Effects of Transcutaneous Trigeminal Electrical Stimulation and Sound Therapy in Patients with Tinnitus

Abstract

Purpose

Tinnitus is one of the most common health conditions worldwide. Although various methods of treatment have been used, the condition is still difficult to manage or cure. This study aimed to evaluate the therapeutic effects of transcutaneous trigeminal electrical stimulation (TTES) combined with notched sound therapy (NST) on patients with tinnitus.

Materials and Methods

A clinical trial was conducted prospectively from September 2020 to September 2021 at a single center in South Korea. In total, 14 patients took part in this trial. Periodic visits and tele-monitoring were used to assess treatment compliance and collect data, including electroencephalography (EEG), photoplethysmography (PPG), tinnitus handicap inventory (THI), tinnitus magnitude index, Beck Depression Inventory (BDI), Pittsburgh Sleep Quality Index (PSQI), and 36-item short-form survey (SF-36) results.

Results

Changes after intervention were analyzed with paired t-test. This study showed that alpha waves in the left hemisphere measured by EEG (p=0.024), autonomic nervous system balance (p=0.007), and stress level (p=0.022) measured by PPG significantly changed after intervention. Also, THI scores especially emotional symptoms (p=0.029) and catastrophic symptoms (p=0.043) decreased after treatment. The SF-36 score, both mental component summary and physical component summary score (each p<0.001), increased significantly, whereas the PSQI score (p<0.001) and BDI score (p<0.001) decreased after TTES and NST.

Conclusion

Based on the results of our study, we could confirm that TTES combined with NST can significantly improve tinnitus, catastrophic symptoms, and the overall quality of life of patients.

Graphical Abstract

INTRODUCTION

Tinnitus is a condition that is highly prevalent worldwide, and its chronic occurrence can reduce the overall quality of life. Tinnitus is defined as a conscious perception of sound even in the absence of an external sound source.¹ Recently, a large epidemiologic study found that 9.6% of American adults experienced tinnitus for at least 5 minutes in the past year. Among them, 36% reported hearing tinnitus almost always, 7.2% considered tinnitus as a major problem, and 49.4% had consulted a doctor.² For 2.4% of the adult population, tinnitus severely affects their quality of life by causing significant distress.³

There are several causes of tinnitus; and among them, pathological changes in the entire auditory pathway are considered a predominant mechanism. Most cases of tinnitus occur due to cochlear lesions followed by aging, noise-induced hearing loss, sudden sensorineural hearing loss, or administration of ototoxic drugs. This hearing loss can cause abnormal nerve activity in the central auditory pathway, which triggers tinnitus.⁴ In addition, tinnitus is closely related to psychiatric problems, such as anxiety and depression,⁵ and symptoms deviate depending on sleep disturbance.⁶

Therefore, the treatment of tinnitus is difficult since it is closely related to the physical and psychological symptoms and status of each individual. Various methods of treatment have been suggested to relieve tinnitus, including hearing aids or cochlear implants for auditory rehabilitation,⁷ cognitive behavioral therapy,⁸ sound therapy,⁹ pharmacotherapy,¹⁰ and brain stimulation therapy.¹¹ Although these treatments are used alone or in combination, the level of evidence for each treatment is not that high as symptoms are widely heterogeneous and it is difficult to evaluate them objectively.¹²

In the 2000s, research on methods of directly stimulating the brain for intractable tinnitus began in earnest. Brain stimulation enables focal control of neural activity and has the potential to normalize abnormal cranial nerve activity related to tinnitus.¹³ Brain stimulation can be accomplished in a variety of ways and, generally, methods are divided into non-invasive and invasive ways. Among non-invasive methods, transcranial magnetic stimulation (TMS) has emerged since the late 1980s. However, TMS has two important limitations. First, the intensity of the magnetic field drops sharply depending on the distance from the coil surface, which limits direct stimulation of the cerebral cortex below the skull, and the nature of the magnetic field makes it impossible to stimulate specific parts of the cerebral cortex locally.¹⁴ One of the other non-invasive methods is transcranial direct current stimulation (tDCS). Currently, various studies on tinnitus using tDCS are in progress, but the number of subjects is limited and additional research is still needed after considering the pre-existing study results.¹⁵ Methods of invasive brain stimulation include epidural stimulation and deep brain stimulation, but these are still in an early phase of investigation.¹³

In the treatment of tinnitus, there have been several attempts to suppress symptoms by stimulating cranial nerves without directly stimulating the brain. Transcutaneous trigeminal electrical stimulation (TTES) is a representative method that stimulates multiple cranial nerves non-invasively.¹⁶ TTES was initially introduced for the management of musculoskeletal pain,¹⁷ but showed promise as a tool in the treatment of tinnitus in the early 1990s.¹⁸ In particular, neuromodulation by Vagus nerve stimulation has been studied most commonly as a new treatment method for tinnitus.¹⁹ The underlying mechanism involves activating the nucleus of the solitary tract, which in turn activates the locus coeruleus and nucleus basalis, and then releases neuromodulators, which regulate brain plasticity by modulating neurons in the cortex.²⁰ TTES can also modulate brain activity in a bottom-up mechanism. In other words, it stimulates cranial nerves with nuclei in the brainstem, making extensive connections to the limbic cortex and monoaminergic nuclei.²¹ Recently, the usage of TTES has been mainly studied for epilepsy, depression, migraine, and trigeminal neuralgia, but not for tinnitus. However, we are convinced that the trigeminal nerve can affect tinnitus due to its extensive connections to the brainstem and other brain structures. In particular, we hypothesized that tinnitus can be alleviated by changing the plasticity of the brain when applied together with sound therapy, which is currently the most widely used method of tinnitus treatment. Therefore, we aimed to explore the efficacy of TTES application along with sound therapy in patients with chronic tinnitus.

MATERIALS AND METHODS

Participants

A total of 23 participants with tinnitus (≥3 months in duration) were recruited for this study. However, they had to use the device at least 5 times a week for 4 weeks and write in a diary every day, but nine patients who failed to keep this were ultimately dropped out. All participants visited an outpatient clinic of the Department of Otorhinolaryngology between November 2020 and May 2021. Inclusion criteria were as follows: 1) age of 19 years or older; 2) tinnitus handicap inventory (THI)²² score ≥18 at screening; 3) hearing threshold of 70 dB or less based on four frequency averages (0.5, 1, 2, and 4 kHz) in both ears; 4) those who voluntarily agreed to participate in the study; and 5) no plan or possibility of pregnancy during the study period. Exclusion criteria included the following: 1) those who did not meet the inclusion criteria; 2) inability to communicate and/or cooperate during examinations; 3) lesions in the external or middle ear, or central nervous system disorders; 4) intellectual disability or cognitive that would hinder or interfere with a participant’s ability to follow the study instructions; 5) pregnancy or lactation; 6) illiteracy or foreign nationality restricting comprehension of the language used on the trial consent form; 7) intake of drugs used to treat tinnitus, including blood circulation enhancers, vasodilators, and tranquilizers within 2 weeks of study registration; and 8) history of rehabilitation treatment for tinnitus within 2 weeks of study registration. This study was approved by the Institutional Review Board (IRB No. 2020-06-007). Written informed consent was obtained from all participants after approval by the ethics committee. The characteristics of study participants are presented in Table 1.

Table 1. Participant Characteristics (n=14).

Subject No.	Age, yr	Sex	Tinnitus duration, months	PTA*, dB HL		Tinnitus location
				AC, right	AC, left
1	44	F	11	11.25	38.75	Left
2	57	M	36	55.00	43.75	Both
3	22	M	6	21.25	8.75	Right
4	50	M	66	13.75	25.00	Left
5	56	M	12	7.50	8.75	Right
6	53	M	36	33.75	37.50	Both
7	58	F	65	3.75	2.50	Both
8	58	F	3	22.50	6.25	Right
9	49	M	36	36.25	18.75	Both
10	54	M	240	5.00	36.25	Left
11	55	M	96	21.25	28.75	Both
12	63	F	120	17.50	17.50	Right
13	46	M	6	25.00	25.00	Both
14	59	F	15	10.00	16.25	Both

AC, air conduction; PTA, pure-tone average.

^*PTA was the average of thresholds at 500, 1000, 2000, and 4000 Hz.

Procedures

All of the participants visited our laboratory on two separate occasions, spaced out a month apart, and took part in a tele-monitoring session 15 days after the first visit. Before being enrolled in the study, pure-tone audiometry was performed and potential candidates were requested to complete the THI questionnaire to determine whether they met the eligibility criteria. Current and past medication history was obtained from all participants via interviews and confirmed by medical records.

Two-channel electroencephalography (EEG), photoplethysmography (PPG), the tinnitus magnitude index (TMI),²³ the Beck Depression Inventory (BDI),²⁴ the Pittsburgh Sleep Quality Index (PSQI),²⁵ and a 36-item short-form survey (SF-36)²⁶ were conducted both pre- and post-intervention. The two-channel EEG and PPG were measured with a neuroNicle FX2 (Omni C&S. Inc., Seoul, South Korea). The EEG reflects potential for the current to pass between two electrodes on both the right and left frontal lobes. The EEGs were classified across six frequency bands, theta power (4–7.99 Hz), alpha power (8–11.99 Hz), low beta power (12–14.99 Hz), middle beta power (15–19.99 Hz), high beta power (20–29.99 Hz), and gamma power (>30 Hz). The lower EEG power refers to internal mental processing; higher EEG power refers to external mental processing.

The PPG signals were extracted from the earlobe sensor and measured autonomic nervous system (ANS) activity, sympathetic nervous system (SNS) activity, parasympathetic nervous system (PNS) activity, ANS balance, the heart rate variability (HRV) index, and stress score according to the manufacturer’s guidelines. The ANS activity refers to the overall activity of the SNS and PNS. The ANS balance is the degree of balance between the SNS and PNS. The higher the HRV index, the healthier the heart.

The questionnaires were filled out pre- and post-intervention. The THI and TMI were performed to compare the severity of the subject’s tinnitus pre- and post-intervention. The BDI was intended to examine whether there was a change in depressive symptoms over time. The PSQI was used to measure changes in subjective sleep quality. Finally, the SF-36 was conducted to evaluate health-related quality of life.

Upon the first visit, instructions to use the electrical stimulation device (NUEYNE-T100, NuEyne, Seoul, South Korea) were provided, and precautions were taken to avoid safety issues. Electrical stimulation was performed by attaching an electrode to the first branch of the trigeminal nerve (Fig. 1), followed by percutaneous nerve stimulation with 30 Hz pulse stimulation at 4–7 mA. In addition, the sound files were uploaded to the mobile phones of the participants. The sound files contained notched sound, with “notched” meaning that a participant’s tinnitus frequency is eliminated. Participants were also asked to keep a daily diary for 4 weeks by simply checking their use of the device. Participants received therapy for 4 weeks at a frequency of at least 5 times a week for at least 30 minutes per day. Measurements obtained in the first visit were also repeated during the follow-up visit. The degree of adherence to the treatment was evaluated from the diary.

Fig. 1. Appearance (A) and electrode patch (B) of the transcutaneous electrical nerve stimulation device used in the present study.

Statistical analysis

Before conducting statistical analysis, a normality test was performed on the variables using the Kolmogorov-Smirnov test. The results indicated a significance level of 0.05 or higher, suggesting that the variables followed a normal distribution. Therefore, parametric statistics were performed based on the assumption of normality. In descriptive statistical analysis, mean and standard deviation (SD) were used for continuous variables, whereas numbers and percentages were used for categorical variables. Paired t-test was applied to determine significant changes between baseline (pre) and follow-up (post). The significance level was set to 0.05 for all tests. All statistical analyses were completed using SPSS version 29.0 (IBM, Corp., Armonk, NY, USA).

RESULTS

EEG

The EEG was measured and analyzed for the left and right hemispheres of the brain using two-channel equipment. EEG was measured in four major waveforms (theta, alpha, beta, and gamma); and to measure concentration, tension, and anxiety in detail. Beta was divided into three categories: low, middle, and high.

In most of the EEG obtained from the left and right hemispheres, there was no significant change before and after treatment, and the effect of the size was small. However, there was a significant difference between the pre- (mean±SD=4.54±0.95) and post-intervention (mean±SD=4.50±0.95) in alpha in the left hemisphere (p=0.024) (Table 2).

Table 2. Results of Electroencephalogram (n=14).

Clinical values		Pre, mean±SD, Hz	Post, mean±SD, Hz	p value
Right hemisphere
	Theta	4.80±1.64	5.12±1.59	0.325
	Alpha	4.54±1.02	4.44±0.85	0.064
	High beta	5.90±1.70	5.92±1.04	0.902
	Middle beta	5.44±1.60	5.56±1.20	0.322
	Low beta	6.49±1.52	7.50±1.99	0.937
	Gamma	5.42±1.84	5.30±0.98	0.726
Left hemisphere
	Theta	4.88±1.47	5.44±1.73	0.193
	Alpha	4.54±0.95	4.50±0.95	0.024*
	High beta	5.81±1.44	6.32±1.20	0.588
	Middle beta	5.35±1.27	5.87±1.27	0.899
	Low beta	6.11±1.01	7.83±1.77	0.904
	Gamma	5.40±1.49	5.74±1.08	0.670

SD, standard deviation.

^*p<0.05.

PPG

To evaluate the stress of the patients caused by tinnitus objectively, the PPG, which can reflect the state of the ANS, was also measured. There was a significant difference between the pre- (mean±SD=48.87±4.34) and post-intervention (mean±SD=49.45±4.90) in ANS balance (p=0.007). In addition, there was also a significant difference between the pre- (mean±SD=47.17±6.70) and post-intervention (mean±SD=45.58±10.25) in stress (p=0.022) (Table 3).

Table 3. Results of Photoplethysmography (n=14).

Clinical values	Pre, mean±SD	Post, mean±SD	p value
ANS activity	6.54±1.11	7.08±0.71	0.219
PNS activity	5.21±0.92	5.63±0.95	0.197
SNS activity	5.07±1.22	5.49±0.72	0.072
ANS balance	48.87±4.34	49.45±4.90	0.007†
HRV index	10.31±5.07	12.81±3.74	0.230
Stress	47.17±6.70	45.58±10.25	0.022*

ANS, autonomic nervous system; HRV, heart rate variability; PNS, parasympathetic nervous system; SD, standard deviation; SNS, sympathetic nervous system.

^*p<0.05; ^†p<0.001.

Questionnaires

Regarding the THI, there were significant differences between the pre- (mean±SD=16.86±9.85) and post-intervention (mean±SD=12.43±6.76) in the emotional symptoms (p=0.029). In addition, there were significant differences between the pre- (mean±SD=12.57±5.29) and post-intervention (mean±SD=9.86±4.19) in the catastrophic symptoms (p=0.043). In the BDI, there was a significant difference between the pre- (mean±SD=9.64±8.12) and post-test score (mean±SD=7.14±5.86) (p<0.001). For the PSQI, there was a significant difference between the pre- (mean±SD=9.15±2.97) and post-test score (mean±SD=7.92±2.50) (p<0.001). For the SF-36, there were significant differences between the pre- (mean±SD=69.82±15.63) and post-intervention (mean±SD=74.69±15.16) in the physical component summary (p<0.001). Similarly, there were significant differences between the pre- (mean±SD=67.71±20.20) and post-intervention (mean±SD=71.74±18.45) in the mental component summary (MCS) (p<0.001). Moreover, there were significant differences between the pre- (mean±SD=68.77±16.69) and post-intervention (mean±SD=73.21±16.40) in the total scores (p<0.001) (Table 4).

Table 4. Results of Questionnaires (n=14).

Clinical values		Pre, mean±SD	Post, mean±SD	p value
THI
	Functional	25.00±8.37	19.86±8.17	0.104
	Emotional	16.86±9.85	12.43±6.76	0.029*
	Catastrophic	12.57±5.29	9.86±4.19	0.043*
	Total	55.71±20.86	42.14±15.70	0.145
TMI
	Loudness	6.57±2.34	6.64±1.15	0.162
	Awareness	78.57±17.03	69.29±25.26	0.111
	Severity	75.71±18.36	67.19±19.43	0.354
BDI		9.64±8.12	7.14±5.86	<0.001†
PSQI		9.15±2.97	7.92±2.50	<0.001†
SF-36
	PCS	69.82±15.63	74.69±15.16	<0.001†
	MCS	67.71±20.20	71.74±18.45	<0.001†
	Total	68.77±16.69	73.21±16.40	<0.001†

BDI, Beck Depression Inventory; MCS, mental component summary; PCS, physical component summary; PSQI, Pittsburgh Sleep Quality Index; SD, standard deviation; SF-36, 36-item short-form survey; THI, tinnitus handicap inventory; TMI, tinnitus magnitude index.

^*p<0.05; ^†p<0.001.

DISCUSSION

This trial has confirmed the clinical efficacy of TTES combined with notched sound therapy (NST) in improving symptoms of tinnitus in patients. In this study, we not only objectively and subjectively analyzed the degree of relief from tinnitus but also evaluated the secondary effects, including EEG, PPG, sleep quality, and overall quality of life, which had not been evaluated in other studies and is an advantage in the current study. The present study has suggested and confirmed the efficacy of specific frequency levels appropriate for TTES based on previous studies. Considering that TTES and NST are non-invasive, conducted by patients, and safe therapies, TTES combined with NST seems to be a very promising treatment modality for tinnitus. By introducing TTES and NST to clinical practices, patients will be able to play leading roles in their course of treatment and effectively treat tinnitus. However, based on this result alone, it is not possible to determine which TTES or NST was more effective for tinnitus in patients. However, it is well-known that multi-modal treatment is effective in the treatment of tinnitus, considering the results of numerous studies and the characteristics of subjective tinnitus.

Although the mechanisms between TTES and the neural circuits involved are unclear, several studies have shown that TTES has the potential for use as an alternative tool to treat tinnitus. The trigeminal nerve has a connection to the dorsal cochlear nucleus (DCN) and plays a major role in integrating somatosensory and auditory input signals. Somatosensory projections including trigeminal nerve connection usually suppress other types of excitatory signals, including auditory signals.²⁷ The somatosensory stimulation of the DCN also prevents self-generated auditory signals, such as masticating and vocalizing sounds, from activating the central auditory system.²⁸ Considering all these inhibitory effects of the somatosensory inputs, especially trigeminal nerve inputs to the DCN, TTES may suppress unnecessary activation of the DCN and central auditory system. However, the effects of stimulating solely the trigeminal nerve without other input signals remain to be demonstrated.

Additionally, TTES changes the response patterns of cochlear nuclei neurons and the deafferentation status of the cochlear nuclei.²⁹ Given that one of the important mechanisms of tinnitus is auditory deafferentation,³⁰ TTES may compensate for its deafferentation status. Consistent with these possible mechanisms of treatment, our study has also shown an improvement in tinnitus symptoms, especially severe symptoms.

We also collected EEG results to determine the effect of TTES on EEG and brain function. As a result, low beta waves, which usually represent concentration and inner thoughts, increased after TTES. A higher frequency of low beta waves might represent increased powers of concentration, and norepinephrine may have contributed to this improvement of function. According to a proposal in a previous study, TTES has the potency to activate the locus coeruleus, increasing cortical norepinephrine levels, and, consequently, enhance the signal-to-noise discriminating function.³¹ Although the correlation between TTES and cortical norepinephrine level is yet to be clearly defined, if it is confirmed, increased cortical norepinephrine level will also be able to improve the overall cognitive function of the patient.

PPG is evaluated as the easiest and most efficient way to reflect ANS in the human body. As is well-known, the balance of the ANS decreases in stressful situations. On the other hand, in a relaxed state, the ANS is more balanced. In the present results, it showed a statistically significant increase in balance score after treatment. When other parameters including heart rate variation were analyzed, it was confirmed that the overall stress value itself was significantly lowered.

The THI used in this study is one of the most commonly used questionnaires to evaluate the severity of tinnitus symptoms.³² Previous studies have demonstrated the reliability, validity, and consistency of the THI.²² The THI consists of 25 items with three subscales (functional, emotional, and catastrophic). In the present study, emotional and catastrophic domains were statistically significantly improved. Among these, catastrophic subscales that have a high correlation with depression, anxiety, somatic symptoms, subjective loudness, and annoyance decrease significantly after TTES. In consideration of this result, the combined treatment of TTES and NST will be able to improve not only subjective symptoms but also the discomfort of patients.

Tinnitus reduces the quality of life of patients by affecting various aspects of their daily lives, including emotion, sleep, and daytime activities. Self-reported BDI scores that evaluate the depressive symptoms of patients also decreased after TTES. Although the median score of BDI decreased from 8 points to 7 points before treatment, all of these results were within the normal range. Therefore, it is difficult to conclude that TTES and NST improve the depression caused by tinnitus in patients.

Tinnitus can significantly affect sleep quality, as several patients experience their most severe tinnitus symptoms during a quiet evening, just before bedtime, or early in the morning. Therefore, measuring the sleep quality of patients with tinnitus is very important, and the results of this study demonstrate that TTES with NST has significantly improved the sleep quality of patients, with significant changes in PSQI scores. Total SF-36 scores representing patient’s quality of life also increased significantly. Among 36 items, MCS scores that assess the mental component show a meaningful increase after TTES. In summary, TTES with NST improves the quality of sleep and overall quality of life of patients. The effects of TTES on emotion require further studies with long-term follow-up.

Our study had several limitations, with the small sample size being a notable example. Due to difficulties in recruiting participants and patients dropping out, a small number of patients were included in the final analysis. In addition, for a more objective comparison, a separate control group should have been selected. Furthermore, NST was applied together with TTES in this study. The effects of TTES alone will also be assessed in further studies. Nevertheless, through this study, we showed that, with non-invasive and minimal side effects, combining TTES and NST has potential for the treatment of patients with chronic tinnitus. A large-scale, double-blind randomized clinical study, including a sham control group, should be conducted in the near future.

This study demonstrated that TTES combined with NST reduced symptoms in patients with chronic tinnitus, alleviated depression, and improved sleep quality. As these therapeutic effects may improve the quality of life of patients with chronic tinnitus, further research should be conducted.