Transcutaneous auricular vagal nerve stimulation (taVNS) has been recently shown to have analgesic potential in patients with chronic functional abdominal (visceral) pain. Functional abdominal pain, as commonly seen in conditions such as irritable…
ID
Source
Brief title
Condition
- Gastrointestinal signs and symptoms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To explore the possible functional brain differences between taVNS vs sham in
the duodenal capsaicin experimental pain model.
Secondary outcome
1. To explore the degree of activation of the Cingulate Cortex, Insula,
Thalamus, Prefrontal cortex, the Primary and Secondary Somatosensory Cortex,
the Amygdala, Periaqueductal grey and possibly cerebellar structures as a
result of taVNS, compared to sham stimulation, in the capsaicin-pain model;
2. To assess the correlation between fMRI findings and Visual Analogue Scores
(VAS) for pain;
3. To assess the effect of taVNS vs sham on pulse rate variability, as a
measure of vagal tone of the autonomous nervous system.
Background summary
One of the most common causes of abdominal pain are irritable bowel syndrome
(IBS) and functional dyspepsia (FD). Abdominal pain in these conditions is of
chronic nature with frequent fluctuations, including acute exacerbations even
on a daily basis. The prevalence of IBS and FD in the general population is 6%
and 10%. Over one third of patients seen in secondary care GI clinics has IBS
or FD (Dutch Gastroenterologists* Association survey 2015), and pain is the
most common and difficult to manage symptom. Despite the large volume of
patients, conventional treatments often do not result in sufficient long-term
symptom relief. This leads to impaired quality of life and substantial
socio-economic burden.
The fact that there is still limited scientific understanding of the underlying
causes of these disorders hampers the development of more effective treatment
strategies. Nonetheless, current consensus considers IBS and FD as *disorders
of the gut-brain interaction,* reflecting the unique bidirectional
communication between these two organ systems. Recent scientific efforts have
focused on the vagus nerve because of its key role in homeostatic control. The
vagus nerve carries afferent sensory from the gastrointestinal tract to the
brainstem, in particular the nucleus tractus solitarius (NTS). Because the NTS
is further connected with other key brain regions, it represents a unique relay
station to higher cortical centers, including those responsible for conscious
pain perception.
The vagus nerve has a single peripheral branch (the auricular branch),
innervating the external ear. This location creates a *gateway* for influencing
a large number of physiological processes and bodily states through electrical
stimulation of the vagus nerve. Given its accessibility, transcutaneous
stimulation of the auricular vagus nerve (taVNS) has been applied
experimentally for diverse painful conditions including migraine and
fibromyalgia. More recently, a first empiric trial in adolescents with
functional abdominal pain has demonstrated analgesic properties of auricular
VNS when applied daily for a period of 4 weeks and beneficial effects were also
shown in a sub-analysis for patients who also met diagnostic criteria for IBS.
In addition, a recent study using 7 Tesla functional magnetic resonance imaging
(fMRI) has shown that taVNS is specifically able to activate the NTS. However,
it remains unclear whether the activation of the NTS is indeed the putative
mechanism leading to a clinical analgesic effect of taVNS by virtue of
modulating nociceptive processing.
Recent advances in neuroimaging techniques now make it possible to study these
mechanisms in detail and have opened new possibilities to gain insight into
gut-brain communication mechanisms and the therapeutic effect of taVNS. Such
mechanistic insight would enable further exploitation of taVNS as an
innovative, low-risk treatment that has the potential to impact both acute and
chronic components of abdominal pain.
Study objective
Transcutaneous auricular vagal nerve stimulation (taVNS) has been recently
shown to have analgesic potential in patients with chronic functional abdominal
(visceral) pain. Functional abdominal pain, as commonly seen in conditions such
as irritable bowel syndrome (IBS), are believed to arise from a disturbance in
the gut-brain interaction, in which the vagus nerve plays a paramount role.
Brain imaging studies allow insight into the exact nature of the gut-brain
interaction. We have recently established and validated an experimental model
for visceral pain for brain imaging based on the duodenal infusion of
capsaicin, the pungent principle in red peppers. In this study in healthy
volunteers, we will explore the potential mechanism of action of taVNS in this
experimental pain model. We will specifically focus on the brainstem, in
particular the nucleus of the solitary tract (NTS), as this is a key relay
stations of vagal afferents originating from the intestine.
Aim:
1) To study the effect of taVNS vs sham stimulation on brain activation (in
particular in the brain stem) with high-resolution 7-Tesla (7T) functional
magnetic resonance imaging (fMRI) in the duodenal capsaicin experimental
visceral pain model;
2) To investigate the effects of taVNS vs sham stimulation on subjective pain
reporting;
3) To explore the effects of taVNS vs sham stimulation on the parasympathetic
(vagal) tone.
Study design
An explorative 7T fMRI study
Intervention
Transcutaneous vagal nerve stimulation to the cymba concha of the right ear. As
a control condition, sham stimulation to the right earlobe will be used, this
area receives no vagal innervation. Infusion of capsaicin via a nasoduodenal
tube will be used as co-intervention.
Study burden and risks
Volunteers will not benefit from participating in this study. There are no
risks associated with the use of taVNS, including in magnetic resonance imaging
(MRI). Moreover, taVNS in the MR environment has been approved by the Scannexus
safety board and, thus far, 16 individuals healthy older individuals and 3
patients with preclinical Alzheimer*s disease) underwent simultaneous
taVNS-fMRI at this prospective site, with this particular equipment before with
nil procedural complications/adverse events (NL51297.068.14). Given the nature
of taVNS (by definition, *neurostimulation*), it can induce a transient
tingling feeling but does not cause pain. Ultra-high magnetic field MRI is very
safe and no adverse events are anticipated when taking into account all
contra-indications. Solely *Certified Users* will operate the MRI according to
approved guidelines and protocol. Subjects will be screened for
contraindications (metal implants etc.) prior to inclusion and again on the day
of scanning. Some participants may experience mild vertigo, nausea or a metal
taste when entering the MRI environment. In extremely rare cases, a small burn
may arise due to heating caused by radiofrequency. All participants will be
informed about any unexpected medical findings (MRI findings). In the rare
event the subject does not wish to be informed, they would not be permitted to
participate in this study.
There are no significant risks associated with the introduction of a
naso-duodenal tube by endoscopy, though the naso-duodenal tube may cause
discomfort located in the nose or throat. Spraying 10% lidocaine on the nasal
mucosa will minimize these symptoms.. Complications caused by replacement via
endoscopy are rare (<0,2%). Possible complications are aspiration, bleeding and
a sore throat. Capsaicin infusion may cause abdominal cramps, a burning
sensation, abdominal pain, nausea or heartburn but symptoms will subside
rapidly after discontinuation of the infusion. The nasoduodenal tube and
infusion pump are safe to use in the magnetic field and has been tested for
this purpose extensively. Completing questionnaires is non-invasive. Subjects
will be informed about the risks and burdens of the measurements beforehand.
Universiteitssingel 50
Maastricht 6229 ER
NL
Universiteitssingel 50
Maastricht 6229 ER
NL
Listed location countries
Age
Inclusion 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, 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
• Any evidence of structural brain abnormalities examined by anatomical MRI
will lead to exclusion
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL77978.068.21 |