Association of VAgus Nerve Stimulation and Treadmill Training for GAit Rehabilitation in DE Novo Parkinson's Disease

NCT ID: NCT07337226

Last Updated: 2026-01-13

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2026-01-31
• Study Completion Date: 2027-10-31

Brief Summary

The goal of this clinical trial is to learn if transcutaneous auricular vagus nerve stimulation (taVNS) can improve gait and brain function in people with diagnosis of idiopathic Parkinson's disease (PD) within 6 months. It will also help researchers learn about the safety and biological effects of taVNS when used together with physical therapy.

The main questions it aims to answer are:

• Does taVNS paired with physical therapy improve walking speed and gait performance in people with PD?
• Does taVNS change brain activity or breain perfusion related to movement?
• Does taVNS reduce markers of inflammation and neurodegeneration in blood and saliva? Researchers will compare active taVNS to sham (placebo) stimulation to see if active taVNS works better when paired with physical therapy.

Participants will:

• Attend 12 rehabilitation sessions over 4 weeks (three per week)
• Receive either active or sham taVNS during each session while doing treadmill and conventional physical therapy
• Undergo gait and cognitive testing, MRI scans, and blood and saliva collection before and after treatment
• Return for a follow-up visit four weeks after therapy to check how long the effects last

Detailed Description

Parkinson's disease (PD) is characterized by gait disturbance, impaired mobility, and progressive involvement of neural circuits responsible for locomotion and postural control. Although physical therapy is effective, its benefits are often modest and short-lived. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulation technique that activates the auricular branch of the vagus nerve and engages ascending brainstem pathways involved in motor control, arousal regulation, and inflammatory modulation. Previous studies have shown that taVNS can influence subcortical β-band oscillations, improve gait parameters, enhance cognitive performance, and modulate systemic inflammatory markers in individuals with PD.

This randomized, double-blind, sham-controlled clinical trial evaluates whether pairing taVNS with gait-focused rehabilitation enhances motor outcomes and neural plasticity in individuals with de novo PD. Participants are newly diagnosed (≤6 months) and undergo a 4-week rehabilitation program consisting of conventional physiotherapy, with or without sensorized treadmill training. Active or sham taVNS is administered during each therapy session. The study includes four parallel arms to independently assess the contributions of taVNS and treadmill-based gait training.

Outcomes are assessed at baseline (T0), immediately post-intervention (T1), and at a 4-week follow-up visit (T2). Primary and secondary outcomes include quantitative gait parameters, clinical motor scales, cognitive performance, and quality-of-life measures. Exploratory outcomes include changes in cerebral blood flow measured with pseudo-continuous arterial spin labeling (PCASL), functional connectivity during a simulated gait task using fMRI, and blood and salivary biomarkers of inflammation and neurodegeneration (e.g., TNF-α, interleukins, and α-synuclein).

The study aims to determine whether taVNS enhances rehabilitation-induced improvements in gait, whether these benefits persist beyond the treatment period, and whether taVNS induces measurable changes in brain perfusion, functional networks, or circulating biological markers relevant to PD pathophysiology. Results may support the development of a scalable, non-invasive therapeutic approach that can be integrated into early PD management.

Conditions

Idiopathic Parkinson's Disease (PD)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

taVNS paired with sensorized treadmill training (STT) and conventional physical therapy (cPT)

Participants will receive active taVNS, stimulation parameters: 25 Hz frequency, 200 μs pulse width, and intensity adjusted to the individual's sensory threshold, delivered to the left auricular tragus for the duration of each session (\~30 minutes). During stimulation, participants will perform treadmill walking on a sensorized treadmill system with simultaneous conventional physical therapy exercises focused on posture, balance, and gait re-education. Sessions will occur three times per week for four weeks (12 sessions total).

Group Type: ACTIVE_COMPARATOR

Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)

Intervention Type: PROCEDURE

Active taVNS delivered at the inner tragus of the left ear (25 Hz, 200 μs, intensity at sensory threshold)

Conventional Physical Therapy (cPT)

Intervention Type: OTHER

Conventional Physical Therapy delivered to all groups consist of exercises aimed at posture alignment, reduction of hypertone, balance improvement and overground gait training.

Sensorized Treadmill Training (STT)

Intervention Type: OTHER

Sensorized Treadmill Training consist of a sensorized gait treadmill training with continuous visual feedback combined with dual cognitive tasks (e.g. repeat digits, repeat sequence of words, counting down the dates).

taVNS paired with conventional physical therapy (cPT)

Participants will receive active taVNS (same parameters and device as Arm 1) during conventional physical therapy sessions without treadmill training.

Sessions will occur three times per week for four weeks.

Group Type: ACTIVE_COMPARATOR

Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)

Intervention Type: PROCEDURE

Active taVNS delivered at the inner tragus of the left ear (25 Hz, 200 μs, intensity at sensory threshold)

Conventional Physical Therapy (cPT)

Intervention Type: OTHER

Conventional Physical Therapy delivered to all groups consist of exercises aimed at posture alignment, reduction of hypertone, balance improvement and overground gait training.

Sham taVNS paired with STT and cPT

Sham stimulation will consist of few impulses delivered at 25 Hz for a duration of 60'' before waning, creating the same initial sensation without continuous current delivering.

Participants will simultaneously undergo treadmill-based and conventional physical therapy as described above.

Schedule: three sessions per week for four weeks.

Group Type: SHAM_COMPARATOR

Sham Transcutaneous Auricular Vagus Nerve Stimulation (Sham taVNS)

Intervention Type: PROCEDURE

Sham taVNS using the electrode placement as active taVNS but without electrical stimulation beyond the initial sensation.

Conventional Physical Therapy (cPT)

Intervention Type: OTHER

Conventional Physical Therapy delivered to all groups consist of exercises aimed at posture alignment, reduction of hypertone, balance improvement and overground gait training.

Sensorized Treadmill Training (STT)

Intervention Type: OTHER

Sensorized Treadmill Training consist of a sensorized gait treadmill training with continuous visual feedback combined with dual cognitive tasks (e.g. repeat digits, repeat sequence of words, counting down the dates).

Sham taVNS paired with cPT

Participants will receive sham stimulation (same device and sham procedure as Arm 3) during conventional physical therapy sessions without treadmill training.

Schedule: three sessions per week for four weeks.

Group Type: SHAM_COMPARATOR

Sham Transcutaneous Auricular Vagus Nerve Stimulation (Sham taVNS)

Intervention Type: PROCEDURE

Sham taVNS using the electrode placement as active taVNS but without electrical stimulation beyond the initial sensation.

Conventional Physical Therapy (cPT)

Intervention Type: OTHER

Conventional Physical Therapy delivered to all groups consist of exercises aimed at posture alignment, reduction of hypertone, balance improvement and overground gait training.

Interventions

Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)

Active taVNS delivered at the inner tragus of the left ear (25 Hz, 200 μs, intensity at sensory threshold)

Intervention Type: PROCEDURE

Sham Transcutaneous Auricular Vagus Nerve Stimulation (Sham taVNS)

Sham taVNS using the electrode placement as active taVNS but without electrical stimulation beyond the initial sensation.

Intervention Type: PROCEDURE

Conventional Physical Therapy (cPT)

Conventional Physical Therapy delivered to all groups consist of exercises aimed at posture alignment, reduction of hypertone, balance improvement and overground gait training.

Intervention Type: OTHER

Sensorized Treadmill Training (STT)

Sensorized Treadmill Training consist of a sensorized gait treadmill training with continuous visual feedback combined with dual cognitive tasks (e.g. repeat digits, repeat sequence of words, counting down the dates).

Intervention Type: OTHER

Other Intervention Names

Transcutaneous Auricular Vagus Nerve Stimulation; taVNS; nVNS; tVNS; Transauricular Vagus Nerve Stimulation; Sham transcutaneous auricular vagus nerve stimulation; sham taVNS; sham; Conventional Physical Therapy; cPT; Sensorized Treadmill Training; STT; treadmill; sensorized treadmill

Eligibility Criteria

Inclusion Criteria

• Idiopathic PD diagnosis within 6 months, confirmed by neurologist specialized in Parkinson's disease and movement disorders;
• Ability to walking independently for at least 10 meters unassisted;
• Age included between 50 and 80;
• MMSE > 24;
• On stable therapy for at least 1 month prior to the experiment.

Exclusion Criteria

• Clinical and radiological red flags for atypical, vascular parkinsonism or alternative diagnosis (e.g., normal pressure hydrocephalus);
• Levodopa equivalent daily dose > 300 mg;
• Any contraindication for taVNS (e.g., ear lesions, auditory prosthesis)
• Any contraindication for MRI (e.g., non compatible pacemakers or prosthesis, claustrophobic subjects);
• Concomitant neurological, orthopedic or active medical/oncological condition that would affect participating to the study;
• Attempting to other neurorehabilitation programs within 3 months.

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fondazione Policlinico Universitario Campus Bio-Medico

OTHER

Sponsor Role: lead

Responsible Party

Massimo Marano

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Massimo Marano, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy

Central Contacts

Massimo Marano, MD, PhD

Role: CONTACT

m.marano@policlinicocampus.it

+39 3333488802

Gaia Anzini, MD

Role: CONTACT

gaia.anzini@unicampus.it

+39 3662007406

Other Identifiers

AVANTGARDE-PD

Identifier Type: -

Identifier Source: org_study_id