Electrical Stimulation for Paresis

Overseen By Brad E Dicianno, MD MS

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: VA Office of Research and Development

Disqualifiers: Vestibular disorders, Seizure, Epilepsy, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 4 weeks

110 Participants Needed

Trial Summary

What is the purpose of this trial?

Vagus nerve stimulation (VNS) is thought to activate neural pathways that release chemicals which promote plasticity and learning. Previous work has shown that the auricular branch of the vagus nerve innervates landmarks on the external ear. Work from the PI's laboratory has shown that electrical current applied to the external ear modulates physiological indexes of brain states implicated in the therapeutic effects of VNS. The broad objective of this project is to better understand physiological mechanisms modulated by auricular stimulation to support possible therapeutic effects in the form of motor learning.

Will I have to stop taking my current medications?

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 Pupil-Indexed Noninvasive Neuromodulation, Auricular Vagus Nerve Stimulation, Transcutaneous Auricular Vagus Nerve Stimulation, Percutaneous Auricular Vagus Nerve Stimulation for paresis?

Research suggests that transcutaneous auricular vagus nerve stimulation (taVNS) may enhance pupil dilation, which is linked to noradrenaline activity in the brain. This indicates a potential mechanism for taVNS to influence brain function, although more studies are needed to confirm its effectiveness for specific conditions like paresis. ^{1 2 3 4 5}

Is electrical stimulation for paresis generally safe in humans?

Non-invasive vagus nerve stimulation, including transcutaneous auricular vagus nerve stimulation (taVNS), is generally considered safe with only mild and temporary side effects like ear pain, headache, and tingling. There is no evidence of severe adverse events directly caused by taVNS, making it a safe option for clinical use. ^{1 2 6 7 8}

What makes Pupil-Indexed Noninvasive Neuromodulation unique compared to other treatments for paresis?

Pupil-Indexed Noninvasive Neuromodulation is unique because it uses electrical stimulation of the auricular vagus nerve, which is a nerve in the ear, to potentially influence brain activity and treat conditions like paresis. This method is noninvasive, meaning it doesn't require surgery, and it targets the vagus nerve, which is involved in many bodily functions, making it different from traditional drug treatments. ^{1 2 4 8 9}

Research Team

Michael A. Urbin, PhD

Principal Investigator

VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA

Eligibility Criteria

This trial is for individuals aged 18-75 who have had a stroke at least six months ago, resulting in hand impairment. It's not suitable for those with vestibular disorders, dizziness, ocular diseases affecting both eyes, seizures, epilepsy or incompatible implants. Pregnant women and people in other high-risk studies can't participate.

Inclusion Criteria

I am between 18 and 75 years old.

I had a stroke over 6 months ago that affected my hand.

Exclusion Criteria

ALL PROSPECTIVE SUBJECTS: History of vestibular disorders or dizziness, Difficulty maintaining alertness and/or remaining still, Pregnant or expecting to become pregnant, Diagnosis of neurological and/or musculoskeletal disorder(s) (other than stroke) that affect movement, Ocular disease and/or impairment in more than one eye, History of seizure and/or epilepsy, Implants, devices, or foreign objects in the brain/body that are incompatible with MRI, Body size that is incompatible with MRI scanner dimensions, Anyone already enrolled and actively participating in another greater than minimal risk study, PROSPECTIVE SUBJECTS DIAGNOSED WITH STROKE: Other impairments secondary to stroke (e.g., attention, cognition, etc.) that would interfere with the ability to understand study goals or follow simple instructions, as judged by the investigators.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive transcutaneous auricular vagus nerve stimulation (taVNS) with different stimulation protocols to investigate physiological mechanisms and effects on motor learning

4 weeks

Weekly visits for stimulation sessions

Follow-up

Participants are monitored for changes in force control and learning outcomes post-treatment

4 weeks

1 visit (1-week post), 1 visit (1-month post)

Treatment Details

Interventions

• Pupil-Indexed Noninvasive Neuromodulation

Trial Overview The study tests whether electrical stimulation on the external ear (auricular stimulation) can help improve brain functions related to motor learning after a stroke. Participants will receive either real transcutaneous electrical stimulation or a sham (fake) treatment as part of the research.

Participant Groups

Group I: Unpaired, Supra-Threshold Stim Experimental Treatment 1 Intervention

Supra-threshold stimulation after successful task repetition

Group II: Unpaired, Sub-Threshold Stim Experimental Treatment 1 Intervention

Sub-threshold stimulation after successful task repetition

Group III: Paired, Supra-Threshold Stim Experimental Treatment 1 Intervention

Supra-threshold stimulation paired with successful task repetition

Group IV: Paired, Sub-Threshold Stim Experimental Treatment 1 Intervention

Sub-threshold stimulation paired with successful task repetitions

Group V: Sham Placebo Group 1 Intervention

No stimulation

Pupil-Indexed Noninvasive Neuromodulation is already approved in European Union, United States for the following indications:

Approved in European Union as Auricular Vagus Nerve Stimulation for:

• Epilepsy
• Depression
• Pain
• Migraine

Approved in United States as Transcutaneous Auricular Vagus Nerve Stimulation for:

• Chronic cervical pain
• Chronic low back pain
• Migraine
• Acute postoperative pain
• Pain due to peripheral arterial occlusive disease

Who Is Running the Clinical Trial?

VA Office of Research and Development

Lead Sponsor

Trials

1,691

Recruited

3,759,000+

Findings from Research

Transcutaneous auricular vagus nerve stimulation (taVNS) can induce significant pupil dilation in healthy subjects, particularly at a stimulation intensity of 2 mA under scotopic lighting conditions.

The study highlights that the effects of taVNS are influenced by specific stimulation parameters and the experimental setup, indicating the need for careful consideration in future research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of transcutaneous auricular vagal nerve stimulation on pupil size. Capone, F., Motolese, F., Di Zazzo, A., et al.[2021]

In a study involving 33 healthy young volunteers, transcutaneous auricular vagus nerve stimulation (taVNS) did not significantly affect pupil size or pupil responses, which were hypothesized to be potential biomarkers for the effectiveness of taVNS.

Despite the expectation that taVNS would enhance pupil responses due to its mechanism of action linked to locus coeruleus activation, the results suggest that pupil measures may not be reliable predictors of individual responses to taVNS in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No modulation of pupil size and event-related pupil response by transcutaneous auricular vagus nerve stimulation (taVNS). Keute, M., Demirezen, M., Graf, A., et al.[2021]

The study involving 49 participants demonstrated that transcutaneous auricular vagus nerve stimulation (taVNS) can enhance pupil dilation, which is a biomarker for noradrenergic activity, indicating a potential mechanism of action for taVNS.

Higher stimulation settings of taVNS resulted in a linear increase in pupil dilation, supporting the idea that taVNS may activate noradrenergic pathways, although it also caused more intense and unpleasant sensations compared to sham stimulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Short bursts of transcutaneous auricular vagus nerve stimulation enhance evoked pupil dilation as a function of stimulation parameters. D'Agostini, M., Burger, AM., Franssen, M., et al.[2023]

A systematic review of 261 studies revealed significant confusion in the nomenclature for transcutaneous stimulation of the auricular branch of the vagus nerve (ABVN), with 67 full and 27 abbreviated terms identified, highlighting the need for standardization.

The most commonly used terms were 'transcutaneous vagus nerve stimulation' and 'tVNS', but there was no consistent one-to-one relationship between full and abbreviated names, indicating a lack of uniformity in terminology across different research teams.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toward Diverse or Standardized: A Systematic Review Identifying Transcutaneous Stimulation of Auricular Branch of the Vagus Nerve in Nomenclature. Wang, Y., Li, L., Li, S., et al.[2023]

Transcutaneous vagus nerve stimulation (tVNS) is gaining interest for its non-invasive application in research and clinical settings, but there is a need for better reporting practices to ensure safety and comparability across studies.

The review proposes a set of minimal reporting items for future tVNS studies, including technical details, participant criteria, and outcome measures, to enhance the reliability and effectiveness of this therapeutic approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020). Farmer, AD., Strzelczyk, A., Finisguerra, A., et al.[2023]

Vagus nerve stimulation (VNS) is effective for treating refractory epilepsy and depression, but traditional methods involve surgical implantation, which carries risks such as infection and bradycardia.

New non-invasive VNS systems eliminate the need for surgery, improving safety and tolerability, and allowing patients to administer stimulation on demand, potentially expanding its use in various medical conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. Ben-Menachem, E., Revesz, D., Simon, BJ., et al.[2022]

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]

Triphasic stimulation (TS) was found to be the most effective pattern for percutaneous electrical stimulation of the auricular vagus nerve (pVNS), requiring less electrical magnitude to achieve comfortable perception levels compared to biphasic (BS) and monophasic (MS) patterns.

The study suggests a shift from empirical methods to a more optimized approach for pVNS settings, as TS demonstrated superior performance in both experimental and numerical models, indicating its potential for more efficient therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stimulation Pattern Efficiency in Percutaneous Auricular Vagus Nerve Stimulation: Experimental Versus Numerical Data. Kaniusas, E., Samoudi, AM., Kampusch, S., et al.[2021]

A new 3D model of the human ear was created to study percutaneous vagus nerve stimulation (pVNS), showing that the position and depth of the electrodes significantly affect nerve stimulation thresholds, with sensitivity changes of up to 15.5% per 0.1 mm.

Biphasic stimulation pulses were found to be more effective than monophasic pulses for activating the vagus nerve, highlighting the importance of stimulation waveform in optimizing pVNS treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Numerical modeling of percutaneous auricular vagus nerve stimulation: a realistic 3D model to evaluate sensitivity of neural activation to electrode position. Samoudi, AM., Kampusch, S., Tanghe, E., et al.[2018]

References

1. Netherlands pubmed.ncbi.nlm.nih.gov

The effects of transcutaneous auricular vagal nerve stimulation on pupil size. [2021]

2. England pubmed.ncbi.nlm.nih.gov

No modulation of pupil size and event-related pupil response by transcutaneous auricular vagus nerve stimulation (taVNS). [2021]

3. Italy pubmed.ncbi.nlm.nih.gov

Short bursts of transcutaneous auricular vagus nerve stimulation enhance evoked pupil dilation as a function of stimulation parameters. [2023]

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

Toward Diverse or Standardized: A Systematic Review Identifying Transcutaneous Stimulation of Auricular Branch of the Vagus Nerve in Nomenclature. [2023]

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

International Consensus Based Review and Recommendations for Minimum Reporting Standards in Research on Transcutaneous Vagus Nerve Stimulation (Version 2020). [2023]

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

Surgically implanted and non-invasive vagus nerve stimulation: a review of efficacy, safety and tolerability. [2022]

7. England pubmed.ncbi.nlm.nih.gov

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

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

Stimulation Pattern Efficiency in Percutaneous Auricular Vagus Nerve Stimulation: Experimental Versus Numerical Data. [2021]

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

Numerical modeling of percutaneous auricular vagus nerve stimulation: a realistic 3D model to evaluate sensitivity of neural activation to electrode position. [2018]