Effect of taVNS of Brainstem Activation in Early and Late Parkinson's Disease Patients - an fMRI Study

NCT05967598 | Completed

• 1 other identifier: 012052/2020-2
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

This is a randomised, within-subject, double-blinded, placebo-controlled study to assess the fMRI correlates of central nervous system (CNS) response to taVNS in early vs late-stage Parkinsons disease (PD), at two different frequencies. Forty PD patients will be included: twenty patients with early-stage (Hoehn and Yahr stage (HY) 1-2) and twenty patients with late-stage (HY 3-4) PD. Each patient will undergo one stimulation session, where they will receive active taVNS at 100 Hz (taVNS100), taVNS at 25Hz (taVNS25) or will have positioned electrodes without stimulation (xVNS). The order of taVNS100, taVNS25 and xVNS will be randomized between subjects. The session will include (1) xVNS and taVNS; (2) MRI and fMRI and (3) heart rate and breathing rate monitoring. Clinical assessment with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale will be done before the session.

Conditions

Parkinson Disease; Neurologic Disorder

Keywords

Parkinson disease; taVNS; transcutaneous auricular vagal nerve stimulation; fMRI; brainstem ROI analysis

Outcome Measures

Primary Outcomes (3)

• Comparison of Brainstem activation pattern on fMRI (ROI analysis) during taVNS compared to xVNS

  Block-design fMRI analysis will be performed on brainstem ROIs to assess activation in neuromodulatory brainstem nuclei during taVNS compared with xVNS using the tools of the AFNI program. Final analysis will be performed on group level.

  Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.

• Comparison of Functional connectivity pattern on fMRI (block design) of nucleus tractus solitarii and the rest of the nervous system during taVNS compared to xVNS

  Functional connectivity (fMRI, block design) between the nucleus tractus solitarii (NTS) and the rest of the central nervous system will be analysed with AFNI Context-Dependent Correlation Analysis to determine whether taVNS produces a different pattern of connectivity compared with xVNS.

  Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.

• Comparison of Functional connectivity pattern on fMRI (block design) of locus coeruleus (LC) and the rest of the nervous system during taVNS compared to xVNS

  Functional connectivity pattern (fMRI, block design) between the nucleus locus coeruleus (LC) and the rest of the central nervous system will be analysed with AFNI Context-Dependent Correlation Analysis to determine whether taVNS produces a different pattern of connectivity compared with xVNS.

  Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.

Secondary Outcomes (3)

• Comparison of Brainstem activation pattern on fMRI (ROI analysis) during taVNS25 compared to taVNS100

  Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.

• Comparison of Functional connectivity pattern on fMRI (block design) of nucleus tractus solitarii and the rest of the nervous system during taVNS25 compared to taVNS100

  Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.

• Comparison of Functional connectivity pattern on fMRI (block design) of locus coeruleus (LC) and the rest of the nervous system during taVNS100 compared to taVNS25

  Only the online/acute effect measured during stimulation (time frame duration of 8 minutes per stimulation type) will be analysed.

Study Arms (6)

taVNS100 in advanced PD patients

ACTIVE COMPARATOR

Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode at 100Hz to advanced PD patients. Participants will complete an 8 minute block design fMRI block.

Device: Noninvasive transcutaneous auricular vagus nerve stimulation at 100Hz

taVNS25 in advanced PD patients

ACTIVE COMPARATOR

Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode at 25Hz to advanced PD patients. Participants will complete an 8 minute block design fMRI block.

Device: Noninvasive transcutaneous auricular vagus nerve stimulation at 25Hz

xVNS in advanced PD patients

PLACEBO COMPARATOR

The electrode will be placed in the left cyma conchae however no electrical current will be applied to advanced PD patients. Participants will complete an 8 minute block design fMRI block.

Device: Sham cyma conchae stimulation

taVNS100 in early PD patients

ACTIVE COMPARATOR

Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode at 100Hz to early PD patients. Participants will complete an 8 minute block design fMRI block.

Device: Noninvasive transcutaneous auricular vagus nerve stimulation at 100Hz

taVNS25 in early PD patients

ACTIVE COMPARATOR

Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode at 25Hz to early PD patients. Participants will complete an 8 minute block design fMRI block.

Device: Noninvasive transcutaneous auricular vagus nerve stimulation at 25Hz

xVNS in early PD patients

PLACEBO COMPARATOR

The electrode will be placed in the left cyma conchae however no electrical current will be applied to early PD patients. Participants will complete an 8 minute block design fMRI block.

Device: Sham cyma conchae stimulation

Interventions

Noninvasive transcutaneous auricular vagus nerve stimulation at 100Hz DEVICE

Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode with the following parameters: square-shaped pseudobiphasic pulse, interpulse duration 80μs, pulse width 300μs, pulse intensity 0,1mA above the perceptual threshold at 100Hz. The intensity for each separate stimulation will be adjusted for each participant at the beginning of the experiment

Also known as: taVNS100

taVNS100 in advanced PD patients; taVNS100 in early PD patients

Noninvasive transcutaneous auricular vagus nerve stimulation at 25Hz DEVICE

Noninvasive electrostimulation will be applied to the left cyma conchae through the Nemos® electrode with the following parameters: square-shaped pseudobiphasic pulse, interpulse duration 80μs, pulse width 300μs, pulse intensity 0,1mA above the perceptual threshold at 25Hz. The intensity for each separate stimulation will be adjusted for each participant at the beginning of the experiment.

Also known as: taVNS25

taVNS25 in advanced PD patients; taVNS25 in early PD patients

Sham cyma conchae stimulation DEVICE

The electrode will be placed at the cymba conchae location, however no electrical current will be applied. All other experimental conditions will be the same as for the active taVNS stimulation.

Also known as: xVNS

xVNS in advanced PD patients; xVNS in early PD patients

Eligibility Criteria

• Age: 45 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• diagnosis of Parkinson's disease according to the UK PD Society Brain Bank criteria
• ability to walk independently for at least 2 minutes
• cognitive impairment that might prevent cooperation during tests
• stable antiparkinsonian medications during the previous 1 month

You may not qualify if:

• medication resistant rest tremor or dyskinesias
• history of seizures
• implanted medical devices or metal implants
• pregnancy
• claustrophobia
• fixed or severe kyphosis
• any conditions that would prevent our patients from lying still for 1 hour in a supine position (i.e. muscle pain, degenerative joint diseases…).

Sponsors & Collaborators

• University of Ljubljana: lead
• University Medical Centre Ljubljana: collaborator

Study Sites (1)

Neurology Department, UMC Ljubljana

Ljubljana, 1000, Slovenia

Location

MeSH Terms

Conditions

Parkinson Disease; Nervous System Diseases

Condition Hierarchy (Ancestors)

Parkinsonian Disorders; Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases

Study Officials

• Andrej Vovk, PhD

  Medical Faculty, University of Ljubljana

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Before the experiment the stimulation threshold (i.e. current) for each stimulation (taVNS25 and taVNS100) will be assessed by a third person. The participant will be told, that the investigators are comparing the effect of 3 different stimulation types and that each will be delivered at a different intensity. The order of stimulation will be randomised across the 3 fMRI slots by a third person and the stimulation type will be noted in a separate log file. The outcomes assessor will be blinded to the stimulation type until the end of the analysis process.
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Model Details: 40 participants with the diagnosis of PD patients aged \> 45 years will be included. Patients will be recruited from the outpatient and inpatient clinics. PD will be diagnosed according to the UK PD Society Brain Bank criteria: the investigators aim to include 20 patients with early-stage and 20 patients with late-stage PD. Each participant will complete 1 visit at the MRI scanning facility, during which they will complete 3 blocks of 8min block design fMRI. During each block they will receive a different kind of stimulation (taVNS25, taVNS100, xVNS; see detailed description). The effect will be compared within each group (early and advanced patients) and between groups (early vs advanced PD patients).

Study Record Dates

• First Submitted: April 5, 2023
• First Posted: August 1, 2023
• Study Start: February 15, 2023
• Primary Completion: September 29, 2023
• Study Completion: September 29, 2023
• Last Updated: October 17, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: Upon request after study publication
• Access Criteria: Data will be shared with researchers upon reasonable request

Locations

SL (1)