Effects of tVNS on Visceral Pain

Abdominal pain is often caused by conditions like irritable bowel syndrome (IBS) and functional dyspepsia (FD), which are chronic and can fluctuate daily. IBS and FD affect about 6% and 10% of the general population, respectively. Many patients visiting gastroenterology clinics suffer from these conditions, and pain is the most challenging symptom to manage. Conventional treatments often don't provide lasting relief, affecting patients' quality of life and causing significant socio-economic impact.

The underlying causes of IBS and FD are not well understood, making it difficult to develop effective treatments. These conditions are considered disorders of the gut-brain interaction, involving communication between the gut and brain via the vagus nerve. The vagus nerve sends sensory information from the gut to the brainstem, particularly the nucleus tractus solitarius (NTS), which then communicates with other brain areas involved in pain perception.

The vagus nerve has a branch that innervates the external ear, making it accessible for non-invasive stimulation. Transcutaneous auricular vagal nerve stimulation (taVNS) has been used experimentally for conditions like migraines and fibromyalgia. A recent trial showed that daily taVNS can reduce abdominal pain in adolescents with functional abdominal pain and IBS. Additionally, studies using advanced brain imaging have shown that taVNS activates the NTS. However, it's unclear if this activation is responsible for the pain-relieving effects of taVNS.

New neuroimaging techniques allow for detailed studies of gut-brain communication and the effects of taVNS. Understanding these mechanisms could help develop taVNS as a safe and effective treatment for abdominal pain.

Preliminary Results:

We developed a human pain model using capsaicin (a component of chili peppers) infused into the duodenum to simulate abdominal pain. This model reliably triggers pain and activates brain regions involved in pain perception, including the NTS. This model is useful for studying treatments like taVNS for visceral pain relief.

Clinical Significance:

taVNS is gaining attention as a treatment for various conditions, but its effects are not yet fully understood. This study aims to explore the neurobiological effects of taVNS on visceral pain using advanced imaging techniques. Establishing these effects is crucial for integrating taVNS into clinical practice.

Vagus Nerve Stimulation (VNS):

VNS was first used in 1988 to treat epilepsy with surgically implanted devices. Recently, non-invasive taVNS methods have been developed, targeting the auricular branch of the vagus nerve in the ear. taVNS is safe, well-tolerated, and user-friendly.

Advanced Imaging:

Using 7 Tesla MRI provides higher resolution imaging than standard 1.5 or 3 Tesla scanners, allowing for detailed brain studies. These scanners are becoming more common and are safe for research. In the Netherlands, several institutions use 7 Tesla scanners for patient research without reported adverse effects.

Inclusion criteria

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

• Of female sex;
• Healthy participants (defined as those without a pre-existing medical comorbidity)
• Age between 18 and 40 years;
• BMI between 18 and 30 kg/m2;
• All subjects should use some form of contraception (for IUDs only Mirena is accepted)
• All subjects should be right-handed.

Exclusion criteria

A potential subject who meets any of the following criteria will be excluded from participation in this study:

• Presence of metallic prostheses, pacemakers, metal clips on blood vessels, metal parts in the eye, an intrauterine device (with the exception of the Mirena IUD), metal braces, facial tattoos and/or other metal objects;
• History of major head trauma or head/brain surgery;
• History of claustrophobia;
• History of severe or chronic cardiovascular, respiratory, urogenital, gastrointestinal/ hepatic, haematological/immunologic, HEENT (head, ears, eyes, nose, throat), dermatological/connective tissue, musculoskeletal, metabolic/nutritional, endocrine, neurological/psychiatric diseases, major surgery and/or laboratory assessments which might limit participation in or completion of the study protocol;
• Use of regular medication, including vitamin and iron supplementation, except oral contraceptives, within 14 days prior to start of the study;
• Pregnancy, lactation, wish to become pregnant;
• High alcohol consumption (>15 alcoholic units consumed per week);
• Using drugs of abuse;
• Administration of investigational drugs or participation in any scientific intervention study which may interfere with this study (to be decided by the principle investigator), in the 180 days prior to the study;
• Participants unable to provide informed consent
• Participants with any systemic disease or medications that may influence the autonomic nervous system (e.g. beta-agonists or Parkinson's disease)
• Current smokers or current use of nicotine in any other way (including E-cigarettes and patches)
• History of clinical anxiety or depression, or a hospital anxiety or depression score >8
• Participants whom score 8 or more on the HADS-questionnaire at study commencement
• Patient whom have cardiovascular conduction problems
• Patient with cochlear implants
• Not meeting any of the inclusion criteria above
• No given permission to register participation in electronic patient file at MUMC+ and to add records of transnasal gastroduodenoscopy
• No given permission to inform incidental findings to the general practitioner
• Any evidence of structural brain abnormalities examined by anatomical MRI will lead to exclusion