Curative Effect and Mechanism of Transcutaneous Auricular Vagus Nerve Stimulation on Non-motor Symptoms of PD

Study on the Efficacy and Mechanism of Transcutaneous Auricular Vagus Nerve Stimulation in the Treatment of Non-motor Symptoms of Parkinson's Disease

This study is a double-blind comparative study examining the curative effect and mechanism of the transcutaneous auricular vagus nerve stimulation treatment on non-motor symptoms of Parkinson's disease patients. The investigators hypothesize that treatment using transcutaneous auricular vagus nerve stimulation will improve the non-motor symptoms, such as improving sleep, and improve cortical activity simultaneously in Parkinson's disease patients.

Study Overview

• Status: Recruiting
• Conditions: Parkinson Disease
• Intervention / Treatment: Device: Transcutaneous auricular vagus nerve stimulation (real stimulation); Device: Transcutaneous auricular vagus nerve stimulation (sham stimulation)

Detailed Description

Patients in the Experimental group underwent fourteen consecutive daily sessions of transcutaneous auricular vagus nerve stimulation (taVNS, twice daily, 30 minutes each time), whereas patients in the sham stimulation group underwent fourteen consecutive daily sessions of sham taVNS. Assessments of motor and non-motor symptoms, excitability of cortex motor (using repetitive transcranial magnetic stimulation), cortical activity (using Functional near-infrared spectroscopy) and blood indicators were performed three times: at baseline, one day post intervention, fourteen days post intervention.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Jiang Su
    • Nanjing, Jiang Su, China, 210029
      • Recruiting
      • The First Affiliated Hospital of Nanjing Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Idiopathic Parkinson's disease (PD), as diagnosed by a neurologist.
• PDSS score<82 (or a subscore<5).
• Age between 40 and 80 years old.
• Mini-Mental State Examination score >24.
• Right-handed patient.
• Stable medication.

Exclusion Criteria:

• Clinically diagnosed as other Parkinson's syndrome.
• Cognitive impairment (MMSE<24), severe anxiety and depression, epilepsy history, severe diabetes, organic brain stem injury (such as stroke, tumor, demyelinating disease, etc.).
• Taking anticholinergic drugs.
• Taking antipsychotic drugs.
• There are contraindications to taVNS stimulation, such as implantation of a cardiac pacemaker after DBS operation, patients with local infection or loss of an ear, or metal implants at the stimulation site.
• There is uncontrolled hypertension, coronary heart disease, or recent acute myocardial infarction.
• Patients who cannot complete follow-up.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: active transcutaneous auricular vagus nerve stimulatio; For Experimental Arm, active transcutaneous auricular vagus nerve stimulation, Patients underwent fourteen consecutive daily sessions of taVNS.	Device: Transcutaneous auricular vagus nerve stimulation (real stimulation); Transcutaneous auricular vagus nerve stimulation was conducted by transcutaneous electrical stimulation therapy instrument to the cymba conchae of left ear in the vicinity of the auricular branch vagus nerve. Stimulation parameters: frequency = 20/4 Hz; pulse width = 200 μs, twice a day, 30 minutes each time.
Sham Comparator: sham transcutaneous auricular vagus nerve stimulation; For sham transcutaneous auricular vagus nerve stimulation arm, Sham Comparator, patients underwent fourteen consecutive daily sessions of sham-taVNS (the electrodes were fixed at the left earlobe with the same stimulation parameters).	Device: Transcutaneous auricular vagus nerve stimulation (sham stimulation); Transcutaneous auricular vagus nerve stimulation was conducted by transcutaneous electrical stimulation therapy instrument to the left earlobe. Stimulation parameters: frequency = 20/4 Hz; pulse width = 200 μs, twice a day, 30 minutes each time.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes of non-motor symptom scale	Non-motor symptoms such as sleep disorders were evaluated by Parkinson's disease sleep scale (PDSS). The minimum and maximum values of the non-motor part of the PDSS Scale are 0 and 150. A lower score means a worse outcome.	Assessed at baseline, one day post intervention, fourteen days post intervention.
Changes of sleep quality scale	Non-motor symptoms such as sleep disorders were evaluated by Parkinson's disease sleep scale-2 (PDSS-2). PDSS-2 is an improved version of PDSS used to screen for common types of sleep disorders in Parkinson's disease patients. The minimum and maximum values of the non-motor part of the PDSS-2 Scale are 0 and 60. A higher score means a worse outcome.	Assessed at baseline, one day post intervention, fourteen days post intervention.
Changes of Rapid-eye-movement Sleep Behavior Disorder scale	Rapid-eye-movement Sleep Behavior Disorder Screening Questionnaire (RBDSQ) was used to assess the behavior disorder of multiple eye movement sleep. The minimum and maximum values of the non-motor part of the RBDSQ Scale are 0 and 13. A higher score means a worse outcome.	Assessed at baseline, one day post intervention, fourteen days post intervention.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Resting motor threshold (RMT)	RMT (% TMS output intensity) is defined as the lowest intensity required to elicit MEPs of > 50 μV in at least 5 of 10 consecutive trials while the target muscle is relaxed. RMT was determined to be the nearest 1% of the maximum stimulator output.	Assessed at baseline, one day post intervention.
Cortical silent period (CSP)	The CSP (ms) is measured through electromyographic signal recording (EMG) on a target muscle and refers to the period of EMG silence following the elicitation of a motor-evoked potential (MEP) through a single TMS pulse delivered over the contralateral primary motor cortex. Individuals were asked to actively contract abductor pollicis brevis (APB) with 20% of the maximum force, while a single pulse with 150% of RMT was applied to the opposite primary motor cortex. We recorded the time from pulse outputting to the recovery of inhibited active contraction as CSP. The above protocol was repeated ten times, and the average value of CSP was calculated.	Assessed at baseline, one day post intervention.
Intracortical facilitation (ICF)	ICF was assessed with a subthreshold conditioning stimulus (80% RMT) and a supra-threshold test stimulus (1 mV MEP) with a 15 ms interstimulus interval between conditioning and test stimuli. Ten trials were acquired for each interstimulus interval. ICF was expressed as the percentage ratio between the test and conditioning MEP.	Assessed at baseline, one day post intervention.
Changes in ΔHbO2 concentration in the brain cortex	The ΔHbO2 concentration in the brain cortex will be recorded in oxyhemoglobin.	Assessed at baseline, one day post intervention.
The motor part of the Unified Parkinson's Disease Rating Scale	The measure mainly reflects the overall severity of Parkinson's disease motor symptoms. The minimum and maximum values of the motor part of the Unified Parkinson's Disease Rating Scale are 0 and 108. A higher score means a worse outcome.	Assessed at baseline, one day post intervention, fourteen days post intervention.
Serological indicators	5ml of the patient's elbow vein blood was collected and centrifuged after standing and stratified. The serum was collected and frozen at - 20 ℃ for testing. Detection of inflammatory factors indicators.	Assessed at baseline, one day post intervention, fourteen days post intervention.
Short interval intracortical inhibition (SICI)	SICI was assessed with a subthreshold conditioning stimulus (80% RMT) and a supra-threshold test stimulus (1 mV MEP) with a 4ms interstimulus interval between conditioning and test stimuli. Ten trials were acquired for each interstimulus interval. SICI was expressed as the percentage ratio between the test and conditioning MEP.	Assessed at baseline, one day post intervention.
Changes in the cognitive changes	The changes of patients' cognition were evaluated with mini-mental state examination (MMSE) scales. The minimum and maximum values of the non-motor part of the MMSE Scale are 0 and 30. The test scores are closely related to cultural level, and the normal threshold classification criteria are: illiteracy>17 points, primary school>20 points, and middle school and above>24 points. Below the boundary value, there is a cognitive impairment, while above is normal.	Assessed at baseline, one day post intervention, fourteen days post intervention.
Change of anxiety level of patients	The anxiety level of patients was assessed with Hamilton anxiety scale (HAMA) scale. The minimum and maximum values of the non-motor part of the HAMA Scale are 0 and 56. A higher score means a worse outcome.	Assessed at baseline, one day post intervention, fourteen days post intervention.
Changes in depression level of patients	The change of patients' depression level was evaluated with Hamilton Depression Scale 24 (HAMD-24) scale. The minimum and maximum values of the non-motor part of the HAMD Scale are 0 and 96. A higher score means a worse outcome.	Assessed at baseline, one day post intervention, fourteen days post intervention.
Changes in sleep quality, sleep efficiency and other sleep indicators of patients	The changes of patients' sleep quality, sleep efficiency and other sleep indicators were evaluated with Epworth Sleepiness Scale (ESS) scales. ESS scale used to evaluate daytime drowsiness. The minimum and maximum values of the non-motor part of the ESS Scale are 0 and 24. A higher score means a worse outcome.	Assessed at baseline, one day post intervention, fourteen days post intervention.
Changes in patients' fatigue	The fatigue degree of patients was evaluated with Fatigue Severity Scale (FSS) scale. The minimum and maximum values of the non-motor part of the FSS Scale are 7 and 63. A higher score means a worse outcome.	Assessed at baseline, one day post intervention, fourteen days post intervention.
Changes in patients' anxiety level	The change of patients' anxiety was evaluated with apathy scale (AS) scale. The minimum and maximum values of the non-motor part of the AS Scale are 0 and 27. A higher score means a worse outcome.	Assessed at baseline, one day post intervention, fourteen days post intervention.
Changes in the cognitive degree	The change of cognitive degree of patients was evaluated with Montreal Cognitive Assessment (MoCA) scale. The total score of the MoCA scale is 30, generally 26 points or higher is considered normal, between 18-26 points is considered mild cognitive impairment, between 10-17 points is moderate cognitive impairment, and less than 10 points is severe cognitive impairment. If the assessed person has less than or equal to 12 years of education, they are generally only at the high school level, and the result can be increased by 1 point, but the total score cannot exceed 30 points.	Assessed at baseline, one day post intervention, fourteen days post intervention.
Plasma indicators	5ml of the patient's elbow vein blood was collected and centrifuged after standing and stratified. The blood plasma was collected and frozen at - 20 ℃ for testing. Detection of changes in plasma ghrelin levels.	Assessed at baseline, one day post intervention, fourteen days post intervention.
Changes in sleep quality, sleep efficiency of patients	Pittsburgh sleep quality index (PSQI) was used to evaluate the sleep quality of participants in the past month. It consists of 19 self-evaluation and 5 other evaluation items. The total score range is 0-21, with higher scores indicating poorer sleep quality.	Assessed at baseline, one day post intervention, fourteen days post intervention.

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University
• Collaborators: National Natural Science Foundation of China
• Investigators: Principal Investigator: Kezhong Zhang, The First Affiliated Hospital with Nanjing Medical University

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2022
• Primary Completion (Anticipated): June 1, 2023
• Study Completion (Anticipated): July 1, 2023

Study Registration Dates

• First Submitted: February 27, 2023
• First Submitted That Met QC Criteria: April 7, 2023
• First Posted (Actual): April 10, 2023

Study Record Updates

• Last Update Posted (Actual): April 10, 2023
• Last Update Submitted That Met QC Criteria: April 7, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Therapeutics; non-motor symptoms
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Parkinson Disease
• Other Study ID Numbers: 2022-SR-519

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No