Vagal Nerve Stimulation for Traumatic Brain Injury and PTSD

(VNS mTBI Trial)

Overseen by Doug J Bremner, MD

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: VA Office of Research and Development

Must not be taking: Neuroleptics, Opiates, Benzodiazepines

Disqualifiers: Schizophrenia, Bipolar, Substance abuse, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

Mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD) are important conditions for the Veterans Administration (VA) that frequently occur together in combat Veterans from the conflicts in Afghanistan and Iraq. In many Veterans these become chronic, raising the risk the burden of neurotrauma can worsen over time. This study will examine a new intervention called non-invasive Vagal Nerve Stimulation (nVNS) and its effects on memory and symptoms of PTSD and mTBI as well as brain and physiology in Veterans with mTBI and PTSD.

Will I have to stop taking my current medications?

The trial requires that participants are not on active neuroleptic, opiate, or benzodiazepine treatment, so you may need to stop these medications if you are currently taking them.

What data supports the effectiveness of the treatment Vagal Nerve Stimulation for Traumatic Brain Injury and PTSD?

Research shows that non-invasive vagus nerve stimulation (nVNS) has been effective in treating headaches and improving memory and emotional regulation in PTSD patients. It has also been shown to improve heart rate variability, which is often impaired in conditions like epilepsy, suggesting potential benefits for traumatic brain injury and PTSD. ^{1 2 3 4 5}

Is vagal nerve stimulation safe for humans?

Non-invasive vagal nerve stimulation (nVNS), including devices like gammaCore, has been shown to have a favorable safety profile in clinical studies for conditions like migraines and cluster headaches. These studies report that nVNS is generally well-tolerated with few adverse events, making it a safe option for many patients. ^{2 3 6 7 8}

How is the treatment nVNS different from other treatments for traumatic brain injury and PTSD?

The treatment nVNS (non-invasive vagal nerve stimulation) is unique because it uses a device to stimulate the vagus nerve through the skin, particularly around the ear, without the need for surgery. This approach is less invasive, more affordable, and easier to apply compared to traditional methods that require surgical implantation, making it a novel option for managing symptoms of traumatic brain injury and PTSD. ^{1 5 9 10 11}

Research Team

Doug J Bremner, MD

Principal Investigator

Atlanta VA Medical and Rehab Center, Decatur, GA

Eligibility Criteria

This trial is for Veterans with mild traumatic brain injury (mTBI) and PTSD. Participants must not have had amnesia for over 24 hours post-event, a low Glasgow Coma Scale score, or loss of consciousness exceeding 30 minutes. They should be free from serious neurological disorders other than mTBI, active substance abuse, major psychiatric conditions like schizophrenia or bipolar disorder, significant medical illnesses, suicidal ideation, and certain medication treatments.

Inclusion Criteria

I am a veteran with mild traumatic brain injury and PTSD.

Exclusion Criteria

You have had problems with drinking or using drugs in the past year.

You have a brain MRI or CT that shows a physical problem in your brain.

You are currently thinking about hurting yourself.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive non-invasive Vagal Nerve Stimulation (nVNS) or sham stimulation twice daily, with assessments of memory, PTSD symptoms, and physiological responses over a three-month period

3 months

Daily treatments

Follow-up

Participants are monitored for safety and effectiveness after treatment, with assessments of memory retention and PTSD symptoms

4 weeks

Treatment Details

Interventions

• nVNS (Behavioural Intervention)
• sham stimulation (Behavioural Intervention)

Trial Overview The study tests non-invasive Vagal Nerve Stimulation (nVNS) against sham stimulation to see its effects on memory and symptoms in Veterans with mTBI and PTSD. It will also assess changes in brain function and overall physiology resulting from the treatment.

Participant Groups

Group I: nVNS Experimental Treatment 1 Intervention

non invasive vagal nerve stimulation

Group II: sham Placebo Group 1 Intervention

sham stimulation

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Dr. Grant Huang

VA Office of Research and Development

Acting Chief Research and Development Officer

PhD in Medical Psychology and Master of Public Health from the Uniformed Services University of Health Sciences

Dr. Erica M. Scavella

VA Office of Research and Development

Chief Medical Officer since 2022

MD from University of Massachusetts School of Medicine

Atlanta VA Medical Center

Collaborator

Trials

28

Recruited

69,700+

Findings from Research

Vagus nerve stimulation (VNS) is a promising treatment for patients with refractory epilepsy, specifically demonstrated in a case of Lennox-Gastaut Syndrome (LGS).

In this patient, VNS led to an improvement in heart rate variability (HRV), suggesting potential benefits beyond seizure control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation improves severely impaired heart rate variability in a patient with Lennox-Gastaut-Syndrome. Koenig, SA., Longin, E., Bell, N., et al.[2022]

In a study involving 248 participants with episodic migraine, noninvasive vagus nerve stimulation (nVNS) was found to be significantly more effective than a sham treatment for achieving pain freedom at 30 and 60 minutes after treatment.

nVNS was safe, well-tolerated, and provided effective pain relief, demonstrating a 13.2% absolute increase in the likelihood of being pain-free 2 hours post-treatment, making it a practical option for acute migraine management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Noninvasive vagus nerve stimulation as acute therapy for migraine: The randomized PRESTO study. Tassorelli, C., Grazzi, L., de Tommaso, M., et al.[2022]

The gammaCore device, a non-invasive vagus nerve stimulation (nVNS) system, has been FDA-cleared for the acute treatment of pain in patients with episodic cluster headaches, showing its efficacy in managing primary headache disorders.

Clinical studies indicate that nVNS effectively stimulates the same vagus nerve fibers as the traditional implanted vagus nerve stimulation (iVNS), suggesting a similar mechanism of action for headache relief without the associated risks of surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanism of action of non-invasive cervical vagus nerve stimulation for the treatment of primary headaches. Simon, B., Blake, J.[2018]

In a study involving 15 PTSD patients, active transcutaneous cervical Vagus Nerve Stimulation (tcVNS) significantly improved paragraph recall performance after two months, indicating potential benefits for memory function in PTSD (p < 0.05).

While active tcVNS showed trends of improved accuracy and recall in working memory tasks, these results were not statistically significant, suggesting that further research is needed to confirm the efficacy of tcVNS in enhancing cognitive functions in PTSD patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of transcutaneous cervical vagus nerve stimulation on declarative and working memory in patients with Posttraumatic Stress Disorder (PTSD): A pilot study. Choudhary, T., Elliott, M., Euliano, NR., et al.[2023]

In a pilot study involving 22 combat veterans, transcutaneous vagal nerve stimulation (tVNS) was found to be well tolerated and improved vagal tone, indicating a positive effect on the autonomic nervous system related to PTSD symptoms.

tVNS also moderated the autonomic response to stress, suggesting it may help regulate emotional dysregulation in veterans with PTSD, particularly those with a history of mild traumatic brain injury (mTBI).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-invasive Vagal Nerve Stimulation Effects on Hyperarousal and Autonomic State in Patients with Posttraumatic Stress Disorder and History of Mild Traumatic Brain Injury: Preliminary Evidence. Lamb, DG., Porges, EC., Lewis, GF., et al.[2020]

Noninvasive vagus nerve stimulation (nVNS) using the GammaCore® device is effective for aborting migraine attacks, but its effect size is modest and not superior to other noninvasive methods or oral triptans.

nVNS has an excellent safety and tolerance profile, making it a favorable option for migraine treatment, although its preventive effects are not significantly better than sham stimulation, except possibly in patients who consistently adhere to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Update on noninvasive neuromodulation for migraine treatment-Vagus nerve stimulation. Schoenen, J., Ambrosini, A.[2021]

Non-invasive vagus nerve stimulation (nVNS) using gammaCore® has been shown to be a safe and effective treatment for acute migraines in adolescents, with 46.8% of migraine attacks successfully treated without the need for rescue medication.

The study reported no device-related adverse events, highlighting nVNS as a well-tolerated option for young patients suffering from migraines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-invasive vagus nerve stimulation (nVNS) as symptomatic treatment of migraine in young patients: a preliminary safety study. Grazzi, L., Egeo, G., Liebler, E., et al.[2022]

The FDA has approved gammaCore, a non-invasive vagus nerve stimulator, for treating episodic cluster headache, showing significant benefits in response rates and pain relief compared to sham treatments in two major trials (ACT1 and ACT2).

GammaCore is practical, safe, and preferred by patients over standard care, effectively reducing headache symptoms and the need for rescue medications, indicating a need for updated reimbursement policies to support its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review of non-invasive vagus nerve stimulation (gammaCore): efficacy, safety, potential impact on comorbidities, and economic burden for episodic and chronic cluster headache. Mwamburi, M., Liebler, EJ., Tenaglia, AT.[2018]

Transcutaneous vagus nerve stimulation (tVNS) was found to be feasible and safe for patients with persistent impairment of consciousness after severe traumatic brain injury (TBI), with minimal side effects reported during an eight-week treatment period.

Out of five patients treated, three showed significant improvements in consciousness as measured by the Coma Recovery Scale-Revised (CRS-R), suggesting that tVNS may have potential benefits for recovery following severe TBI.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous Vagus Nerve Stimulation in Patients With Severe Traumatic Brain Injury: A Feasibility Trial. Hakon, J., Moghiseh, M., Poulsen, I., et al.[2022]

Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive and less expensive alternative to invasive vagus nerve stimulation (VNS), which is used to treat conditions like epilepsy and depression, but requires further research to optimize stimulation sites and parameters.

tVNS has the potential to activate various brain areas and may be effective for a wide range of conditions, including medication-refractory epilepsy, depression, migraines, and more, suggesting it could become a standard treatment for enhancing autonomic function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation - A brief introduction and overview. Hilz, MJ.[2022]

The ADNS-300 system for vagus nerve stimulation (VNS) was successfully implanted in all three patients, demonstrating its feasibility for therapeutic use and recording of nerve activity.

Two out of three patients experienced a significant reduction in seizure frequency (43% and 40%), indicating that the ADNS-300 system may effectively reduce seizures in refractory epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A novel implantable vagus nerve stimulation system (ADNS-300) for combined stimulation and recording of the vagus nerve: pilot trial at Ghent University Hospital. El Tahry, R., Raedt, R., Mollet, L., et al.[2012]

References

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

Vagus nerve stimulation improves severely impaired heart rate variability in a patient with Lennox-Gastaut-Syndrome. [2022]

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

Noninvasive vagus nerve stimulation as acute therapy for migraine: The randomized PRESTO study. [2022]

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

Mechanism of action of non-invasive cervical vagus nerve stimulation for the treatment of primary headaches. [2018]

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

Effect of transcutaneous cervical vagus nerve stimulation on declarative and working memory in patients with Posttraumatic Stress Disorder (PTSD): A pilot study. [2023]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Non-invasive Vagal Nerve Stimulation Effects on Hyperarousal and Autonomic State in Patients with Posttraumatic Stress Disorder and History of Mild Traumatic Brain Injury: Preliminary Evidence. [2020]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Update on noninvasive neuromodulation for migraine treatment-Vagus nerve stimulation. [2021]

7. Italy pubmed.ncbi.nlm.nih.gov

Non-invasive vagus nerve stimulation (nVNS) as symptomatic treatment of migraine in young patients: a preliminary safety study. [2022]

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

Review of non-invasive vagus nerve stimulation (gammaCore): efficacy, safety, potential impact on comorbidities, and economic burden for episodic and chronic cluster headache. [2018]

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

Transcutaneous Vagus Nerve Stimulation in Patients With Severe Traumatic Brain Injury: A Feasibility Trial. [2022]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Transcutaneous vagus nerve stimulation - A brief introduction and overview. [2022]

11. Netherlands pubmed.ncbi.nlm.nih.gov

A novel implantable vagus nerve stimulation system (ADNS-300) for combined stimulation and recording of the vagus nerve: pilot trial at Ghent University Hospital. [2012]