Healthy VolunteerNCT04282226
Brain Effect of Vagal Nerve Stimulation at Rest and Pain
A study testing active transcutaneous Vagal Nerve Stimulation (tVNS) in people with Healthy Volunteer, run by Queen Mary University of London at 1 site in United Kingdom.
Trial summary
Pain is a ubiquitous distressing sensory experience and is the most frequent symptom in numerous gastrointestinal disorders including inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Visceral pain is especially difficult to treat with conventional medications and new treatments are needed. Read more about this study
- Who is it for?
- Ages 18 to 65 yearsHealthy volunteers can take part
- Conditions the study is for
- Healthy Volunteer
- What is being tested?
- active transcutaneous Vagal Nerve Stimulation (tVNS)
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 0 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- 16 Mar 2020to 31 Oct 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Healthy participants (defined as those without pre-existing medical comorbidity) from staff, students and the local population of Queen Mary, University of London and/or King's College London
- Inclusion will be determined on the basis of availability. They should be able to attend the Denmark Hill King's College London Campus for 2 sessions.
- Women should be studied in the follicular phase of their menstrual cycle or taking oral contraceptives.
Who cannot join
- 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)
- Pregnant or breastfeeding females
- Participants unable to lie flat in the MRI scanner, suffer from claustrophobia or are unsuitable for MRI scanning due to contraindications, comorbidity or in situ metalwork
- Current smokers
- History of anxiety or depression, or hospital anxiety or depression score >8
Show all 13Show fewer
- History of drug or alcohol abuse
- Patients who have cardiovascular condition problems
- Patient with cochlear implants
- Recent nasal trauma, base of skull fracture and/or facial surgery that would contraindicate insertion of a nasogastric tube
- A positive urinary drugs screen
- Head circumference exceeding the limits of the scanner
- Not meeting any of the inclusion criteria above
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
Queen Mary University of London
London, UK, E1 2AJ
About this study
Official title: Randomised Cross-over Study of the Effect of Transcutaneous Vagal Nerve Stimulation (tVNS) on Brain Activation at Rest and During Oesophageal Pain in Healthy Humans
Pain is a ubiquitous distressing sensory experience and is the most frequent symptom in numerous gastrointestinal disorders including inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Visceral pain is especially difficult to treat with conventional medications and new treatments are needed.
Recently, the relationship between autonomic nerve system (ANS) and pain has gathered attention because it could represent an effective treatment target for visceral pain. The parasympathetic nervous system (PNS), one of the two main branches of the ANS, is considered to play an important role for analgesia possibly due to vagal nerve-mediated activation of key brain areas implicated in descending analgesia of pain. Transcutaneous vagal nerve stimulation (tVNS) can non-invasively modulate vagal nerve and be expected as a new method to treat visceral pain. For example, the preliminary study showed that vagal nerve stimulation experimentally modulated cardiac vagal tone (CVT) and prevented the development of acid-induced oesophageal hyperalgesia.
Read more
Disturbances in ANS function have been reported not only in IBS patients but also in fibromyalgia and chronic pelvic pain syndrome. Many of these disorders have been associated with differences in brain structure and/or function as demonstrated by the use of structural and functional magnetic resonance imaging (fMRI). Of note, the investigators have recently shown that these differences in brain structure and function may be in part attributable to the aforementioned disturbance in ANS function, adding weight to the proposition that autonomic neuromodulation may be efficacious in pain disorders. For instance, in healthy participants the investigators have recently shown, using functional connectivity analysis, that higher resting parasympathetic CVT predicts the engagement of a subcortical functional network that is implicated in descending analgesia, thereby supporting the notion that vagal-mediated analgesia is achieved via descending inhibitory pathways1,4. Thus, tVNS seems a reasonable method to treat pain. However, to date, the precise real-time effect of tVNS on brain function, including during the processing of visceral pain is unknown.
Hence, the aims of this study are to investigate the real-time effect of tVNS compared to sham stimulus on brain activity whilst experiencing acute oesophageal pain, using fMRI in double-blind, randomised crossover study of tVNS vs sham stimulation in healthy subjects.
Read the detailed description
Following informed written consent and screening questionnaires to characterize psychophysiological traits including personality and anxiety/depression inventory, each subject will have a nasogastric tube inserted with the attached distensible balloon positioned in the distal oesophagus. Painful oesophageal stimulation will be achieved by inflation of the balloon to a pain threshold pre-determined in each subject, defined as the point at which subject describes the transition from sensation to pain. The MR-safe tVNS probe will be attached to the neck for cervical vagal nerve-directed tVNS, and subjects will then be positioned in the MRI scanner. Real-time activity of the ANS will be monitored by heart rate variability as described in the previous study, which has been adapted for use in the MR-environment. All subjects will undergo MRI. For each visit, there will be two scanning periods. High-resolution structural imaging will first be required, and subsequently resting fMRI data will be acquired whilst subjects are asked to relax in the scanner, and their baseline autonomic tone is monitored, using validated methods of acquiring ANS data. This will illustrate a brain signature of real-time brain activity mapped to their parasympathetic tone.
Subjects will then be randomised to either the active-tVNS paradigm or sham and a second fMRI data acquisition will then be performed so as to acquire brain activity in conjunction with active and sham-tVNS. Following this, painful oesophageal stimulation will be repeated 20 times while active or sham tVNS continues. Following a two-week washout period, subjects will be crossed over and re-examined to receive the intervention they did not receive in visit 1.
- Conditions
- Healthy Volunteer
- Being tested
- active transcutaneous Vagal Nerve Stimulation (tVNS), sham transcutaneous Vagal Nerve Stimulation (tVNS)
- Keywords
- transcutaneous vagal nerve stimulation, functional magnetic resonance imaging, visceral pain, oesophageal stimulation
- Medical subject headings
- Visceral Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
active transcutaneous Vagal Nerve Stimulation (tVNS)Device
The tVNS device will be attached to the left aspect of the neck to stimulate the cervical branch of the vagal nerve and connected to an MR safe electrical stimulator.
sham transcutaneous Vagal Nerve Stimulation (tVNS)Device
The tVNS device will be attached to anatomically distinct from the cervical branch of the vagal nerve.
| Study group | Role | What they receive |
|---|---|---|
| active tVNS | Active comparator | The tVNS device will be attached to the left aspect of the neck to stimulate the cervical branch of the vagal nerve and connected to an MR safe electrical Receives: Device: active transcutaneous Vagal Nerve Stimulation (tVNS) |
| sham tVNS | Placebo comparator | The tVNS device will be attached to anatomically distinct from the cervical branch of the vagal nerve. Receives: Device: sham transcutaneous Vagal Nerve Stimulation (tVNS) |
What is being measured
The primary outcome is the main question the study is designed to answer.
The effect of tVNS compared to sham stimulus on brain activity whilst experiencing oesophageal pain
Comparison of fMRI results between sham and active tVNS.
Measured: 2 weeks
Secondary outcomes (6)
The effect of tVNS on functional brain activity at baseline and following painful oesophageal stimulation
Comparison of fMRI results before and after oesophageal stimulation.
Measured: 2 weeks
The effect of tVNS on participant pain ratings to acute oesophageal pain
Participants is asked to rate the severity of the pain they received using a simple 100-point visual analogue scale. (The minimum and maximum values are 1 and 100, respectively)
Measured: 2 weeks
The effect of baseline autonomic tone on structural brain morphology (both gray and white matter)
Cardiac vagal tone is calculated using electrocardiogram data to evaluate autonomic tone, which is measured on a linear vagal scale (LVS). The correlation between cardiac vagal tone and MRI results is evaluated.
Measured: 2 weeks
The effect of tVNS on resting brain function coupled to resting parasympathetic tone, compared to sham stimulus
fMRI results are compared between active and sham tVNS.
Measured: 2 weeks
The correlation of structural MR, DTI and resting fMRI data on the efficacy of tVNS for use in visceral pain
Investigating whether or not brain morphology predict efficacy with tVNS in pain.
Measured: 2 weeks
The effect of tVNS on state anxiety following oesophageal pain.
State and Trait Anxiety Inventory state, trait (Maximum and minimum values are 80 and 20, respectively. The higher value indicates more nervous status) is used.
Measured: 2 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Feb 2020
- Study start16 Mar 2020
- Primary completion31 Oct 2022
- Study completion31 Oct 2022
Why it stopped: There was a serious delay in the study due to the COVID pandemic. So the grant period was over.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Healthy VolunteerStudies of the same condition, open and under way.
- More trials run by Queen Mary University of LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Model description
- Randomised, cross-over design with placebo control
- Masking
- Double blind
- Who is masked
- Participant, Outcomes assessor
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Queen Mary University of London
- Sponsor type
- University, hospital or other
- Collaborators
- King's College London
- Responsible party
- Sponsor
- Investigators
- Qasim Aziz, Study chair, Queen Mary University of London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04282226
- Sponsor's protocol ID
- QMERC2017/59
- Status last verified
- Oct 2022
- First submitted
- 14 Feb 2020
- Last updated
- 13 Jan 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Jan 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Randomised Cross-over Study of the Effect of Transcutaneous Vagal Nerve Stimulation (tVNS) on Brain Activation at Rest and During Oesophageal Pain in Healthy Humans
- ClinicalTrials.gov ID
- NCT04282226
- Acronym / sponsor ID
- QMERC2017/59
- Conditions
- Healthy Volunteer
- Keywords
- transcutaneous vagal nerve stimulation, functional magnetic resonance imaging, visceral pain, oesophageal stimulation
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: There was a serious delay in the study due to the COVID pandemic. So the grant period was over.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Queen Mary University of LondonUniversity, hospital or other
- Collaborators
- King's College London
- Study start
- 16 Mar 2020 (actual)
- Primary completion
- 31 Oct 2022 (actual)
- Study completion
- 31 Oct 2022 (actual)
- First posted
- 24 Feb 2020 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Pain is a ubiquitous distressing sensory experience and is the most frequent symptom in numerous gastrointestinal disorders including inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Visceral pain is especially difficult to treat with conventional medications and new treatments are needed.
Recently, the relationship between autonomic nerve system (ANS) and pain has gathered attention because it could represent an effective treatment target for visceral pain. The parasympathetic nervous system (PNS), one of the two main branches of the ANS, is considered to play an important role for analgesia possibly due to vagal nerve-mediated activation of key brain areas implicated in descending analgesia of pain. Transcutaneous vagal nerve stimulation (tVNS) can non-invasively modulate vagal nerve and be expected as a new method to treat visceral pain. For example, the preliminary study showed that vagal nerve stimulation experimentally modulated cardiac vagal tone (CVT) and prevented the development of acid-induced oesophageal hyperalgesia.
Disturbances in ANS function have been reported not only in IBS patients but also in fibromyalgia and chronic pelvic pain syndrome. Many of these disorders have been associated with differences in brain structure and/or function as demonstrated by the use of structural and functional magnetic resonance imaging (fMRI). Of note, the investigators have recently shown that these differences in brain structure and function may be in part attributable to the aforementioned disturbance in ANS function, adding weight to the proposition that autonomic neuromodulation may be efficacious in pain disorders. For instance, in healthy participants the investigators have recently shown, using functional connectivity analysis, that higher resting parasympathetic CVT predicts the engagement of a subcortical functional network that is implicated in descending analgesia, thereby supporting the notion that vagal-mediated analgesia is achieved via descending inhibitory pathways1,4. Thus, tVNS seems a reasonable method to treat pain. However, to date, the precise real-time effect of tVNS on brain function, including during the processing of visceral pain is unknown.
Hence, the aims of this study are to investigate the real-time effect of tVNS compared to sham stimulus on brain activity whilst experiencing acute oesophageal pain, using fMRI in double-blind, randomised crossover study of tVNS vs sham stimulation in healthy subjects.
Detailed description
Following informed written consent and screening questionnaires to characterize psychophysiological traits including personality and anxiety/depression inventory, each subject will have a nasogastric tube inserted with the attached distensible balloon positioned in the distal oesophagus. Painful oesophageal stimulation will be achieved by inflation of the balloon to a pain threshold pre-determined in each subject, defined as the point at which subject describes the transition from sensation to pain. The MR-safe tVNS probe will be attached to the neck for cervical vagal nerve-directed tVNS, and subjects will then be positioned in the MRI scanner. Real-time activity of the ANS will be monitored by heart rate variability as described in the previous study, which has been adapted for use in the MR-environment. All subjects will undergo MRI. For each visit, there will be two scanning periods. High-resolution structural imaging will first be required, and subsequently resting fMRI data will be acquired whilst subjects are asked to relax in the scanner, and their baseline autonomic tone is monitored, using validated methods of acquiring ANS data. This will illustrate a brain signature of real-time brain activity mapped to their parasympathetic tone.
Subjects will then be randomised to either the active-tVNS paradigm or sham and a second fMRI data acquisition will then be performed so as to acquire brain activity in conjunction with active and sham-tVNS. Following this, painful oesophageal stimulation will be repeated 20 times while active or sham tVNS continues. Following a two-week washout period, subjects will be crossed over and re-examined to receive the intervention they did not receive in visit 1.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, outcomes assessor)
- Number of arms
- 2
- Model description
- Randomised, cross-over design with placebo control
| Arm | Type | Receives |
|---|---|---|
| active tVNS | Active comparator | Device: active transcutaneous Vagal Nerve Stimulation (tVNS)The tVNS device will be attached to the left aspect of the neck to stimulate the cervical branch of the vagal nerve and connected to an MR safe electrical |
| sham tVNS | Placebo comparator | Device: sham transcutaneous Vagal Nerve Stimulation (tVNS)The tVNS device will be attached to anatomically distinct from the cervical branch of the vagal nerve. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- Healthy participants (defined as those without pre-existing medical comorbidity) from staff, students and the local population of Queen Mary, University of London and/or King's College London
- Inclusion will be determined on the basis of availability. They should be able to attend the Denmark Hill King's College London Campus for 2 sessions.
- Women should be studied in the follicular phase of their menstrual cycle or taking oral contraceptives.
Key exclusion criteria (13 listed)
- 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)
- Pregnant or breastfeeding females
- Participants unable to lie flat in the MRI scanner, suffer from claustrophobia or are unsuitable for MRI scanning due to contraindications, comorbidity or in situ metalwork
- Current smokers
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| active transcutaneous Vagal Nerve Stimulation (tVNS)The tVNS device will be attached to the left aspect of the neck to stimulate the cervical branch of the vagal nerve and connected to an MR safe electrical stimulator. | Device | active tVNS |
| sham transcutaneous Vagal Nerve Stimulation (tVNS)The tVNS device will be attached to anatomically distinct from the cervical branch of the vagal nerve. | Device | sham tVNS |
Primary outcome
The effect of tVNS compared to sham stimulus on brain activity whilst experiencing oesophageal pain
Time frame: 2 weeks
Comparison of fMRI results between sham and active tVNS.
6 secondary outcomes
The effect of tVNS on functional brain activity at baseline and following painful oesophageal stimulation
Time frame: 2 weeks
The effect of tVNS on participant pain ratings to acute oesophageal pain
Time frame: 2 weeks
The effect of baseline autonomic tone on structural brain morphology (both gray and white matter)
Time frame: 2 weeks
The effect of tVNS on resting brain function coupled to resting parasympathetic tone, compared to sham stimulus
Time frame: 2 weeks
The correlation of structural MR, DTI and resting fMRI data on the efficacy of tVNS for use in visceral pain
Time frame: 2 weeks
The effect of tVNS on state anxiety following oesophageal pain.
Time frame: 2 weeks
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Jan 2023.
- Individual participant dataSharing planned: No
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Screening Protocol
Pain
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Qasim Aziz study chair
Queen Mary University of London
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing active transcutaneous Vagal Nerve Stimulation (tVNS) in people with Healthy Volunteer, run by Queen Mary University of London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: withdrawn, as of the sponsor's last update on 13 Jan 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The effect of tVNS compared to sham stimulus on brain activity whilst experiencing oesophageal pain (time frame: 2 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Jan 2023.