VIBRANT-IBD: Brain Effects of Non-Invasive Vagus Nerve Stimulation in IBD Remission

Resting-state functional magnetic resonance imaging will be used to assess changes in functional connectivity between baseline (pre-intervention) and post-intervention measurements following 28 days of daily auricular non-invasive vagus nerve stimulation using the Nurosym device. Analyses will focus on brain networks associated with emotional regulation, interoception, autonomic regulation, and stress processing.

Structural magnetic resonance imaging (MRI) assessments, including high-resolution 3D T1-weighted imaging (MPRAGE), diffusion-weighted imaging (DWI), and MR angiography, will be used to explore potential changes in brain morphology, microstructural integrity, and vascular characteristics between baseline and post-intervention measurements.

Changes in psychological distress will be assessed using the Depression Anxiety Stress Scales-21 (DASS-21). The DASS-21 is a 21-item self-report questionnaire measuring symptoms of depression, anxiety, and stress over the past week. It includes three 7-item subscales. Each item is rated from 0 to 3, and subscale scores are summed for each subscale, yielding raw subscale scores ranging from 0 to 21. Scores may also be multiplied by 2 to obtain scores comparable with the full 42-item DASS, resulting in subscale scores ranging from 0 to 42. Higher Depression, Anxiety, or Stress scores indicate greater symptom severity in the respective domain.

Fatigue-related symptoms and their impact on functioning will be assessed using the Inflammatory Bowel Disease Fatigue Scale (IBD-F). The IBD-F Scale includes a section on fatigue severity, frequency, and duration, and a section on the impact of fatigue on daily functioning. Items are scored from 0 to 4, with higher scores indicating greater fatigue or a greater impact of fatigue on everyday life. The fatigue severity, frequency, and duration section has a maximum score of 20, while the impact of fatigue on daily functioning section has a maximum score of 120. Higher scores reflect more severe fatigue-related symptoms and greater functional impact.

Quality of life will be evaluated using the Polish version of the World Health Organization Quality of Life questionnaire, WHOQOL-BREF. The WHOQOL-BREF is a short, generic self-report questionnaire. The tool contains 26 items: 24 items grouped into four domains - physical health, psychological health, social relationships, and environment - plus two general items assessing overall quality of life and satisfaction with health. Items are rated from 1 to 5, with higher scores generally indicating better quality of life. Raw domain scores are calculated by summing the items within each domain: physical health has a maximum raw score of 35, psychological health has a maximum raw score of 30, social relationships has a maximum raw score of 15, and environment has a maximum raw score of 40. The two general items are scored separately, each with a maximum score of 5. Domain scores may also be transformed to a 4-20 or 0-100 scale, with higher scores indicating better quality of life.

The Brief Multidimensional Assessment of Interoceptive Awareness, version 2 (Brief MAIA-2), is a 24-item self-report questionnaire used to assess interoceptive awareness, meaning how a person perceives, attends to, interprets, and trusts internal bodily sensations. The tool includes eight 3-item subscales: Noticing, Not Distracting, Not Worrying, Attention Regulation, Emotional Awareness, Self-Regulation, Body Listening, and Trusting. Items are rated from 0 (never) to 5 (always). Subscale scores are typically calculated as the mean of the three items in each subscale and therefore range from 0 to 5. If item scores are summed within each subscale, each 3-item subscale has a maximum score of 15, and the total maximum score across all 24 items is 120. Higher scores indicate greater interoceptive awareness or a stronger ability to perceive and use bodily sensations.

Psychological resilience will be measured using the Resilience Scale (RS-14). The scale consists of 14 items, each rated on a 7-point scale from 1 (strongly disagree) to 7 (strongly agree). Total scores range from 14 to 98, with higher scores indicating higher resilience.

The self-constructed study-specific questionnaire will assess fear of disease relapse, emotional tension, stress-related gastrointestinal symptoms, body awareness, perceived control over health, psychosocial functioning, and expectations toward non-invasive vagus nerve stimulation. It will also assess participants' general health status on a 1-10 scale, where 1 indicates very poor health and 10 indicates very good health. Items are mainly rated on a 5-point Likert scale from 1 (strongly disagree) to 5 (strongly agree), with higher scores indicating stronger agreement with each statement. As a study-specific tool, it should be treated as an exploratory questionnaire rather than a standardised validated scale.

Participant adherence, usability, comfort, and acceptability of the intervention will be assessed using a study-specific post-intervention questionnaire. The questionnaire includes items on the frequency of stimulation, ease of device use, technical difficulties, perceived comfort, safety, willingness to continue therapy, and whether the participant would recommend it to others with IBD. It will also assess participants' general health status on a 1-10 scale, where 1 indicates very poor health and 10 indicates very good health. Most items are rated on a 5-point scale, with higher scores indicating more positive evaluation of the intervention. The questionnaire also records perceived changes in well-being, IBD-related functioning, stress response, adverse effects, and open-ended feedback about the therapy experience. As a study-specific tool, it should be treated as an exploratory questionnaire rather than a standardised validated scale.

Occurrence of adverse events will be measured using the study-specific post-intervention questionnaire. Participants will be asked whether any adverse events occurred during therapy, with multiple-choice response options including: no adverse events, discomfort at the stimulation site, headache, dizziness, fatigue, sleepiness, worsening of gastrointestinal symptoms, anxiety, and other symptoms specified by the participant. Additional comments can be provided in an open-text field. As a study-specific tool, it should be treated as an exploratory questionnaire rather than a standardised validated scale.

Optional semi-structured qualitative interviews will explore participant experiences related to living with IBD and using vagus nerve stimulation therapy. Interviews will be conducted up to one week after completion of the intervention, depending on participant availability.