tVNS and obesity-related inflammation: a prospective sham-controlled randomized crossover study protocol.

Abstract

Background: 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.

Methods: 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.

Discussion: 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.

Trial registration: The study has been preregistered at ClinicalTrials.gov ( https://clinicaltrials.gov/study/NCT06954844 ) on March 21, 2025, Version 1.