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
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;
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);
Parallel
Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)
Procedure/SurgeryActive taVNS delivered at the inner tragus of the left ear (25 Hz, 200 μs, intensity at sensory threshold)
Sham Transcutaneous Auricular Vagus Nerve Stimulation (Sham taVNS)
Procedure/SurgerySham taVNS using the electrode placement as active taVNS but without electrical stimulation beyond the initial sensation.
Conventional Physical Therapy (cPT)
Other interventionConventional 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)
Other interventionSensorized 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).
Evaluation of objective changes in gait speed (m/s) through gait analysis.
Gait speed (m/s) is measured using a 3D optoelectronic motion-capture system with inertial sensors during level walking on a 10-meter walkway with integrated force platforms. Standard lower-limb reflective markers and surface EMG are used to capture kinematic and muscle-activation patterns. Average gait speed is calculated as the mean forward velocity.
Spatiotemporal and Kinematic Gait Parameters assessment (gait quality parameter).
Spatiotemporal and kinematic gait parameters are measured using a 3D motion-capture system with inertial sensors and surface EMG while participants walk across a walkway with integrated force platforms. Parameters include stance and swing phase duration (s), single and double support time (s), step and stride length (cm) and variability (%), swing speed (m/s) and cadence (steps/min), lower-limb joint flexion-extension angles (°), peak vertical ground reaction force (N/kg), and muscle-activation timing (ms) from surface EMG. All listed parameters will be analyzed collectively as a single composite secondary outcome and will not be reported as separate outcome measures.
Change in Motor Function (MDS-UPDRS Part III Total Score).
Motor function will be assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale, Part III (MDS-UPDRS III), which evaluates bradykinesia, rigidity, tremor, posture, and gait-related motor signs. Total scores range from 0 to 132, with higher scores indicating worse motor impairment. Improvement is reflected by a decrease in the MDS-UPDRS III score.
Cognitive Function (MoCA Total Score) assessment
Cognitive function is assessed using the Montreal Cognitive Assessment (MoCA), a validated screening tool designed to detect mild cognitive impairment. The MoCA evaluates multiple cognitive domains including attention, executive functions, memory, language, visuospatial abilities, abstraction, calculation, and orientation. Total scores range from 0 to 30, with higher scores indicating better cognitive performance.
Quality of Life (PDQ-39 Total and Domain Scores) assessment.
Quality of life is assessed using the Parkinson's Disease Questionnaire-39 (PDQ-39), which measures mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. Domain and total scores range from 0 to 100, with higher scores indicating poorer quality of life. Improvement is reflected by a decrease in PDQ-39 scores.
Imaging Outcomes (PCASL).
Brain perfusion will be assessed using pseudo-continuous arterial spin labeling (PCASL). Imaging is performed at baseline (T0) and post-treatment (T1). Primary imaging endpoints include: \- Change in cerebral blood flow (CBF) in locomotor and motor-control regions (PCASL)
Imaging Outcomes (fMRI).
Functional connectivity will be assessed by functional MRI (fMRI). Imaging is performed at baseline (T0) and post-treatment (T1). The fMRI assessment includes a simulated gait task using a custom pedal system with synchronized visual feedback. Primary imaging endpoints include: \- Change in functional connectivity within gait-related cortical-subcortical networks (fMRI).
Inflammatory Biomarkers (Serum and Salivary Cytokines)
Serum and salivary levels of inflammatory cytokines (TNF-α, IL-1β, IL-13, IL-10, IL-6) will be measured using standardized ELISA or multiplex immunoassays. Concentrations will be expressed in pg/mL. Cytokines will be analyzed collectively as a composite inflammatory outcome.
Neurodegenerative Biomarker (α-Synuclein)
Serum and salivary levels of α-synuclein will be measured using standardized immunoassays. Concentrations will be expressed in ng/mL.
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