The Evaluation of Effects of Electrical Stimulation in Treatment of Patients with Chronic Tinnitus with Normal Hearing Sensitivity

Abstract

Tinnitus is usually associated with different comorbidities such as anxiety, annoyance and depression. Evidences have targeted two main places for tinnitus treatment, namely the auditory cortex and the dorsolateral prefrontal cortex (DLPFC). Transcranial direct current stimulation (tDCS) has been reportedly associated with improvement of cognitive functions in individuals. This study was conducted to evaluate the therapeutic effects of repeated sessions of anodal bifrontal tDCS on tinnitus symptoms. Furthermore, the tDCS impacts on the comorbid depression and anxiety of the patients were investigated. Forty-two voluntaries that suffers from chronic tinnitus were randomly assigned into “real tDCS” (n = 21) and “sham tDCS” (n = 21) groups. The tDCS group, received tDCS with the protocol consisted of 2 mA current, daily one session of 20 min, 6 consecutive days per week and for 4 consecutive weeks. The tinnitus handicap inventory (THI) scale, was measured before the first tDCS session and at one-week and two weeks follow-up. With the same intervals; the distress-related tinnitus was evaluated using visual analogue scale. Depression and anxiety scores were also measured using the Beck depression inventory and Beck anxiety inventory scales, respectively. Our findings indicated that THI score, depression and anxiety level has been gradually diminished across subsequent measurement intervals. We also find significant reduction of distress-related tinnitus in the real-tDCS group after treatment. We conclude that application of tDCS to the bilateral DLPFC region alleviates chronic tinnitus and it should be considered in patients with refractory tinnitus.

Introduction

Tinnitus is defined as the phantom perception of the sound or noise in the absence of an external physical sound source [1]. This auditory phantom perception is usually associated with different comorbidities such as anxiety, annoyance, depression, sleep disturbances, and concentration problems. Multiple parallel and overlapping cortical networks such as the somatosensory cortex, auditory cortex, memory regions (hippocampus and amygdala), salience areas (anterior insula and dorsal anterior cingulate cortex), and distress networks (amygdala and anterior insula) are believed to be involved in the pathophysiology of tinnitus [2–4].

Although most early investigations in the tinnitus field focused on the role of peripheral auditory system abnormality in the tinnitus percept, recently focus has changed to the idea that differential neural connectivity in the cortex may also describe the amount of discomfort reported by tinnitus patients. It seems that tinnitus is originated from enhanced spontaneous activity in the auditory cortex and that chronic tinnitus may be similar to neuropsychiatric disorders related to plastic alterations of the brain. Auditory system hyperactivity might be evident not only in focal changes in neural activation but in functional connectivity across cortical networks [5–8]. If dysfunctional neural connectivity in central auditory system networks is an origin of tinnitus distress, changing this activity may be a beneficial treatment.

Transcranial direct current stimulation (tDCS) is a non-invasive and safe neuromodulation procedure that has been reportedly associated with beneficial effects in improving cognitive functions in healthy individuals as well as symptoms of various neuropsychiatric dysfunctions including obsessive–compulsive disorder, depression, stroke, chronic pain, and auditory-verbal hallucinations [9–15].

Several studies have shown the efficacy of tDCS for the treatment of chronic tinnitus [16–20]. Recent evidences have targeted two main places for tinnitus treatment, namely the auditory cortex and the dorsolateral prefrontal cortex (DLPFC) [21–23]. The DLPFC seems to play an important role in auditory processing. The DLPC has a bilateral facilitatory impact on auditory memory storage and contains auditory memory cells. The DLPFC also regulates the input to the primary auditory cortex in humans and is related to auditory attention which leads to top-down modulation of central auditory processing [24, 25].

In a double-blind, placebo-controlled trial, Faber et al.[24] investigated the effects of multi-session cathodal (cathode left/ anode right) or anodal (anode left/cathode right) DLPFC tDCS in 15 tinnitus patients. The results of this study suggested that both active cathodal/anodal conditions reduced tinnitus annoyance, whereas no significant improvement was reported regarding tinnitus intensity. The authors also found that left DLPFC anodal tDCS significantly improved depression ratings, while left DLPFC cathodal tDCS improved anxiety ratings. Furthermore, these results support the role of the prefrontal cortex as a potential target for cortical stimulation and/or modulation procedures for tinnitus treatment, especially regarding tinnitus with comorbid mood dysfunctions and in combined treatment protocols.

Frank et al. [20] designed an open-label study to investigate the impact of repeated sessions of prefrontal tDCS (six sessions of 30 min, 1.5 mA, two sessions per week, three consecutive weeks) in patients with chronic tinnitus. Treatment impacts were measured with a visual analogue scale for tinnitus loudness and distress. They reported a significant reduction for both tinnitus-related loudness and tinnitus discomfort. Furthermore, the amount of suppression for tinnitus-related distress was moderated by an interaction between tinnitus type and tinnitus laterality.

Few studies have aimed to evaluate possible long-lasting treatment consequences of the tDCS approach by assessing the influences of repeated sessions of tDCS on tinnitus symptoms. The purpose of this study was to evaluate the therapeutic effects of electrical stimulation on tinnitus symptoms. Furthermore, the tDCS impacts on the comorbid depression and anxiety of the patients were investigated.

Materials and Methods

Participants

Forty-two right-handed participants (mean age 46.29 ± 8.16 years; range: 24–63 years) without any tDCS contraindications (stroke, cardiovascular disease, neurological disease, previous brain surgery, metal or electronic implants, or mental illnesses) were enrolled. All subjects had normal hearing sensitivity (< 20 dB HL hearing thresholds) and reported a chronic tinnitus lasting for at least 12 months, with an average tinnitus duration of 7.36 years (ranging from 3 to 12 years). Fifteen patients (10 left-sided and 5 right-sided) had unilateral and 27 had bilateral tinnitus. The quality of tinnitus was documented for each patient, and 26.19% (n = 11) rated it as hissing, 19.04% (n = 8) as high-pitch whistling, 23.80% (n = 10) as ringing, 16.66% (n = 7) as buzzing, and 14.28% (n = 6) as other qualities. Written voluntary consent for their participation was obtained after a detailed explanation regarding the potential risks of the test and precautions were provided. The protocol of the current study was approved by the local Ethics Committee (Ethics number: IR.AJUMS.HGOLESTAN.REC.1400.010) and registered as a clinical trial in the Iranian registry of clinical trials (IRCT registration number: IRCT20210429051130N1).

Experimental Protocol

After inclusion, the study population (n = 42) were randomly assigned into two groups: “real tDCS” (n = 21) and “sham tDCS” (n = 21). In the sham tDCS group, the electrode montage was similar to real tDCS, but the device was turned off after 30 s without the participant’s knowledge. These parameters for sham stimulation were chosen according to previously reported findings where the perceived sensations of electrical stimulation on the skin (e.g., tingling) usually disappear in the first 30 s of active tDCS.

tDCS Procedure

The tDCS was conducted using a battery-driven OASIS Pro™ DC-Stimulator (Mind Alive Inc., Edmonton, Alberta, Canada). A pair of electrodes (surface of 35 cm²) was placed in saline-soaked sponges. The tDCS protocol consisted of 2 mA current, daily one session of 20 min, 6 consecutive days per week and for 4 consecutive weeks (total 24 sessions). The anodal or cathodal electrode was placed over the left (F3) or right (F4) dorsolateral prefrontal cortex (DLPFC) region according to the International 10–20 EEG system.

Hearing Assessment

All the recruited subjects underwent hearing assessment in a soundproof room (ISO 82531–2009). Pure tone audiometry (PTA) was conducted using a dual-channel audiometer across the 125 to 8000 Hz frequency range. PTA was carried out using the modified Hughson-Westlake approach.

Clinical Evaluation

The tinnitus handicap inventory (THI) scale was measured before the first tDCS session and at one-week and two-weeks follow-up. The “distress” resulting from tinnitus was evaluated using a 0–10 rating numerical visual analogue scale (VAS) prior to tDCS stimulation and at one and two weeks post-stimulation intervals. A lower score of loudness reveals a reduction in perceived tinnitus loudness rating. Depression and anxiety scores were also measured before the first tDCS session, and at one-week and two-weeks follow-up sessions, using the Beck depression inventory (BDI) and Beck anxiety inventory (BAI) scales, respectively.

The BAI consists of 21 items that measure symptoms of anxiety on a 4-point Likert scale ranging from 0 = not at all to 3 = severely. The anxiety level will be scored using ordinal categories: minimal (1–5 points), mild (6–15), moderate (16–30) and severe (31–63). Higher scores indicate greater anxiety symptoms.

The BDI consists of 21 items that evaluate symptoms of depression using a 4-point rating scale (0–3). The anxiety level will be scored using ordinal categories: minimal (1–13 points), slight (14–19), moderate (20–28) and severe (29–63). Higher scores demonstrate greater depressive symptomology.

Statistical Analysis

The primary outcome parameter of the current study was the THI score. Secondary outcome measures were BDI, BAI, and tinnitus distress scores. A mixed repeated-measures analysis of variance (RM-ANOVA) with the within‐subject factor Time and the between‐subject factor Stimulation was conducted to compare primary and secondary outcomes between the pre- and post-treatment time intervals. For the ANOVAs, sphericity was assessed with the Mauchly's test, and in the event of a violation of Mauchly’s test, the Greenhouse–Geisser correction was applied. All data analysis was performed by SPSS 24.0 software (IBM Corporation, New York, USA). A criterion for statistical significance of 0.05 was chosen.

Results

Table 1 shows the subject’s demographic and baseline clinical characteristics. At baseline, both study groups were well-matched for age, sex, and duration of tinnitus symptoms. The chi-square test indicated that there was a similar proportion of males and females across groups (χ² = 1.52, p = 0.354) and that the duration of symptoms was proportionate across groups (p = 0.056). The mean hearing thresholds showed no statistical differences between the two groups or between ears (p > 0.05). The majority of patients (29/42 = 69.05%) had unilateral tinnitus, while 30.95% of patients suffered from bilateral tinnitus.

Table 1.

Demographic and clinical features of patients with tinnitus

Variable	Group		p-Value	Test
	Real tDCS (n = 21)	Sham (n = 21)
Age (yrs) mean ± SD	46.38 ± 7.16	46.19 ± 9.23	t = 0.75; p = 0.941	Independent sample t
Tinnitus duration (yrs) mean ± SD	8.14 ± 2.90	6.62 ± 2.04	t = 1.96; p = 0.056	Independent sample t
Gender (n)	13 M; 8 F	9 M; 12 F	x2 = 1.52; p = 0.354	Chi square

tDCS transcranial direct current stimulation

*Values are in mean ± SD

For the primary outcome parameter, THI, we found no significant difference between both groups before stimulation (Independent samples t-test, p = 0.286) (see Table 2). The repeated-measures ANOVA demonstrated a significant main effect of Time, Stimulation, and a significant two-way interaction between Time and Stimulation factors (p = 0.002). Our results showed that THI scores were highest at the “pre-treatment” condition, and following real-tDCS stimulation, the THI score has been gradually diminished across subsequent measurement intervals (see Fig. 1).

Table 2.

Comparison of baseline primary and secondary outcome measures between real-tDCS (n = 21) and sham (n = 21) groups

Variable	Group		p-Value	Test
	Real tDCS	Sham
THI	69.95 ± 10.01	66.67 ± 9.66	t = 1.082; p = 0.286	Independent Sample t
BDI	27.14 ± 3.92	25.68 ± 3.51	t = 1.289; p = 0.205
BAI	26.76 ± 3.79	24.95 ± 4.45	t = 1.616; p = 0.114
Distress	6.81 ± 0.928	7.11 ± 1.09	t = -0.914; p = 0.367

tDCS transcranial direct current stimulation; BAI Beck anxiety inventory; THI Tinnitus handicap inventory; BDI Beck depression inventory

*Values are in mean ± SD

Fig. 1.

The comparison of tinnitus handicap inventory (THI) score between real tDCS and sham groups across different time-points

To assess the impact of symptom duration on tinnitus perception, the subjects were classified into two groups (≤ 6-year and > 6-year tinnitus duration). Our results showed that the tinnitus improvement in THI score from the pre- treatment to post-treatment condition was not statistically significant in both groups (Independent samples t-test; p > 0.05).

There was no significant difference in BDI ratings between either treatment group prior to stimulation (Independent samples t-test, p = 0.205) (see Table 2). Pairwise comparisons on the significant main effect of Time revealed that depression change scores reduced overtime under the real-tDCS stimulation. The repeated measure ANOVA exhibited a significant main effect of Time (p = 0.001), Stimulation (p = 0.001) and Time × Stimulation interaction (p < 0.001).

For the BAI scale, we found no significant difference between either group before treatment (Independent samples t-test, p = 0.114) (see Table 2). The repeated-measure ANOVA shows a significant main effect of Time (p < 0.001), and Stimulation (p < 0.001), and a significant interaction effect between Time and Stimulation factors (p < 0.001). Our findings indicated that anxiety-related tinnitus was highest at the “pre-treatment” phase, and following real-tDCS stimulation, the anxiety level has been gradually decreased across subsequent measurement intervals (see Table 3).

Table 3.

Results on self-report inventories in real tDCS (n = 21) and Sham (n = 21) groups across different time intervals

Variable	Pre-treatment	1-week Post-treatment	2-week Post-treatment	p-Value
THI
Real tDCS	69.95 ± 10.01	55.05 ± 12.34	41.05 ± 10.52	< 0.001
Sham	66.67 ± 9.66	64.76 ± 9.06	65.62 ± 9.50	0.143
BDI
Real tDCS	27.14 ± 3.92	21.52 ± 4.52	15.71 ± 3.34	< 0.001
Sham	25.68 ± 3.51	24.90 ± 3.39	24.38 ± 3.01	0.127
BAI
Real tDCS	26.76 ± 3.79	18.57 ± 2.94	14.48 ± 3.85	< 0.001
Sham	24.95 ± 4.45	23.81 ± 3.41	23.29 ± 4.17	0.158
Distress
Real tDCS	6.81 ± 0.928	5.62 ± 1.43	5.43 ± 1.07	0.002
Sham	7.11 ± 1.09	7.01 ± 0.84	6.76 ± 1.14	0.451

tDCS transcranial direct current stimulation; BAI Beck anxiety inventory; THI Tinnitus handicap inventory; BDI Beck depression inventory

*Values are in mean ± SD

There was no significant difference in tinnitus distress level between the real-tDCS and sham groups before treatment (Independent samples t-test, p = 0.367). For tinnitus distress, we observed a significant main effect of Stimulation (p < 0.001), Time (p = 0.001), and Stimulation × Time interaction (p < 0.001). Our results demonstrated that distress-related tinnitus in the real-tDCS group revealed a significant reduction at the post-treatment compared to the pre-treatment condition (see Table 3).

Our results also indicated that the correlations between the final THI and BDI scores (Pearson’s correlation coefficient: 0.631; p < 0.001), and between the final THI and BAI values (Pearson’s correlation coefficient: 0.605; p < 0.001) were statistically significant.

Discussion

In this study, patients with chronic intractable tinnitus were randomly assigned to two groups to receive 10 daily sessions of sham or real tDCS. In this study, 2 mA current intensity and 20-min duration was chosen, as it has been indicated to be the most effective setting for tinnitus suppression using tDCS of temporoparietal area. We expected cumulative long-lasting influences of tDCS on tinnitus intensity and tinnitus-related distress. Our findings demonstrated that repeated application of bilateral tDCS over the DLPFC indeed resulted in cumulative suppression of the primary outcome parameter, i.e. the THI score, which persisted for two weeks. Secondary outcome parameters, namely tinnitus distress, loudness, BDI, and BAI scores were also reduced by real tDCS.

Mechanistically, tDCS consequences might be mediated both by direct modulation of DLPFC activity and indirect modulation of activity in connected subcortical and cortical regions. A distinctive role of frontal areas in the pathophysiology of tinnitus has been shown by neuroimaging investigations. The DLPFC exerts an inhibitory modulation of input to the primary auditory cortex. Neuroimaging and electrophysiological data suggest a hyperactivity of the auditory cortex and maladaptive plasticity in this area in tinnitus. Thus, the decrease in tinnitus intensity accomplished by frontal tDCS might result from the respective impact of the DLPFC on the auditory cortex, most probably via its top-down modulatory role in auditory processing and involvement in auditory attention [20, 26–32].

The primary purpose of this study was to measure the therapeutic effect of tDCS on tinnitus symptom using THI scale. After sham and real tDCS stimulation, the reduction of the THI total scores was pronounced following active tDCS, suggesting that real stimulation is more effective than sham stimulation. These findings confirm that application of tDCS to the bilateral DLPFC region is an efficient neuromodulatory strategy to transiently alleviate chronic tinnitus, and maximum/amount of benefit was achieved immediately after intervention.

Shekhawat and Vanneste [33] conducted a study on optimizing the parameters of tDCS of DLPFC for tinnitus treatment and concluded that tDCS of DLPCF significantly reduced tinnitus loudness but intensity and duration of stimulation did not have a significant difference. Multiple sessions reduced tinnitus loudness better although after 6 sessions this effect plateaued.

Song et al. [34] ran a systemic review and meta-analysis on tDCS effect on tinnitus patients and showed that all the included studies implied significant improvement of intensity of tinnitus but they could not fully confirm tDCS role in tinnitus treatment due to limited number of studies.

In addition to suppressive effect of DLPFC tDCS on THI scores, a pronounced reduction of tinnitus-related anxiety and depression had been occurred too. These findings indicated that tDCS leads to transient suppression of tinnitus distress. These findings are in line with Vanneste et al. [21, 22] studies who also indicated a decrement not only for tinnitus loudness, but also for perceived tinnitus-related distress and depression after bifrontal stimulation of the DLPFC. They showed tinnitus perception and tinnitus distress declined for 41.67% and 43.20% respectively after tDCS in compression to baseline.[21]. This suppressive effect seems to be related to increasing excitability of right prefrontal cortex and decreasing excitability of the left prefrontal cortex, depending on stimulation sites. DLPFC is involved in anxiety, depression, and pain sensation [29, 30]. Furthermore, DLPFC plays an important role in auditory processing such as auditory attention, auditory memory storage and hypothetically in tinnitus [35, 36]. DLPFC’s inhibitory modulation of the auditory cortex may have an effect on tinnitus intensity, which is playing important role in coding of tinnitus loudness [37].

The current study limitation was small sample size and the results may be different in future studies with larger samples. Also it may be beneficial to evaluate tDCS effects on different subgroups of tinnitus patients according to their type of tinnitus.

Conclusion

We suggest tDCS as a complementary treatment of patients who suffer from tinnitus and has not responded to other modalities although more extended studies are needed to assess its potential capacity.

Declarations

Conflict of interest

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Approval

This research involved human participants and The protocol of the current study was approved by the local Ethics Committee (Ethics number: IR.AJUMS.HGOLESTAN.REC.1400.010) and registered as a clinical trial in the Iranian registry of clinical trials (IRCT registration number: IRCT20210429051130N1) in 2021–05-28.

Informed Consent

Informed consent was obtained from all individual participants included in the study.