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
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
60
Active taVNS delivered at the inner tragus of the left ear (25 Hz, 200 μs, intensity at sensory threshold)
Sham taVNS using the electrode placement as active taVNS but without electrical stimulation beyond the initial sensation.
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 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.
Time frame: Baseline (T0) and Post-intervention (T1, 4 weeks)
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.
Time frame: Baseline (T0), Post-intervention at 4 weeks (T1)
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.
Time frame: Baseline (T0) and Post-intervention at 4 weeks (T1).
Cognitive Function (RBANS Total Score) assessment.
Cognition is assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), which evaluates immediate memory, visuospatial/constructional abilities, language, attention, and delayed memory. Total scores range from 40 (severely impaired) to 160 (very superior), with higher scores indicating better performance.
Time frame: Baseline (T0) and Post-intervention at 4 weeks (T1)
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.
Time frame: Baseline (T0) and Post-intervention at 4 weeks (T1)
Change in Gait Speed from Post-intervention to Follow-up.
Average gait speed (m/s) is measured using a 3D motion-capture system during level walking. This outcome represents the change in gait speed between the post-intervention visit (T1) and the follow-up visit (T2) to evaluate persistence of treatment effects.
Time frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
Change in Spatiotemporal and Kinematic Gait Parameters (gait quality parameter) from Post-intervention to Follow-up.
Spatiotemporal and kinematic gait parameters (stance and swing duration (s), single and double support time (s), step and stride length (cm) and variability (%), swing speed (cm/s) and cadence (steps/min), joint flexion-extension angles (°), peak vertical ground reaction force (N/kg), and muscle-activation timing (ms)) are assessed with 3D motion capture, force platforms, and surface EMG. All listed parameters will be analyzed collectively as a single composite secondary outcome and will not be reported as separate outcome measures. This outcome reflects change in these parameters from T1 to T2.
Time frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
Change in Motor Function (MDS-UPDRS Part III Total Score) from Post-intervention to Follow-up.
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.
Time frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
Change in Cognitive Function (RBANS Total Score) from Post-intervention to Follow-up.
Cognition is assessed with the RBANS, which evaluates immediate memory, visuospatial/constructional abilities, language, attention, and delayed memory. This outcome captures the change in RBANS total score from T1 to T2 to evaluate persistence of cognitive effects. Higher scores indicate better performance.
Time frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
Change in Quality of Life (PDQ-39) from Post-intervention to Follow-up.
Quality of life is assessed using the PDQ-39, which measures mobility, activities of daily living, emotional well-being, stigma, social support, cognition, communication, and bodily discomfort. This outcome represents the change in PDQ-39 total score from T1 to T2, where higher scores indicate poorer quality of life and improvement is reflected by a decrease in scores.
Time frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
Change in Inflammatory Biomarkers (Serum and Salivary Cytokines) from Post-intervention to Follow-up.
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.
Time frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
Change in Neurodegenerative Biomarker Levels (α-Synuclein) from Post-intervention to Follow-up.
Serum and salivary levels of α-synuclein will be measured using standardized immunoassays. Concentrations will be expressed in ng/mL.
Time frame: Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2)
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