Clinical trial NCT06282406: Pupil-Indexed Noninvasive Neuromodulation
Official title: Transcutaneous Auricular Vagus Nerve Stimulation: Motor Learning & Mechanisms
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Paresis
Keywords: Learning
Neurological Rehabilitation
Lead sponsor: VA Office of Research and Development
Sponsor class: FED
First posted: 2024-02-28
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Subjects will be randomized into one of 5 groups and receive the designated stimulation/sham during a training protocol designed to facilitate motor learning.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: Existing evidence supports the use of VNS to enhance the effects of traditional therapy on impairments due to neurological injury. It is known that the vagus nerve forms contacts with neuromodulatory nuclei in the brainstem that release of chemicals shown to be critically involved in attentional control and memory formation. It is also known that the auricular branch of the vagus nerve innervates portions of the external ear providing a possible means to engage similar neural pathways noninvasively via transcutaneous auricular vagus nerve stimulation (taVNS). Recent work from the PI's laboratory shows that electrical current applied to landmarks on the external ear elicits transient effects on pupil dilation, an established physiological index of brain states that support learning. Given the ability to engage the biomarker, the investigators aim to further investigate physiological mechanisms modulated by taVNS and possible effects on learning.

Eligibility criteria: Inclusion Criteria:

ALL PROSPECTIVE SUBJECTS:

1. 18-75 years of age

   PROSPECTIVE SUBJECTS DIAGNOSED WITH STROKE:
2. Diagnosis of a single stroke resulting in hand impairment
3. Diagnosis of stroke at least six months prior to the time of participation

Exclusion Criteria:

ALL PROSPECTIVE SUBJECTS:

1. History of vestibular disorders or dizziness
2. Difficulty maintaining alertness and/or remaining still
3. Pregnant or expecting to become pregnant
4. Diagnosis of neurological and/or musculoskeletal disorder(s) (other than stroke) that affect movement
5. Ocular disease and/or impairment in more than one eye
6. History of seizure and/or epilepsy
7. Implants, devices, or foreign objects in the brain/body that are incompatible with MRI
8. Body size that is incompatible with MRI scanner dimensions
9. Anyone already enrolled and actively participating in another greater than minimal risk study.

   PROSPECTIVE SUBJECTS DIAGNOSED WITH STROKE:
10. 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.

Primary outcomes:
measure: Force Control Change
timeFrame: Pre, 1-week Post, 1-month Post
Secondary outcomes:
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
state: Pennsylvania
Study officials:
affiliation: VA Pittsburgh Healthcare System University Drive Division, Pittsburgh, PA
name: Michael A. Urbin, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dawson J, Liu CY, Francisco GE, Cramer SC, Wolf SL, Dixit A, Alexander J, Ali R, Brown BL, Feng W, DeMark L, Hochberg LR, Kautz SA, Majid A, O'Dell MW, Pierce D, Prudente CN, Redgrave J, Turner DL, Engineer ND, Kimberley TJ. Vagus nerve stimulation paired with rehabilitation for upper limb motor function after ischaemic stroke (VNS-REHAB): a randomised, blinded, pivotal, device trial. Lancet. 2021 Apr 24;397(10284):1545-1553. doi: 10.1016/S0140-6736(21)00475-X.
citation: Follesa P, Biggio F, Gorini G, Caria S, Talani G, Dazzi L, Puligheddu M, Marrosu F, Biggio G. Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain. Brain Res. 2007 Nov 7;1179:28-34. doi: 10.1016/j.brainres.2007.08.045. Epub 2007 Aug 25.
citation: Roosevelt RW, Smith DC, Clough RW, Jensen RA, Browning RA. Increased extracellular concentrations of norepinephrine in cortex and hippocampus following vagus nerve stimulation in the rat. Brain Res. 2006 Nov 13;1119(1):124-32. doi: 10.1016/j.brainres.2006.08.048. Epub 2006 Sep 7.
citation: Safi S, Ellrich J, Neuhuber W. Myelinated Axons in the Auricular Branch of the Human Vagus Nerve. Anat Rec (Hoboken). 2016 Sep;299(9):1184-91. doi: 10.1002/ar.23391. Epub 2016 Jul 12.
citation: Butt MF, Albusoda A, Farmer AD, Aziz Q. The anatomical basis for transcutaneous auricular vagus nerve stimulation. J Anat. 2020 Apr;236(4):588-611. doi: 10.1111/joa.13122. Epub 2019 Nov 19.
citation: Urbin MA, Lafe CW, Simpson TW, Wittenberg GF, Chandrasekaran B, Weber DJ. Electrical stimulation of the external ear acutely activates noradrenergic mechanisms in humans. Brain Stimul. 2021 Jul-Aug;14(4):990-1001. doi: 10.1016/j.brs.2021.06.002. Epub 2021 Jun 18.