Transcutaneous Auricular Neuromodulation for Ehlers-Danlos Syndrome

(hEDS-tAN Trial)

Overseen By Katherine Tucker

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Medical University of South Carolina

Disqualifiers: Pregnant, Seizures, Ear trauma, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

Trial Summary

Do I need to stop my current medications for this trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

What data supports the effectiveness of the treatment Transcutaneous Auricular Neuromodulation for Ehlers-Danlos Syndrome?

Research shows that transcutaneous auricular vagus nerve stimulation (taVNS), a similar treatment, is safe and effective for various conditions like epilepsy, depression, and anxiety. It also helps improve heart rate variability, which is linked to better autonomic function. ^{1 2 3 4 5}

Is transcutaneous auricular neuromodulation safe for humans?

Transcutaneous auricular neuromodulation, also known as taVNS, is generally considered safe for humans, with mild and temporary side effects like ear pain, headache, and tingling. Studies show no significant risk of severe adverse events compared to controls. ^{1 5 6 7 8}

How does transcutaneous auricular neuromodulation differ from other treatments for Ehlers-Danlos Syndrome?

Transcutaneous auricular neuromodulation is unique because it uses electrical stimulation of the ear to influence the vagus nerve, which can help manage various conditions without the need for surgery. This non-invasive approach is different from other treatments for Ehlers-Danlos Syndrome, as it targets the nervous system directly through the ear, potentially offering benefits for pain and other symptoms. ^{1 2 9 10 11}

What is the purpose of this trial?

Investigate whether at-home transcutaneous auricular VNS (tAN: transcutaneous auricular neurostimulation) improves a battery of nine key physical and psychological symptoms of a group of hEDS (Hypermobile Ehlers-Danlos Syndrome \& Hypermobile Spectrum Disorder) patients (n=30) using a randomized, double blind, sham controlled design. The study team will collect clinical measures at baseline, after a two-week double-blind intervention phase, after a following two-week open-label phase and finally at three months post intervention. The study team will test patients in the following domains: pain, fatigue, sleep, anxiety, depression, quality of life, GI function, immune function and autonomic function.

Eligibility Criteria

This trial is for individuals with Hypermobile Ehlers-Danlos Syndrome or Hypermobility Spectrum Disorder who experience persistent symptoms in at least two areas such as pain, fatigue, sleep issues, anxiety, depression, and more. Participants must be able to read and write and follow instructions. Those with MRI-unsafe implants, seizure history or ear trauma are excluded.

Inclusion Criteria

I have been diagnosed with hEDS or HSD and experience persistent symptoms in at least two areas such as pain or fatigue.

I can read, write, give consent, and follow instructions.

Exclusion Criteria

You have a medical device in your body that makes it unsafe for you to have an MRI.

I have a history of seizures.

Pregnant

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Double-blind Intervention

Participants receive either active or sham transcutaneous auricular neurostimulation (tAN) for 2 weeks

2 weeks

At-home, self-administered

Open-label Phase

All participants receive active transcutaneous auricular neurostimulation (tAN) for 2 weeks

2 weeks

At-home, self-administered

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Treatment Details

Interventions

• Transcutaneous Auricular Neuromodulation

Trial Overview The study tests if using a device for transcutaneous auricular neurostimulation at home can improve physical and psychological symptoms of hEDS/HSD patients. It's a randomized trial where half the participants will receive a sham (fake) treatment to compare results.

Participant Groups

Group I: Four Weeks of Active Transcutaneous Auricular Neurostimulation Experimental Treatment 1 Intervention

Participants will be randomized to receive 2 weeks of at-home, self-administered active Transcutaneous Auricular Neurostimulation (tAN), followed by 2 additional weeks of at-home, self-administered active Transcutaneous Auricular Neurostimulation (tAN)

Group II: 2 Weeks Sham tAN followed by 2 Weeks Active tAN Experimental Treatment 1 Intervention

Participants will be randomized to receive 2 weeks of at-home, self-administered sham Transcutaneous Auricular Neurostimulation (tAN), followed by 2 weeks of at-home, self-administered active Transcutaneous Auricular Neurostimulation (tAN).

Who Is Running the Clinical Trial?

Medical University of South Carolina

Lead Sponsor

Trials

994

Recruited

7,408,000+

Findings from Research

Transcutaneous auricular vagus nerve stimulation (taVNS) is a safe and effective neuromodulation therapy for a variety of conditions, including epilepsy, depression, and anxiety, indicating its broad therapeutic potential.

Despite its effectiveness, there is currently no standardization among taVNS devices, and further research is needed to clarify the relationship between stimulation parameters and therapeutic outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulators: a review of past, present, and future devices. Wang, L., Wang, Y., Wang, Y., et al.[2022]

Transcutaneous vagus nerve stimulation (tVNS) significantly reduced postural tachycardia in patients with POTS, showing a mean heart rate increase of 17.6 beats/min in the active group compared to 31.7 beats/min in the sham group after 2 months.

tVNS also led to lower levels of antiadrenergic autoantibodies and inflammatory cytokines, along with improved heart rate variability, indicating its potential as a safe and effective noninvasive treatment for POTS without any reported side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninvasive Vagus Nerve Stimulation in Postural Tachycardia Syndrome: A Randomized Clinical Trial. Stavrakis, S., Chakraborty, P., Farhat, K., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) effectively increases heart rate variability (HRV), indicating a shift towards parasympathetic dominance, with the most significant effects observed at the cymba conchae and fossa triangularis targets.

The study found that HRV increases in a charge-dependent manner, with optimal stimulation parameters being bursts of taVNS at a pulse duration of 100 μs and a current intensity of 2 mA, suggesting these parameters are both comfortable and effective for enhancing HRV.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation and heart rate variability: Analysis of parameters and targets. Machetanz, K., Berelidze, L., Guggenberger, R., et al.[2021]

Transcutaneous auricular vagus nerve stimulation (taVNS) showed promising results in two patients with structural focal epilepsy, leading to seizure freedom in one patient after 4 weeks and significant reduction in seizures for the other after 20 weeks.

Both patients experienced improved quality of life with no significant adverse events reported, suggesting that taVNS could be a safe and effective treatment option for individuals with focal epilepsy and preserved cognitive function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation therapy in patients with cognitively preserved structural focal epilepsy: A case series report. Shiraishi, H., Egawa, K., Murakami, K., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive and cost-effective method for modulating the vagus nerve, making it a promising alternative to traditional surgical vagus nerve stimulation.

taVNS allows for easy and safe administration, with considerations for proper electrode placement and individual dosing based on perception thresholds, which enhances its potential for treating various central and peripheral diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations. Badran, BW., Yu, AB., Adair, D., et al.[2020]

Transcutaneous auricular vagus nerve stimulation (taVNS) is generally safe, with a low incidence of mild and transient adverse effects, such as ear pain, headache, and tingling, reported in only 24.86% of the studies analyzed.

In a systematic review of 177 studies involving 6322 subjects, there was no significant difference in the risk of adverse events between taVNS and control groups, indicating that taVNS is a feasible option for clinical intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. Kim, AY., Marduy, A., de Melo, PS., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (TaVNS) effectively normalized gastric dysrhythmias in healthy individuals during a water-load test, indicating its potential as a treatment for gastric symptoms.

The study found that TaVNS at 40 Hz improved heart rate variability and reduced bloating, suggesting it positively influences both parasympathetic and sympathetic nervous system pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous Auricular Vagus Nerve Stimulation Normalizes Induced Gastric Myoelectrical Dysrhythmias in Controls Assessed by Body-Surface Gastric Mapping. Du, P., Maharjan, A., Calder, S., et al.[2023]

Transcutaneous auricular vagus nerve stimulation (taVNS) significantly improves depression symptoms, as evidenced by reduced scores on the Hamilton Depression Scale in a review of 12 studies involving 838 participants.

taVNS shows comparable response rates to traditional antidepressants and has fewer side effects, suggesting it could be a safe alternative or complementary treatment for depression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of transcutaneous auricular vagus nerve stimulation in the treatment of depressive disorder: A systematic review and meta-analysis of randomized controlled trials. Tan, C., Qiao, M., Ma, Y., et al.[2023]

In a study involving 26 subjects, simultaneous stimulation of the cymba and concha (CC) areas of the ear using extra-large electrodes was found to be the most effective for eliciting vagus somatosensory evoked potentials (VSEP), indicating strong neuromodulation effects.

The research demonstrated that the earlobe is not an effective target for taVNS, and using larger electrodes not only increased the amplitude of the response but also made the stimulation more comfortable for participants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of different vagus nerve stimulation anatomical targets in the ear by vagus evoked potential responses. de Gurtubay, IG., Bermejo, P., Lopez, M., et al.[2021]

In a study with 66 healthy participants, transcutaneous auricular vagus nerve stimulation (taVNS) did not significantly affect markers of noradrenergic activity, despite expectations that it would enhance this activity.

The results indicated that continuous taVNS stimulation at the tested parameters was ineffective in modulating both phasic and tonic noradrenergic responses, suggesting that this method may not be a viable approach for increasing noradrenergic activity through vagal pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No evidence for a modulating effect of continuous transcutaneous auricular vagus nerve stimulation on markers of noradrenergic activity. D'Agostini, M., Burger, AM., Villca Ponce, G., et al.[2022]

Vagus nerve stimulation (VNS), particularly through non-invasive methods like transcutaneous VNS (tVNS), shows promise for treating various clinical disorders, including heart failure and migraines, by stimulating the auricular branch of the vagus nerve without the need for surgical implantation.

Current research highlights the need for more detailed studies on the neuroanatomy of the auricular branch of the vagus nerve (ABVN) to better understand its therapeutic effects and optimize stimulation parameters, as existing literature lacks consensus on the most effective stimulation sites.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anatomical basis for transcutaneous auricular vagus nerve stimulation. Butt, MF., Albusoda, A., Farmer, AD., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulators: a review of past, present, and future devices. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Noninvasive Vagus Nerve Stimulation in Postural Tachycardia Syndrome: A Randomized Clinical Trial. [2023]

3. Netherlands pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation and heart rate variability: Analysis of parameters and targets. [2021]

4. Netherlands pubmed.ncbi.nlm.nih.gov

Transcutaneous auricular vagus nerve stimulation therapy in patients with cognitively preserved structural focal epilepsy: A case series report. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Laboratory Administration of Transcutaneous Auricular Vagus Nerve Stimulation (taVNS): Technique, Targeting, and Considerations. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Safety of transcutaneous auricular vagus nerve stimulation (taVNS): a systematic review and meta-analysis. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Transcutaneous Auricular Vagus Nerve Stimulation Normalizes Induced Gastric Myoelectrical Dysrhythmias in Controls Assessed by Body-Surface Gastric Mapping. [2023]

8. Netherlands pubmed.ncbi.nlm.nih.gov

The efficacy and safety of transcutaneous auricular vagus nerve stimulation in the treatment of depressive disorder: A systematic review and meta-analysis of randomized controlled trials. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Evaluation of different vagus nerve stimulation anatomical targets in the ear by vagus evoked potential responses. [2021]

10. United States pubmed.ncbi.nlm.nih.gov

No evidence for a modulating effect of continuous transcutaneous auricular vagus nerve stimulation on markers of noradrenergic activity. [2022]

11. England pubmed.ncbi.nlm.nih.gov

The anatomical basis for transcutaneous auricular vagus nerve stimulation. [2022]