Effects of Vagal Nerve Stimulation on Leg Muscle Activity and Posture in Parkinson's Disease

Official title

The Effects of Vagus Nerve Stimulation on Intrinsic Lower Leg Spinal Motoneuron Excitability in Parkinson's Disease.

Overview

This study is designed to better understand the mechanisms contributing to impaired activation of leg muscles in people with Parkinson's disease (PD) and to test if stimulation of a nerve at the neck can improve muscle activation, walking and balance.

Detailed description

The goals of this project are twofold: (i) to test the hypothesis that persistent inward currents (PICs) in spinal motoneurons of the ankle extensors are reduced in people with Parkinson's disease and that these changes are associated with impaired postural control and (ii) to examine the acute effects of non-invasive vagus nerve stimulation (nVNS) on PICs and postural control.

This project will conduct experiments to test the hypothesis that the firing properties of muscles that control the ankle are significantly altered in people with PD compared to matched healthy adults and that these changes in activity are related to the severity of postural control deficits. In addition, this project will examine the acute effects of non-invasive vagal nerve stimulation (nVNS), an intervention that increases activity in the locus coeruleus and raphe nucleus, on the firing properties of ankle muscles and postural control. If successful, this work will be the first to demonstrate that brainstem pathways that control muscle firing properties are altered in people with PD and are associated with postural impairment. The preliminary trial of nVNS will provide evidence that postural muscle activity can be improved with stimulation and improve postural control. These findings will provide critical preliminary data required to move forward with a clinical trial of nVNS in PD.

Interventions

• Device Vagal nerve stimulation
  The gammaCore non-invasive vagus nerve stimulator (nVNS) is a hand-held portable device that is used to apply electrical stimulation to the vagus nerve via two electrodes.
• Other No intervention
  No nVNS is applied in the baseline experiment. Sham nVNS is applied for experiment two

Primary outcome measures

• Change in delta-F [Time frame: Within-session VNS: 0-60 minutes. Between VNS sessions: 1 - 4 weeks.]

Secondary outcome measures (4)

• Change in Braceheight [Time frame: Within-session VNS: 0 -60 minutes; between VNS sessions: 1-4 weeks]
• Step length [Time frame: Within-session VNS: 0-60 minutes; between VNS sessions: 1-4 weeks]
• Peak magnitude force on step leg [Time frame: Within-session VNS: 0-60 minutes; between VNS sessions: 1-4 weeks]
• Postural sway magnitude [Time frame: Within-session VNS: 0-60 minutes; between VNS sessions: 1-4 weeks]

Eligibility criteria

Inclusion criteria

• Diagnosis of idiopathic Parkinson's disease,
• On stable medication for the preceding month and anticipated over the next 3 months,
• Able to ambulate without the use of an assistive device for more than 50 meters.

Control Cohort:

• Age (± 3 years) and sex distribution matched to the PD cohort,
• Able to ambulate without the use of an assistive device for more than 50 meters.

Exclusion criteria

• Failure to demonstrate capacity to consent (based on UBACC and/or MacArthur-CR),
• History of significant neurological disorder (besides PD in the PD group),
• History of stroke, traumatic brain injury, intracranial aneurysm, intracranial hemorrhage, brain tumor or atypical parkinsonian disorder,
• Severe orthopedic or other related musculoskeletal pathology that has significant adverse effects on gait,
• Women who are pregnant or may be pregnant,
• Insufficient comprehension of the English language,
• History of substance abuse in past 2 years;

Additional exclusion criteria for VNS experiment

• Pain at the nVNS treatment site (e.g., dysesthesia, neuralgia, cervicalgia);
• Lesion (including lymphadenopathy), previous surgery (including carotid endarterectomy or vascular neck surgery) or abnormal anatomy at the stimulation site (open wound, rash, infection, swelling, cut, sore, drug patch, surgical scar\[s\]);
• Known or suspected severe atherosclerotic cardiovascular disease, severe carotid artery disease (e.g., bruits or history of TIA or stroke), congestive heart failure, known severe coronary artery disease or prior myocardial infarction;
• Abnormal baseline electrocardiogram (ECG) within the last year (e.g., second or third-degree heart block, prolonged QT interval, atrial fibrillation, atrial flutter, history of ventricular tachycardia or ventricular fibrillation);
• Recent history of uncontrolled high blood pressure, bradycardia, tachycardia, or know recent history orthostatic hypotension;
• Previous unilateral or bilateral vagotomy;
• Implanted metal cervical spine hardware, other metallic implants or implantable medical devices such as deep brain stimulator, hearing aid implant, pacemaker, implanted cardioverter defibrillator, cranial aneurysm and/or cranial aneurysm clips, history of facial/orbital/metallic fragments, implanted electronic device, neurostimulator, valve replacements/stents, metallic implants/prostheses) near the stimulation site such as a bone plate or bone screw;
• History of syncope or seizures (within the last 2 years);

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Double blind

Primary purpose

Treatment

Study locations

United States · 1 center

• Movement Disorders Laboratory — Minneapolis

Publications

• Mondal B, Choudhury S, Simon B, Baker MR, Kumar H. Noninvasive vagus nerve stimulation improves gait and reduces freezing of gait in Parkinson's disease. Mov Disord. 2019 Jun;34(6):917-918. doi: 10.1002/mds.27662. Epub 2019 Mar 14. No abstract available. PMID 30869809
• Morris R, Yarnall AJ, Hunter H, Taylor JP, Baker MR, Rochester L. Noninvasive vagus nerve stimulation to target gait impairment in Parkinson's disease. Mov Disord. 2019 Jun;34(6):918-919. doi: 10.1002/mds.27664. Epub 2019 Mar 19. No abstract available. PMID 30889295
• Negro F, Muceli S, Castronovo AM, Holobar A, Farina D. Multi-channel intramuscular and surface EMG decomposition by convolutive blind source separation. J Neural Eng. 2016 Apr;13(2):026027. doi: 10.1088/1741-2560/13/2/026027. Epub 2016 Feb 29. PMID 26924829
• Stebbins GT, Goetz CG, Burn DJ, Jankovic J, Khoo TK, Tilley BC. How to identify tremor dominant and postural instability/gait difficulty groups with the movement disorder society unified Parkinson's disease rating scale: comparison with the unified Parkinson's disease rating scale. Mov Disord. 2013 May;28(5):668-70. doi: 10.1002/mds.25383. Epub 2013 Feb 13. PMID 23408503
• Evancho A, Do M, Fortenberry D, Billings R, Sartayev A, Tyler WJ. Vagus nerve stimulation in Parkinson's disease: a scoping review of animal studies and human subjects research. NPJ Parkinsons Dis. 2024 Oct 24;10(1):199. doi: 10.1038/s41531-024-00803-1. PMID 39448636
• Factor SA, Weinshenker D, McKay JL. A possible pathway to freezing of gait in Parkinson's disease. J Parkinsons Dis. 2025 Mar;15(2):282-290. doi: 10.1177/1877718X241308487. Epub 2025 Jan 14. PMID 39973500
• Espay AJ, LeWitt PA, Kaufmann H. Norepinephrine deficiency in Parkinson's disease: the case for noradrenergic enhancement. Mov Disord. 2014 Dec;29(14):1710-9. doi: 10.1002/mds.26048. Epub 2014 Oct 9. PMID 25297066
• Robichaud JA, Pfann KD, Comella CL, Brandabur M, Corcos DM. Greater impairment of extension movements as compared to flexion movements in Parkinson's disease. Exp Brain Res. 2004 May;156(2):240-54. doi: 10.1007/s00221-003-1782-0. Epub 2004 Jan 28. PMID 14747885

Identifiers

NCT: NCT07226284 · NEUR-2025-34303

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗