1. Introduction
Tinnitus is the subjective perception of a sound without an external source [
1] and is a symptom that can be caused by various conditions (e.g., hearing loss, cardiovascular or neurological disease, thyroid disease, diabetes, or cancer). Several etiological factors were identified for tinnitus, such as peripheral differentiation and synaptopathy, spontaneous ascending activity, GABA-ergic deficiency, or cholinergic excess, all likely contributing to central plasticity [
2]. However, in clinical settings, the cause of tinnitus frequently remains unknown, in which case tinnitus is idiopathic. There is currently no drug treatment available for this condition. Sometimes, causal treatments can effectively reduce or even eliminate tinnitus. A good example is auditory therapy, such as fitting hearing aids [
3,
4] or auditory rehabilitation with cochlear implants [
5] in patients with tinnitus caused by hearing loss.
There are currently no FDA-approved pharmacologic treatments for tinnitus. Cognitive and multimodal behavioral therapies are used to reduce the psychological distress caused by tinnitus and to prevent or treat psychological complications. The need for such treatment is determined by the level of distress caused by tinnitus and existing or developing comorbidities. However, even with all therapeutic options, patients with high tinnitus burden may experience severe limitations in daily life and work ability [
6,
7]. In addition to decreased quality of life, tinnitus is associated with high socioeconomic costs [
8]. Therefore, a reliable and effective treatment for tinnitus would be of significant medical and socioeconomic importance.
Therapeutic approaches using electrical stimulation of the cochlea to reduce tinnitus perception have been developed since the 1970s [
9,
10]. In addition, numerous studies that have analyzed the effects of cochlear implants (CI) on tinnitus have found them effective in reducing tinnitus loudness [
11,
12,
13,
14]. However, despite the evidence that CI can reduce tinnitus, it is unclear whether the reduction is achieved by counteracting peripheral deafferentation [
15], electrical stimulation via an implanted electrode [
16], or by the interaction of both. In addition, although several clinical studies have provided data on partial or complete reduction of tinnitus in patients with cochlear implants, it is not yet clear before implantation which patients will respond positively to tinnitus reduction after CI activation. Research suggests an association between a higher degree of hearing loss and a greater likelihood of tinnitus improvement after cochlear implantation [
17]. Still, this is not a rule that always works.
The literature confirms the beneficial effects of cochlear implants on tinnitus in many CI users [
11,
13,
18]. In addition, there is evidence that auditory rehabilitation with CI improves quality of life and reduces stress and psychological comorbidities [
18]. Therefore, developing an extracochlear implant for tinnitus patients, regardless of the degree of hearing loss, is essential in clinical audiology. Hence, the need emerged to create a system that could electrically stimulate the inner ear in tinnitus sufferers without the necessity for irreversible tissue damage—for example, in the form of a micro-implant placed on the round window. As part of the “INTAKT” initiative funded by the German Federal Ministry of Education and Research and dedicated to designing implants to help resolve various physiological deficits, the current project focused on determining the feasibility and effectiveness of external electrical stimulation through the ear canal in reducing tinnitus. Another project goal was to identify factors that may influence the anti-tinnitus efficacy of electrical stimulation. Obtaining such information is critical to developing an extracochlear implant for treating tinnitus and is an essential contemporary topic in clinical audiology.
To address these issues, the current proof-of-principle feasibility study aimed to determine if electrical stimulation using an electrode placed in the ear canal could decrease loudness and tinnitus-induced distress in human subjects. In addition, the results were analyzed based on the type of stimulation, the subjects’ gender, and the severity or laterality of the tinnitus.
4. Discussion
In the current proof-of-concept study, we wanted to determine if non-invasive electrical stimulation through the ear canal can suppress loudness and tinnitus-induced distress. Moreover, we sought to determine the factors influencing the suppressing effect. The study was designed to deliver proof of concept and demonstrate the feasibility of electrical stimulation in reducing tinnitus loudness and distress. The factors tested included the frequency of current used for stimulation, the sequence of application of different stimulation currents, tinnitus grade at admission, tinnitus laterality, sex, and age of the patients. Some intermediate results obtained during this project have already been reported in the literature [
20] to satisfy the funding agency’s requirements.
Analysis of the electrical stimulation results showed that 47% of patients in our study experienced a statistically significant reduction in tinnitus loudness. Other studies using a similar electrical stimulation system to reduce tinnitus have had mixed results. Mielczarek et al. performed two studies. The first included six patients who received unilateral stimulation, after which improvement was noted in 83.3% of the ears and no change in 16.7% [
24]. In the second study, the ears of 28 patients with tinnitus were tested individually, and a reduction in tinnitus intensity was found in 75%, no change in 18%, and worsening in 7% [
25]. The study by Zeng et al. [
26] included ten patients with tinnitus, four of whom received non-invasive stimulation via the outer ear. Two patients reported no change during or after stimulation. The other two reported a slight reduction in tinnitus during stimulation, and one found its complete disappearance after stimulation. Finally, a study by Suh et al. [
27] in 14 tinnitus patients showed an average 22% reduction in tinnitus when stimulated through the ear canal. There are fundamental differences between our current study and those conducted by other researchers. The first difference is in the number of patients, which were 66 in our study, 6 and 28 in Mielczarek’s study, 4 in Zeng’s study, and 14 in Suh’s study. Not only the number but also the age of the patients varied (mean 54.4 ± 10.44 years in our study, 53.4 ± 15.6 and 58.5 ± 11.83 years in Mielczarek’s study, 61.5 ± 9.25 years in Zeng’s study, and 44 years in Suh’s study with no SD mentioned).
Other differences are the parameters used for stimulation, such as frequency (100 or 1000 Hz for us, 250 Hz [
24], or 0.25, 1, 2, 3, 4, 5, 6, 7, and 8 kHz [
25] for Mielczarek, 10 to 10,000 Hz for Zeng and 0.01 to 10 kHz for Suh), as well as stimulation duration (10 min for us, not specified for Mielczarek, 2–3 min and sometimes longer for Zeng, and 3 min or longer for Suh). In addition, due to a lack of suitable commercially available equipment, we and other groups used homemade stimulation devices, which could have also contributed to differences in the results.
The frequency of the current used (100 Hz or 1000 Hz) and the sequence of its application did not produce significant differences in reducing tinnitus loudness or distress under the applied conditions. The subjective loudness of the tinnitus measured in the entire group had already decreased significantly on the first day after the 10-min stimulation and on the second and third days. In contrast, tinnitus distress did not decrease significantly until the second and third days of stimulation.
Women reported reduced tinnitus loudness after the first, second, and third stimulation. In contrast, men reported a reduction after the second and third stimulation. Gender differences in sensory reactivity to external electrical stimulation are known to explain the greater sensitivity to pain in women [
28,
29], likely due to differences in body fat or water content [
30]. This type of study has not yet been conducted in audiological research. Still, the physical factors affecting women’s greater sensitivity to electrical stimulation could likely be universal, explaining the results of our study.
We also found that patients with compensated/habituated and decompensated/unhabituated tinnitus reported significantly reduced loudness after the second and third stimulations. Despite this, only patients with compensated/habituated tinnitus experienced a significant reduction in tinnitus distress after the 3 days of electrical stimulation. No comparable data are available in published research; however, it is known that the emotional status of patients affects both loudness and tinnitus-induced distress [
31,
32] and can be subject to fluctuations [
33]. We hypothesize that the patients with decompensated/unhabituated tinnitus may have negative valence and emotional status that contribute to tinnitus-induced distress but are not a target of electrical stimulation. However, since the emotional status of the patients was not the subject of our study, we cannot confirm or reject such a hypothesis.
There were differences in stimulation efficacy between patients with unilateral and bilateral tinnitus. The latter group reported a reduction in tinnitus loudness after the first stimulation as well as the second and third stimulations. In contrast, patients with unilateral tinnitus improved only after the third stimulation. We thought this result could be attributed to possible differences in tinnitus habituation between the groups. Still, the proportion of compensated/habituated cases within the two groups (7 cases (58.3%) in the unilateral group and 30 (55.6%) in the bilateral group) were comparable and cannot explain the effect seen. However, our sample was relatively small, and no data were available on compensation for three patients with unilateral tinnitus (25% of the group) and four patients in a bilateral group (7.4%). Different results were obtained by Genitsaridi et al. [
34] and Song et al. [
35], who suggested that unilateral tinnitus is more distressing than bilateral. Nevertheless, our observations are consistent with those made by Aazh et al. [
36], who used a large sample of patients (n = 311) with unilateral and bilateral tinnitus for the comparative analysis and did not find differences in tinnitus severity between the two groups by Tinnitus Handicap Inventory THI. Furthermore, sex distribution was similar within the groups (W/M 33%/67% in unilateral and 46%/54% in bilateral group), therefore unlikely accounting for the effect seen. We also sought to explain the differences in the efficacy of electrical stimulation on tinnitus-induced distress in terms of audiological parameters. Using degrees of hearing loss in the comparative analysis, we found no explanation for the observed differences, which agrees with the study of Yang et al. [
37]. Aazh et al. pointed out the importance of interaural asymmetry in unilateral but not bilateral tinnitus patients [
36]. That aspect should be studied in the future in electrical stimulation. Moreover, neuropsychological differences between the patients with unilateral and bilateral tinnitus suggest significant deficits in the auditory memory and attention of the unilateral and not bilateral group [
34], highlighting the disparity between unilateral and bilateral tinnitus.
Spearman’s rank-order correlation confirmed the long-known association between hearing loss and tinnitus grade [
38] or age and degree of hearing loss [
39]. Still, it did not reveal any association between the electrical stimulation results and the patient’s age, duration of tinnitus, degree of tinnitus, or hearing loss, suggesting complex mechanisms underlying the efficacy of stimulation.
The information gathered during this study fulfilled the expectations of the INTAKT project by providing parameters relevant to extracochlear electrical stimulation for tinnitus. This knowledge will be helpful in the future development of a tinnitus implant. In addition, the results should help select patients for cochlear implantation and may help predict tinnitus reduction after CI.
Our study is not without limitations. The first is the relatively small sample size, which should be increased. Initially, at least 100 patients were supposed to be included. However, because we conducted the study during the pandemic period (from the end of 2019 to the end of 2021), we were limited by patient access to the hospital, national and internal regulations governing the clinical research activities of tertiary healthcare centers during the pandemic, as well as the high incidence of COVID-19 among staff. The second limitation is the lack of a control group, which agrees with the proof-of-concept design but leaves questions about the placebo effect open. Future randomized controlled trials should include control, sham-stimulated tinnitus patients, who would be informed that the stimulation begins when, in fact, the equipment would be switched off. A final pitfall of our research is the insufficient audiometric information on matched tinnitus loudness and frequency and possible comorbid psychological conditions. It is recommended that such information be collected in future studies.
We envision a twofold future for this project. First, continuing the stimulation scheme described here would be essential to determine if stimulation on four or more consecutive days could extinguish or decrease the tinnitus sound and distress, as it did in one patient in our sample. It would also be essential to know how long the positive effect of electrical stimulation lasts. Second, this project was designed as a pilot one in preparation for the design of an extracochlear anti-tinnitus implant. The information gained during this study should help draw a blueprint for such a device in the near future.