Tinnitus is a disease with significant heterogeneity in terms of etiology, perception, and degree of severity, ranging from mild annoyance to terrible impact on daily life [33]. To our knowledge and up to date, there are no universally known therapies (medical or non- medical therapies) with precise therapeutic effects for tinnitus, thereby making tinnitus still a challenging disease to be treated [5, 13, 14]. Therefore, the generation of robust evidence regarding the efficacy and safety of ta-VNS on alleviation of tinnitus will guide clinicians, to determine whether ta-VNS can be an optional treatment approach for tinnitus, thereby enriching the current treatment strategies.

In this study 64 subjects suffering from tinnitus with normal hearing were subjected to TENS of the auricular branch of vagus nerve. The severity of tinnitus before and after TENS was assessed by VAS. Our results showed a statistically significant reduction in severity of tinnitus after TENS. 45 out of 64 (70.31%) patients had improvement, from them nine patients had a complete reduction of tinnitus. Stimulation of the vagus nerve modulates the release of norepinephrine and acetylcholine [34, 35]. These neuromodulators enhance neuroplasticity by modulating the cortex, hippocampus, and amygdala. It has also been reported that norepinephrine and acetylcholine can affect the selective plasticity of auditory cortical neurons [36,37,38].

According to the study of Yang et a l [39], they revealed that the threshold of auditory brainstem response could be modulated by ta-VNS combined with sound masking, and it is attributed to modulation of neurotransmitters such as gamma- aminobutyric acid, 5- hydroxytryptamine and acetylcholine in the inferior colliculus.

In last years, several studies have been conducted to explore the effect of ta-VNS (alone or adjunctively) on tinnitus. For example, some studies reported that ta-VNS combined with sound masking can significantly improve the handicap and psychological symptoms of tinnitus [27, 40], while other studies revealed that there was no clinically relevant improvement of tinnitus symptoms in patients with chronic tinnitus who received ta-VNS treatment [26, 41]. Various parameters of ta-VNS stimuli, such as different stimulation frequencies, pulses and stimulation duration as well as electrode placement may contribute in this differences between our study and others. Also, tinnitus heterogeneity and patient expectation have a role in this difference.

The prediction of tinnitus therapy outcome is difficult. To our knowledge, several studies addressing different therapies and using different variables reported significant predictors but there is no study aiming to assess tinnitus related variables effect on ta-VNS treatment. The second aim in our study was to evaluate the effect of different tinnitus related variables on the degree of alleviation of tinnitus.

Our results revealed that the amount of tinnitus reduction is not related to the personal variables (age, gender, and presence of chronic disease) so age and gender could not be used as predictors for TENS results. On the other hand, some of studied tinnitus characteristics (localization and sound) has a difference effect on the amount of tinnitus reduction. It was found that the degree of tinnitus reduction is higher when tinnitus is presented in right ear in comparison to left or bilateral. Also, the tinnitus reduction was highest when the tinnitus is whistling in character followed by machinery and hissing, then ringing and the lowest reduction was found when tinnitus is a mix of more than one of them but these differences are not significant.

As we mentioned before, some studies revealed the effect of different variables on the outcome of different tinnitus therapy. Regarding personal variables, age was a significant predictor in some studies, but with only partly corresponding results [42]. Caffier et al., described a U-shaped relationship of age and outcome, they found that younger and older patients displayed a highly significant beneficial response to therapy that was not seen in middle-aged persons [43]. In the study by Graul et al., responders to treatment were younger [44]. Also, gender turned out to be a predictor in several studies, but also with inconsistent results [42]. Treatment outcome was reported to be better in men [45], but also women [46]. In another study, the gender effect on treatment depended on the type of therapy [47]. Moreover, it was found that being female in combination with long tinnitus duration predicted less benefit of treatment [48].

Regarding the tinnitus characteristics, some studies found that a shorter duration of tinnitus was a beneficial predictor [43, 49]. In one study using TENS of C2, Vanneste et al., found that the amounts of transient tinnitus suppression is independent of tinnitus type (pure tone or narrow band noise), tinnitus side (unilateral or bilateral), and tinnitus duration as well as gender, which makes it difficult to decide who might benefit from TENS and who not [50].

By the end of the discussion, we could conclude that ta-VNS is an effective treatment of subjective tinnitus in 70.31% of the studied group from them 20% have a complete reduction of tinnitus, but we could not assess for how long this residual inhibition persists due to lack of long term follow up. Residual inhibition means the suppression of tinnitus loudness for a period. However, it is difficult to decide who might benefit from ta-VNS, patients with unilateral tinnitus on right ear and those with whistling sound have more reduction in tinnitus loudness than others. TENS represents a safe and feasible treatment option for tinnitus and might be commendable among the spectrum of interventions developed for tinnitus.