Endocrinology · Medical Literature
tVNS and obesity-related inflammation: a prospective sham-controlled randomized crossover study protocol.
Abstract
Overweight and obesity are characterized by detrimental effects on energy metabolism and an increase in adipose tissue, leading to chronic low-grade inflammation. This metaflammation may contribute to mental symptoms, such as reduced mood and motivation. Inflammatory processes are modulated by the cholinergic anti-inflammatory pathway (CAIP) that can be targeted with vagus nerve stimulation (VNS). However, the effects of non-invasive transcutaneous VNS (tVNS) on inflammation have predominantly been investigated in small feasibility studies in humans. Whereas acute anti-inflammatory effects of tVNS have been reported, no study has investigated the effect of daily home-based application on obesity-related metaflammation to date. To assess tVNS-induced effects on inflammation, motivation, and mood, we are conducting a single-blind, randomized crossover study in participants with an elevated BMI (target N = 60, 27-35 kg/m², 18-40 y). Participants will self-administer high- (active) and low-intensity (sham) stimulation daily (≥ 30 min) for ~ 14 days each (≥ 7 d washout). We will assess peripheral (cytokine levels, circulating immune cells) and central (diffusion weighted imaging) inflammation, motivation (using an effort allocation task during functional MRI), and mood at baseline and after each stimulation phase. During each stimulation phase, participants will complete daily ecological momentary assessments of mood and food choices. We will use mixed-effects models to evaluate differences in slopes of high- vs. low-intensity tVNS. This study uses a 14-day home-based tVNS protocol (≥ 30 min daily) accompanied by daily ecologocial momentary assessments to investigate mid-term effects on chronic low-grade inflammation, mood, and motivation. The multimodal study design including a comprehensive panel of peripheral and central inflammatory markers enables the integration of inflammatory and behavioral outcomes and will provide important evidence regarding the efficacy of tVNS in chronic inflammation, based on a study with sufficient statistical power. In addition, the study could provide pathophysiological insights into the link between obesity and symptoms of depression via inflammatory processes. Ultimately, the study will facilitate future research on vagus nerve stimulation to complement the current set of therapies in overweight and obesity. The study has been preregistered at ClinicalTrials.gov ( https://clinicaltrials.gov/study/NCT06954844 ) on March 21, 2025, Version 1.
Clinical relevance
Does daily home-based transcutaneous vagus nerve stimulation (tVNS) at high intensity (active) versus low intensity (sham) reduce obesity-related metaflammation and improve mood and motivation in adults with elevated BMI over approximately 14 days? __SNAPSHOT__ {"studyDesign":"Prospective, single-blind, randomized sham-controlled crossover study — PROTOCOL PUBLICATION ONLY; no efficacy results reported","setting":"University Hospital Bonn (Section of Medical Psychology, Department of Psychiatry and Psychotherapy), Germany; home-based stimulation with laboratory neuroimaging sessions","sampleSize":"Target N = 60; no results data available at time of protocol publication","population":"Adults aged 18–40 years with a BMI of 27–35 kg/m² (overweight to class I obesity); characterized as healthy participants with obesity-related elevated BMI; excludes severe obesity (BMI >35), acute infection, and likely standard neuromodulation contraindications (not fully detailed in abstract)","intervention":"High-intensity transcutaneous vagus nerve stimulation (tVNS; active condition) self-administered at home for ≥30 min/day over a minimum of 14 days","comparator":"Low-intensity tVNS (sham condition) self-administered at home for ≥30 min/day over a minimum of 14 days, with a ≥7-day washout period between conditions","primaryOutcome":"Not formally designated as a single primary endpoint in the protocol abstract; five pre-registered hypotheses address: (1) reduction in peripheral pro-inflammatory cytokines and circulating immune cell profiles; (2) changes in central inflammation assessed via neuroimaging (fMRI, DBSI); (3) improvement in mood (PANAS); (4) enhancement of motivation to work for rewards (effort allocation task during fMRI); and (5) mediation of mood/motivation changes by tVNS-induced reductions in central and peripheral inflammation","followUp":"Approximately 5 weeks total per participant: baseline assessment (t0), ~14-day first intervention arm, ≥7-day washout, ~14-day second intervention arm, post-crossover assessment (t3); four in-laboratory sessions total (t0–t3)","fundingSource":"Not reported in abstract; institutional affiliation with University of Bonn, German Center for Mental Health (DZPG), and German Center for Diabetes Research (DZD) identified from linked publications by the same group; no industry sponsorship declared in available protocol materials"}
Key findings
This is a study protocol publication. No efficacy, safety, or outcome data are reported. The document describes planned assessments including: peripheral inflammation markers (cytokine levels [pro- and anti-inflammatory], circulating immune cell phenotyping); central neuroinflammation (fMRI and diffusion basis spectrum imaging [DBSI]); mood (Positive and Negative Affect Schedule [PANAS] via visual analogue scale, ecological momentary assessment [EMA]); and motivation (effort allocation task [EAT] administered during fMRI, EMA). Secondary assessments include metabolic parameters (insulin sensitivity, blood lipid levels), heart rate, blood pressure, body composition, eating behavior (food frequency questionnaire), physical activity (IPAQ), and validated psychiatric scales (BDI-II, SHAPS-D, Apathy Motivation Index). All participants will be assessed in a fasted state (12-hour fast) at laboratory visits. No p-values, confidence intervals, effect sizes, or NNT/NNH are calculable or applicable at this stage.
Practice implications
This protocol publication establishes the rationale and methodology for a mechanistic crossover trial testing whether non-invasive, home-based tVNS can modulate obesity-related metaflammation and associated neuropsychiatric sequelae (reduced mood and motivation) in adults with overweight or class I obesity. The cholinergic anti-inflammatory pathway (CAIP) — through which vagal efferents release acetylcholine that binds α7 nicotinic receptors on macrophages to suppress pro-inflammatory cytokine production — provides the mechanistic basis. Prior small feasibility studies have reported acute anti-inflammatory effects of tVNS in humans, but no completed study has examined daily home-based application specifically targeting obesity-related metaflammation. This trial is designed to fill that gap. What the study does NOT establish at this stage: any clinical efficacy signal, safety profile in this specific population, magnitude of expected anti-inflammatory or mood effects, or applicability to patients with more severe obesity (BMI >35), older age groups, or those with established inflammatory comorbidities (e.g., type 2 diabetes, rheumatologic disease). Results, if positive, would be hypothesis-generating for mechanistic understanding of the inflammation–mood–motivation axis; they would not constitute sufficient evidence to change clinical practice without replication in larger, ideally double-blind trials with clinical endpoints. Only the protocol has been peer-reviewed at this time; results are not yet available. __LIMITATIONS__ As a protocol publication, the following methodological limitations and uncertainties are identifiable prospectively: (1) Single-blind design — participants are not blinded to stimulation intensity allocation, introducing potential performance and reporting bias, particularly for subjective mood and motivation endpoints; (2) Small target sample (N=60) may be underpowered to detect modest anti-inflammatory effects given the heterogeneity of cytokine responses and individual variability in vagal tone; (3) Short intervention duration (~14 days per arm) may be insufficient to produce sustained or measurable changes in chronic low-grade inflammation (metaflammation), which evolves over months to years; (4) Washout adequacy — a minimum 7-day washout may be insufficient to eliminate carryover effects on inflammatory markers or central nervous system remodeling detected by DBSI; (5) Restricted age range (18–40 years) and BMI range (27–35 kg/m²) limit generalizability to older adults, those with severe obesity, or those with overt metabolic disease; (6) Surrogate endpoints — cytokine levels, fMRI BOLD signal, and DBSI metrics are mechanistic surrogates; no clinical endpoints (cardiovascular events, diabetes incidence, quality of life scales with established MCID) are included; (7) Low-intensity sham may not be fully inert — the sensory properties of low-intensity tVNS could produce partial vagal activation, potentially attenuating the detectable between-arm difference; (8) Home-based, self-administered stimulation introduces adherence uncertainty and lacks objective compliance monitoring beyond participant report; (9) Funding source and potential conflicts of interest are not fully disclosed in available protocol materials. __BOTTOM_LINE_CATEGORY__ not_ready_for_clinical_application __BOTTOM_LINE__ This is a prospectively registered, methodologically detailed protocol for a single-blind randomized crossover trial examining whether daily home-based tVNS reduces obesity-related metaflammation and improves mood and motivation in adults with BMI 27–35 kg/m²; no results are yet available. The mechanistic framework (cholinergic anti-inflammatory pathway) is biologically plausible and supported by prior acute-stimulation feasibility data, but the efficacy of sustained, home-based tVNS in this population has not been demonstrated. Clinicians should not alter practice based on this publication; this trial, if completed and positive, would represent preliminary mechanistic evidence requiring confirmatory replication before any clinical application.