effort maintenance as well as on the association between ratings (i.e., wanting and exertion) during the effort task from the Intake session and effort (i.e., their correspondence expressed as slopes).
tVNS-induced changes in brain responses
时间窗: During MRI scan of effort allocation task (20 minutes), tVNS vs. sham session
Brain activity (BOLD signal) in response to monetary and food rewards and during exerting effort on a grip force device will be analyzed by focusing on brain regions associated with the vagal afferent pathway. Brain activity will be compared between groups (CP, MDD) and stimulation conditions (tVNS, sham), and will be associated with insulin sensitivity.
Association of insulin sensitivity with anhedonia severity
时间窗: oGTT (120 minutes)
Here, insulin sensitivity (Matsuda ISI) is considered a predictor variable, and the primary outcome is the association coefficient with anhedonia (SHAPS).
Association of insulin sensitivity with motivation during an effort allocation task
时间窗: ~40 minutes during Intake Session
Here, insulin sensitivity (Matsuda ISI) is considered a predictor variable, and the primary outcome is the association coefficient with invigoration, which will be operationalized via the relative effort (frequency button presses, controller) using the effort allocation task. Invigoration is captured by the slope of the initial approach (i.e., the increase of force until a first plateau is reached). Motivation will be compared between groups (CP, MDD), and in association with anhedonia, insulin-sensitivity. We will also investigate effects on effort maintenance and subjective ratings during the effort task (i.e., wanting and exertion) as well as the association between ratings and effort (slopes).
次要结局
- tVNS-induced changes in peripheral Insulin Sensitivity (oGTT)(oGTT (120 minutes), tVNS vs. sham sessions)
- tVNS-induced changes in stomach-brain coupling(During MRI scan (up to 120 minutes))
- tVNS-induced changes in gastric motility(During MRI scan (up to 120 minutes))
- tVNS-induced changes in positive and negative affect(Before and after tVNS (vs. sham) stimulation (for oGTT, at the end of a 120 minutes stimulation period; for neuroimaging at the end of a 40 minutes stimulation period).)
- Association of insulin sensitivity with anticipation of daily rewarding activities(During 2 week period, 2 times daily.)
- Association of insulin sensitivity with consummation of daily rewarding activities(During 2 week period, 2 times daily.)
- Association of insulin sensitivity with anticipatory reward ratings(~40 minutes task during Intake Session)
- Association of insulin sensitivity with consummatory reward responses(~35 minutes during Intake Session)
- Association of insulin sensitivity with learning during a Go-noGo-learning Task(~20 minutes during Intake)
- Association of insulin sensitivity with daily choices between food rewards(~2 weeks, ~2 times daily EMA period)
- tVNS-induced effects in interstitial glucose(120 minminutes during an OGTT, tVNS vs. sham)
- tVNS-induced changes in brain responses during task-free fMRI(10 minutes baseline (pre-stimulation) and 10 minutes stimulation (tVNS vs. sham) during MRI scan; task-free (inscapes).)
- tVNS-induced changes in functional connectivity(10 minutes baseline (pre-stimulation) and 10 minutes stimulation (tVNS vs. sham) during task-free MRI.)
- tVNS-induced changes in effort maintenance(During MRI scan of effort allocation task (20 minutes), tVNS vs. sham session)
- Association of insulin sensitivity with continuous glucose monitoring(CGM data from EMA period (2 weeks))
- Association of continuous glucose monitoring and hunger ratings as a measure of interoceptive accuracy(CGM data from EMA period (2 weeks))
研究者
Dr. Nils B. Kroemer
Prof. Dr. rer. nat.
University Hospital, Bonn