Vagal Nerve Stimulation for Traumatic Brain Injury and PTSD

(VNS mTBI Trial)

Overseen By Doug J Bremner, MD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: VA Office of Research and Development

Must not be taking: Neuroleptics, Opiates, Benzodiazepines

Disqualifiers: Schizophrenia, Bipolar, Substance abuse, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 3 months

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called non-invasive Vagal Nerve Stimulation (nVNS) to determine its effectiveness in improving memory and symptoms for Veterans with mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD). These conditions often co-occur in Veterans who served in Afghanistan and Iraq, sometimes becoming long-lasting issues. The trial compares nVNS to a placebo (a fake treatment) to assess its effectiveness. Veterans with both mTBI and PTSD, who do not have certain other medical or mental health conditions, might be suitable candidates for this trial. As an unphased trial, this study offers Veterans the chance to contribute to groundbreaking research that could lead to new treatment options.

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 prior data suggests that this non-invasive Vagal Nerve Stimulation is safe for Veterans with mTBI and PTSD?

Research has shown that non-invasive Vagal Nerve Stimulation (nVNS) is generally well-tolerated, with few side effects. In a study involving 102 patients with mild traumatic brain injuries, nVNS significantly improved symptoms for most participants. These positive results suggest the treatment is safe for many individuals. However, limited safety information exists for those with heart conditions. Overall, the treatment appears promising, with only minor side effects reported. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about non-invasive vagal nerve stimulation (nVNS) for traumatic brain injury (TBI) and PTSD because it offers a unique approach compared to traditional treatments like cognitive behavioral therapy and medication. Unlike these standard options, nVNS targets the vagus nerve directly, which plays a critical role in regulating mood and stress responses. This method could potentially provide quicker and more direct relief without the side effects typically associated with psychiatric medications. Additionally, its non-invasive nature makes it a safer and more accessible treatment option for patients who may not respond well to conventional therapies.

What evidence suggests that non-invasive Vagal Nerve Stimulation is effective for mTBI and PTSD?

Research has shown that non-invasive Vagal Nerve Stimulation (nVNS), a treatment participants in this trial may receive, can alleviate symptoms of mild traumatic brain injury (mTBI) and posttraumatic stress disorder (PTSD). In a study involving 102 individuals with mild TBI, the use of a device called gammaCore (a type of nVNS) improved 22 out of 27 concussion-related symptoms. For PTSD, nVNS reduced heart rate variability, often linked to stress. These findings suggest that nVNS might help manage symptoms of both mTBI and PTSD by calming the body's stress responses and enhancing overall well-being. ^{1 2 3 6 7}

Who Is on the Research Team?

Doug J Bremner, MD

Principal Investigator

Atlanta VA Medical and Rehab Center, Decatur, GA

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• nVNS
• sham stimulation

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.

How Is the Trial Designed?

Group I: nVNS Experimental Treatment 1 Intervention

non invasive vagal nerve stimulation

Group II: sham Placebo Group 1 Intervention

sham stimulation

nVNS is already approved in United States for the following indications:

Approved in United States as gammaCore Sapphire for:

• Acute treatment of pain associated with migraine headache
• Acute treatment of pain associated with episodic cluster headache
• Adjunctive use for the preventive treatment of cluster headache
• Emergency use for acute treatment of exacerbation of asthma-related dyspnea and reduced airflow in adult patients with known or suspected COVID-19

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Atlanta VA Medical Center

Collaborator

Trials

28

Recruited

69,700+

Published Research Related to This Trial

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]

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]

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]

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]

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 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 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]

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]

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]

Citations

1. electrocore.com electrocore.com/medical-affairs/ptsd/

nVNS for Treating the Symptoms of PTSD nVNS led to significantly greater decreases in long-term heart rate variability over the course of multiple traumatic stress and stimulation protocols.

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04071743

NCT04071743 | Study of Gammacore Sapphire for the ... The study will enroll 60 subjects over a period of 14 weeks each. Subjects will use either a sham or active device to treat acute Post Traumatic Headache.

3. electrocore.gcs-web.com electrocore.gcs-web.com/news-releases/news-release-details/gammacore-non-invasive-vagus-nerve-stimulation-nvns-shown-be

gammaCore Non-Invasive Vagus Nerve Stimulation (nVNS ... In a study involving 102 patients with mild TBI, adjunctive use of gammaCore (nVNS) significantly improved 22 out of 27 measured concussive symptoms.

4. globenewswire.com globenewswire.com/news-release/2025/04/17/3063288/0/en/gammaCore-Non-Invasive-Vagus-Nerve-Stimulation-nVNS-Shown-to-be-Effective-in-Treating-Concussive-Symptoms-Associated-with-Mild-Traumatic-Brain-Injuries.html

gammaCore Non-Invasive Vagus Nerve Stimulation (nVNS ... Importantly, the data showed no significant difference in symptom improvement between patients with recent traumatic brain injuries (three ...

5. neurologylive.com neurologylive.com/view/veterans-affairs-gammacore-post-traumatic-headache

Veterans Affairs Investigates gammaCore for Treatment of ... The US Department of Veterans Affairs (VA) is initiating a new study investigating the use of its gammaCore Sapphire device for the treatment of post-traumatic ...

6. nyemetoder.no nyemetoder.no/4a2a53/siteassets/documents/rapporter/id2021_075-transcutaneous-non-invasive-vagus-nerve-stimulation-gammacore_offentlig-publiserbar.pdf

Transcutaneous non-invasive vagus nerve stimulation ( ... However, there is very limited safety and efficacy data related to patients with cardiological histories, and the. 'instructions for use' includes warnings ...

7. withpower.com withpower.com/trial/vagal-nerve-stimulation-for-traumatic-brain-injury-and-ptsd-ecfad

Vagal Nerve Stimulation for Traumatic Brain Injury and PTSD These studies report that nVNS is generally well-tolerated with few adverse events, making it a safe option for many patients. Show more.