Study Title: Research on the Brain Mechanism of Transcutaneous Auricular Vagus Nerve Stimulation in Regulating PD Motor Symptoms
Intervention: Transcutaneous Auricular Vagus Nerve Stimulation (taVNS)
Phase: Not Applicable
Status: Recruiting
Sponsor: The First Affiliated Hospital with Nanjing Medical University
Principal Investigator: Zhang Kezhong
Enrollment: 32 patients (estimated)
Transcutaneous Auricular Vagus Nerve Stimulation (taVNS) represents an emerging non-invasive neuromodulation strategy for Parkinson's disease (PD) that targets the vagal pathway to modulate central nervous system function[1]. Unlike invasive VNS which requires surgical implantation, taVNS stimulates the auricular branch of the vagus nerve through surface electrodes placed on the outer ear, making it a safer and more accessible therapeutic option. This mechanistic trial (NCT06409338) aims to elucidate how taVNS modulates cortical excitability and functional brain networks in PD patients using advanced neuroimaging techniques including functional near-infrared spectroscopy (fNIRS) and transcranial magnetic stimulation (TMS)[2][3].
Parkinson's disease is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta, leading to classic motor symptoms including bradykinesia, resting tremor, rigidity, and postural instability[4]. However, accumulating evidence demonstrates that PD pathology extends beyond the basal ganglia to involve widespread cortical and subcortical changes. The motor cortex in particular shows altered excitability patterns in PD, with impaired intracortical inhibition and abnormal sensorimotor integration[5].
The motor cortex dysfunction in PD manifests as:
While dopaminergic medications (levodopa, dopamine agonists) effectively manage classic PD motor symptoms, they have significant limitations, particularly for axial symptoms[9]:
These unmet needs have driven interest in non-dopaminergic approaches, including vagus nerve stimulation[10].
The vagus nerve (cranial nerve X) plays a crucial role in modulating neuroinflammation and central nervous system function through the cholinergic anti-inflammatory pathway[11]. VNS activates the nucleus tractus solitarius (NTS) in the brainstem, which subsequently projects to multiple brain regions including:
The auricular branch of the vagus nerve (ABVN) innervates the external ear, particularly the cymba conchae region, providing a accessible pathway for non-invasive stimulation[12].
Recent clinical studies have demonstrated that taVNS can improve motor symptoms in PD patients[1:1]. The proposed mechanisms include:
This is a randomized, double-blind, sham-controlled clinical trial investigating the neural underpinnings of taVNS modulating Parkinson's disease motor deficits. The study employs functional near-infrared spectroscopy (fNIRS) and transcranial magnetic stimulation (TMS) to assess cortical excitability and network connectivity changes[2:1][3:1].
| Attribute | Value |
|---|---|
| NCT ID | NCT06409338 |
| Status | Recruiting |
| Phase | Not Applicable |
| Allocation | Randomized |
| Intervention Model | Parallel Assignment |
| Masking | Double-blind (Participant, Investigator) |
| Enrollment | 32 patients |
| Sponsor | The First Affiliated Hospital with Nanjing Medical University |
| Principal Investigator | Zhang Kezhong |
| Arm | Type | Description |
|---|---|---|
| Active taVNS | Active Comparator | 14 consecutive daily sessions of taVNS, twice daily, 30 minutes each |
| Sham taVNS | Sham Comparator | 14 consecutive daily sessions of sham taVNS with electrodes fixed at left earlobe |
The selection of 20 Hz frequency is based on previous studies demonstrating optimal activation of vagal afferent fibers at this frequency range[12:1]. The cymba conchae region was chosen because it has the highest density of auricular vagal innervation, ensuring maximum afferent stimulation.
The study is based on the hypothesis that taVNS might improve PD motor deficits by regulating the balance between excitation and inhibition in the Primary Motor Cortex[5:1]. Specifically:
The trial uses two advanced neuroimaging techniques to probe cortical mechanisms:
Functional Near-Infrared Spectroscopy (fNIRS): Measures cortical oxyhemoglobin changes during resting state, allowing construction of functional brain networks[2:2]. fNIRS is particularly suitable for PD research because it:
Transcranial Magnetic Stimulation (TMS): Assesses motor cortex excitability through motor evoked potentials (MEPs), resting motor threshold (RMT), cortical silent period (SICI/ICF)[3:2]. TMS parameters provide insight into:
Gait and postural dysfunction in PD are poorly addressed by dopaminergic therapies. This mechanistic study explores a non-dopaminergic approach that may[9:1][15]:
Functional near-infrared spectroscopy provides measures of functional brain network topology that characterize how cortical regions communicate during rest[8:1].
| Measure | Description | Timeframe | Significance |
|---|---|---|---|
| Small-worldness (Sigma) | Global network parameter evaluating small-world attributes | Baseline → 1 day post-intervention | Small-world architecture enables efficient information processing; PD disrupts this topology |
| Global efficiency (Eg) | Global efficiency of parallel information transmission | Baseline → 1 day post-intervention | Measures how efficiently information can be exchanged across the entire network |
| Local efficiency (Eloc) | Functional separation in cortical networks | Baseline → 1 day post-intervention | Reflects specialized processing within local clusters of brain regions |
| Nodal efficiency (Ne) | Nodal efficiency of information transmission at specific nodes | Baseline → 1 day post-intervention | Identifies critical hub regions that may be particularly affected in PD |
Transcranial magnetic stimulation provides direct measures of motor cortex physiological function[3:3][6:1].
| Measure | Description | Timeframe | Clinical Relevance |
|---|---|---|---|
| MEP amplitude | Motor evoked potential peak-to-peak amplitude | Baseline → 1 day post-intervention | Reflects corticospinal tract integrity and excitability |
| RMT | Resting motor threshold (minimum stimulus to evoke MEP ≥0.05mV) | Baseline → 1 day post-intervention | Indicates membrane excitability of corticospinal neurons |
| CSP | Cortical silent period duration at 130% RMT | Baseline → 1 day post-intervention | Reflects GABA-B mediated intracortical inhibition |
| SICI | Short-interval intracortical inhibition (ISIs: 2ms, 4ms) | Baseline → 1 day post-intervention | Measures GABA-A mediated intracortical inhibition; typically reduced in PD |
| ICF | Intracortical facilitation (ISIs: 10ms, 15ms) | Baseline → 1 day post-intervention | Reflects glutamatergic intracortical facilitation mechanisms |
| Measure | Description | Timeframe | Clinical Relevance |
|---|---|---|---|
| UPDRS-III Change | Unified Parkinson's Disease Rating Scale Part III (motor examination, 0-56 points) | Baseline → 1 day post-intervention | Standard clinical measure of motor symptom severity in PD |
The UPDRS Part III is the gold standard for assessing motor symptoms in PD, with higher scores indicating greater disability[4:1].
The inclusion of patients with Hoehn and Yahr stage ≤2 ensures a population with primarily tremor-dominant or mixed phenotype PD without significant axial impairment that might confound the neuroimaging assessments.
Exclusion criteria are designed to ensure patient safety and data quality by removing confounding factors.
Site: The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
The vagus nerve (CN X) provides a non-invasive pathway to modulate central nervous system function:
Parkinson's disease affects motor cortex excitability through:
The trial hypothesis is that taVNS can normalize these patterns.
Functional near-infrared spectroscopy measures:
The trial assesses functional connectivity using these hemodynamic signals.
Transcranial magnetic stimulation measures:
taVNS offers advantages over dopaminergic therapies:
If successful, taVNS could complement:
This mechanistic trial addresses critical knowledge gaps in our understanding of taVNS as a therapeutic modality for PD. By using both fNIRS and TMS, the study provides complementary information about:
Network-level changes: fNIRS measures of small-worldness, global efficiency, and local efficiency characterize how taVNS modulates large-scale brain network organization[8:2]
Cellular-level changes: TMS measures of SICI and ICF provide insight into the neurophysiological mechanisms at the level of cortical neurons[6:2]
Clinical translation: UPDRS-III scores determine whether changes in brain activity translate to functional motor improvements
The combination of neuroimaging biomarkers and clinical outcomes will enable researchers to:
Several clinical trials have investigated taVNS in PD, but most have focused on clinical outcomes without mechanistic neuroimaging. This trial complements those efforts by providing direct evidence of cortical modulation:
taVNS is generally well-tolerated with minimal side effects. Common considerations include:
Results from this mechanistic trial will inform:
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