Chronic Subjective Tinnitus
Conditions
Brief summary
This study is a prospective, multicenter, randomized, controlled, open-label clinical trial designed to evaluate the superiority of transauricular vagus nerve microcurrent stimulation (taVNS) combined with Tailor-Made Notched Music Training (TMNMT) compared with Tinnitus Retraining Therapy (TRT) in patients with chronic subjective tinnitus. A total of 386 participants aged 18-70 years with a tinnitus duration of at least 6 months and a Tinnitus Handicap Inventory (THI) score ≥38 will be enrolled, excluding individuals with severe hearing loss, organic cranial diseases, or other contraindications. Eligible participants will be randomly assigned in a 1:1 ratio to either the experimental group or the control group. The control group will receive standardized TRT, including habituation sound therapy and structured educational counseling, while the experimental group will receive TMNMT combined with taVNS (0.1 Hz pulse-train stimulation, sub-pain threshold intensity of 0.5-10 mA). Although the trial is open-label, outcome assessors and statisticians will remain blinded to group allocation. Baseline and follow-up assessments include THI, visual analog scale (VAS), Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Pittsburgh Sleep Quality Index (PSQI), audiological evaluations, and multimodal neuroimaging using EEG and fMRI. The primary outcome is the tinnitus improvement response rate at 3 months after treatment initiation, defined as a reduction of more than 7 points in the THI score from baseline. Secondary outcomes include treatment response rates at 6 and 12 months, changes in tinnitus severity and tinnitus-related comorbid symptoms, and neuroplasticity-related changes in central neural mechanisms.
Interventions
DEVICEtranscutaneous auricular vagus nerve stimulation combined with tailor-made notched music training therapy
This group receives combined transcutaneous auricular vagus nerve stimulation (taVNS) and tailor-made notched music training (TMNMT) delivered through a single, registered Class II medical device. The device synchronously administers taVNS (0.1 Hz, pulse train, 0.5-10 mA, titrated below individual pain threshold) and delivers TMNMT via integrated, phase-synchronized algorithms. The notched music is centered at the patient's tinnitus frequency with a ½-octave bandwidth. Treatment consists of 30-minute sessions, four times daily for 3 months.
This group receives standard Tinnitus Retraining Therapy (TRT) using the same device platform, but without active microcurrent output. Therapy includes structured counseling and sound therapy, where broadband natural sounds are delivered at a individually set "mixing" level via the device. Daily sound exposure totals 2 hours over 3 months, supported by initial education and follow-up counseling sessions focused on habituation and cognitive restructuring.
Sponsors
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Patients whose primary complaint is tinnitus and who seek medical care for this reason 2. Patients diagnosed with chronic tinnitus for more than 6 months 3. Age between 18 and 70 years 4. Tinnitus frequency within the range of 125-8000 Hz 5. Hearing threshold not exceeding 70 dB HL 6. Tinnitus Handicap Inventory (THI) score ≥ 38 points.
Exclusion criteria
1. Patients with conductive hearing loss, history of middle ear surgery, pulsatile tinnitus due to vascular malformations, or tinnitus associated with Meniere's disease 2. History of head trauma, central nervous system disorders, psychiatric disorders, or substance abuse/dependence 3. Patients unwilling or unable to comply with the study protocol requirements 4. Patients with space-occupying lesions in the peripheral auditory pathway or central nervous system (e.g., acoustic neuroma, middle ear cholesteatoma, meningioma) as identified by imaging studies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tinnitus Improvement Response Rate | Before treatment and at the end of the 3-month treatment period | The Tinnitus Improvement Response Rate is evaluated based on the change in Tinnitus Handicap Inventory (THI) scores. A higher score indicates greater interference of tinnitus with quality of life. Treatment response is defined as a reduction in the THI score of \>7 points from the baseline assessment after 3 months of treatment, based on the internationally recognized Minimal Clinically Important Difference (MCID) threshold. Calculation Formula: Tinnitus Improvement Response Rate (%) = (Number of Responders / Total Number of Cases in the Corresponding Group) × 100% |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pittsburgh Sleep Quality Index (PSQI) Global Score | Baseline, Month 3, Month 6, Month 12 | The PSQI assesses sleep quality. The Global Score ranges from 0 to 21, where a higher score indicates poorer sleep quality. The outcome is reported as the change in Global Score from Baseline. |
| Change in Self-Perceived Tinnitus Loudness assessed by Visual Analogue Scale (VAS) Score | Baseline, Month 3, Month 6, Month 12 | Patients rate their current perception of tinnitus loudness on a Visual Analogue Scale (VAS) ranging from 0 to 10. A score of 0 represents "extremely faint/imperceptible" tinnitus, and 10 represents "extremely loud/intolerable" tinnitus. The outcome is reported as the change in score from Baseline. |
| Change in Tinnitus Loudness Matching Threshold | Baseline, Month 3, Month 6, Month 12 | Based on the pitch characteristics described by the patient, a test stimulus (pure tone or narrow-band noise, 0.125-8.0 kHz) is selected. Using a bracketing procedure with 2 dB steps, the loudness is matched to the patient's tinnitus perception. The outcome is measured in decibels sensation level (dB SL/HL) relative to the patient's hearing threshold. |
| Number of Participants with Treatment-Related Adverse Events | From Baseline through Month 3 | Total number of participants who experience treatment-related adverse events. Events include auditory system-related reactions (e.g., burns, earache, hearing deterioration, worsening tinnitus) and non-auditory reactions (e.g., dizziness, headache, palpitations, vomiting) deemed related to the intervention. |
| Change in Beck Anxiety Inventory (BAI) Standardized Score | Baseline, Month 3, Month 6, Month 12 | The BAI requires patients to rate 21 anxiety symptoms. The raw score is converted to a standardized score using the formula Y = int(1.19x). Scores range from 0 to 63, with higher scores indicating more severe anxiety. The outcome is reported as the change in standardized score from Baseline. |
| Percentage of Participants Achieving Minimal Clinically Important Difference in THI Score | Month 6, Month 12 | Evaluated based on the Tinnitus Handicap Inventory (THI). A "Responder" is defined as a participant showing a reduction in THI score of \>7 points from baseline (the Minimal Clinically Important Difference). Reported as the percentage of participants in each group who meet this criterion. |
| Change in Quantitative EEG (qEEG) Spectral and Connectivity Metrics (0.5-100 Hz) | Baseline, Month 3, Month 6 | Resting-state EEG data will be recorded and analyzed across the broad frequency spectrum (0.5-100 Hz). The outcome measures include: 1) Power Spectral Density (PSD) across global and local regions; 2) Functional connectivity metrics (e.g., Coherence, Phase Lag Index); and 3) Neural network synchronization. Analysis will be performed to assess changes in cortical activity and inhibition/excitation balance. |
| Change in Functional MRI (fMRI) BOLD Signal and Network Connectivity | Baseline, Month 3, Month 6 | Assessed using resting-state fMRI. Metrics include: 1) Amplitude of Low-Frequency Fluctuations (ALFF) and Regional Homogeneity (ReHo) to reflect local spontaneous brain activity; and 2) Functional Connectivity (FC) strength (z-transformed correlation coefficients) within auditory and non-auditory networks (e.g., Limbic system, Salience network, Default Mode Network). |
| Change in Structural MRI Morphometry (Gray Matter Volume and Cortical Thickness) | Baseline, Month 3, Month 6 | Structural MRI data (T1-weighted images) will be analyzed using Voxel-Based Morphometry (VBM) and surface-based methods. Key metrics include changes in regional Gray Matter Volume (GMV) and Cortical Thickness in tinnitus-related regions (e.g., auditory cortex, prefrontal cortex, hippocampus). |
| Change in Beck Depression Inventory (BDI) Total Score | Baseline, Month 3, Month 6, Month 12 | The BDI consists of 21 groups of items. Scores are summed to obtain a total score ranging from 0 to 63. Higher scores indicate a more severe degree of depression. The outcome is reported as the change in total score from Baseline. |
| Change in Diffusion MRI Metrics and Glymphatic System Activity (DTI-ALPS) | Baseline, Month 3, Month 6 | Diffusion Tensor Imaging (DTI) will be used to assess white matter integrity and glymphatic function. Metrics include: 1) Fractional Anisotropy (FA) and Mean Diffusivity (MD) of auditory pathways; and 2) The DTI-ALPS (Analysis along the Perivascular Space) index, used as a proxy for measuring glymphatic system activity and waste clearance efficiency. |
Countries
China
Contacts
CONTACTYuexin Cai
CONTACTJiahong Li
STUDY_CHAIRYuexin Cai
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Outcome results
None listed