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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:
Participants will:
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| taVNS paired with sensorized treadmill training (STT) and conventional physical therapy (cPT) | Active Comparator | 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). |
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| taVNS paired with conventional physical therapy (cPT) | Active Comparator | 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. |
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| Sham taVNS paired with STT and cPT | Sham Comparator | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) | Procedure | Active taVNS delivered at the inner tragus of the left ear (25 Hz, 200 μs, intensity at sensory threshold) |
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| Measure | Description | Time Frame |
|---|---|---|
| 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. | Baseline (T0) and Post-intervention (T1, 4 weeks) |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | Baseline (T0) and Post-treatment at 4 weeks (T1) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Massimo Marano, MD, PhD | Contact | +39 3333488802 | m.marano@policlinicocampus.it | |
| Gaia Anzini, MD | Contact | +39 3662007406 | gaia.anzini@unicampus.it |
| Name | Affiliation | Role |
|---|---|---|
| Massimo Marano, MD, PhD | Fondazione Policlinico Universitario Campus Bio-Medico, Via Alvaro del Portillo, 200, 00128 Roma, Italy | Principal Investigator |
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| Sham taVNS paired with cPT | Sham Comparator | 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. |
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| Sham Transcutaneous Auricular Vagus Nerve Stimulation (Sham taVNS) | Procedure | Sham taVNS using the electrode placement as active taVNS but without electrical stimulation beyond the initial sensation. |
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| Conventional Physical Therapy (cPT) | Other | Conventional Physical Therapy delivered to all groups consist of exercises aimed at posture alignment, reduction of hypertone, balance improvement and overground gait training. |
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| Sensorized Treadmill Training (STT) | 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). |
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| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Post-intervention at 4 weeks (T1) and Follow-up at 8 weeks (T2) |
| 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). |
| Baseline (T0) and Post-treatment at 4 weeks (T1) |
| 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. | Baseline (T0) and Post-treatment at 4 weeks (T1) |
| Neurodegenerative Biomarker (α-Synuclein) | Serum and salivary levels of α-synuclein will be measured using standardized immunoassays. Concentrations will be expressed in ng/mL. | Baseline (T0) and Post-treatment at 4 weeks (T1) |
| ID | Term |
|---|---|
| D010300 | Parkinson Disease |
| ID | Term |
|---|---|
| D020734 | Parkinsonian Disorders |
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D009069 | Movement Disorders |
| D000080874 | Synucleinopathies |
| D019636 | Neurodegenerative Diseases |
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| ID | Term |
|---|---|
| C005703 | salicylhydroxamic acid |
| C000708228 | 2-cyclohexylidenhydrazo-4-phenyl-thiazole |
| D005080 | Exercise Test |
| ID | Term |
|---|---|
| D006334 | Heart Function Tests |
| D003935 | Diagnostic Techniques, Cardiovascular |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D012129 | Respiratory Function Tests |
| D003948 | Diagnostic Techniques, Respiratory System |
| D016552 | Ergometry |
| D008919 | Investigative Techniques |
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