Study selection process
During our database search, 897 studies were initially retrieved, and 524 were selected after eliminating duplicates. Then 477 without high-relevant to our topic were discarded after reading titles and abstracts, and 47 studies were further evaluated by reading the full manuscripts. As a result, 18 full-text articles were abandoned because of the following reasons: 4 described topics irrelevant to the efficacy and safety of rTMS on chronic tinnitus; 1 was a viewpoint; 2 were protocol designs; 8 were non-randomized controlled studies; 3 did not provide free online full-text materials. Ultimately, 29 RCTs with 1,228 patients were included in this systematic review and meta-analysis. The flow chart depicting the study selection process was shown in Figure 1.
Study characteristics and methodological quality
The 29 eligible studies were randomized controlled studies, published from 2004 to 2017. Six were conducted in the USA, 4 in Germany, 3 in China (including 1 in Taiwan), Turkey, and South Korea, 2 in the Czech Republic, and 1 in Italy, Egypt, Brazil, Australia, Netherlands, Finland, the UK, and Belgium. These clinical trials exhibited sample sizes that varied between 8 and 146 participants, the mean duration of tinnitus between 6 and 420 months, and the mean treatment course between 5 and 20 days. Of the 29 studies included (34 comparisons), 25 studies (30 comparisons) assessed the auditory cortex, 2 examined the non-auditory cortex, and 1 did not target the specific cerebral area. Among the 30 comparisons in the 25 studies focusing on the auditory cortex, 18 comparison analyses showed the superiority of rTMS over sham-rTMS. Also, among the 2 of the non-auditory cortex that contained 2 comparisons, both revealed the advantage of rTMS compared to sham-rTMS. In terms of the number of rTMS sessions, 11 studies (15 comparisons) reported treatment for 10 days, 12 (12 comparisons) reported treatment for 5 days, 4 (4 comparisons) reported treatment for 20 days, 1 (1 comparison) reported treatment for 4 days, and 1 (2 comparisons) did not provide the stimulation duration. With insights into different courses of rTMS treatment, 9 comparison analyses about a 5-day treatment showed that rTMS had better efficacy than sham-rTMS; however, the advantage of rTMS was nonsignificant after the 20-day treatment in all studies. Of the 29 studies (34 comparisons) included, 20 (23 comparisons) explored the left auditory cortex in patients with unilateral or bilateral tinnitus. In all eligible studies, 2 only included patients with bilateral tinnitus, 3 did not describe the tinnitus-affected side, and the remaining 24 included patients with either unilateral or bilateral tinnitus. Fifteen studies (18 comparisons) reported hearing loss in some or all of the included patients. The basic characteristics of the 29 studies were summarized in Table 1. The methodological quality graphs (Figs. 2 and 3) presented each item for each included study, and each item was shown as percentages across all trails according to our established quality evaluation standard.
The clinical efficacy and safety of rTMS in the treatment of chronic tinnitus
The THI score 1-week post-intervention
Of the 29 included studies, 3 reported[16,25,27] the THI scores 1-week post-intervention. Because of nonsignificant heterogeneity (I2 = 0%, P = 0.57) among the studies, a fixed-effect model was utilized. The outcome manifested a statistically significant difference in the item between the rTMS and sham-rTMS groups (MD: -7.92, 95%CI: -14.18,-1.66, P =0.01) (Fig.4).
The THI scores 2-week post-intervention
Three studies[15,25,26] containing statistics for THI scores 1-week post-intervention were available for the analysis using a random-effect model, with significant heterogeneity among the studies (I2 = 72%, P = 0.03). The results exhibited no statistically significant differences in the THI score 2-week post-intervention between the two groups (MD:-1.51, 95%CI: -13.42,10.40, P = 0.80).
The THI score 1-month post-intervention
Seven studies[16,17,20,22,24,25,27,] assessing THI scores 1-month post-intervention were included in the meta-analysis. There was no statistically significant heterogeneity among the studies (I2 = 0%, P = 0.53), so a fixed-effect model was utilized. The results showed a significant difference in THI scores 1-month post-intervention between the two groups (MD: -8.52, 95%CI: -12.49,-4.55, P < 0.0001) (Fig.5).
The THI score 6-month post-intervention
Four studies[15,20,22,27] estimating THI scores 6-month post-intervention were available for the meta-analysis using a fixed-effect model, with no statistically significant heterogeneity among the studies (I2 = 21%, P = 0.28). The results showed a significant difference in THI scores 6-month post-intervention between the two groups (MD: -6.53, 95%CI: -11.40,-1.66, P =0.009) (Fig.6).
The mean change in THI scores 1-month post-intervention
Three studies[20,22,24] evaluating the mean change in THI scores from baseline to 1-month post-intervention were meta-analyzed using a random-effect model, with significant heterogeneity among the studies (I2 = 56%, P = 0.08). The results exhibited a statistically significant difference in the mean change of THI scores 1-month post-intervention between the two groups (MD:-14.86, 95%CI: -21.42,-8.29, P <0.00001).
The mean change in THI scores 6-month post-intervention
Two studies[20,22] evaluating the mean difference in THI scores from baseline to 6-month post-intervention were meta-analyzed using a fixed-effect model, with no statistically significant heterogeneity among the studies (I2 = 0%, P = 0.87). The results showed that there was a significant difference in the mean change in THI scores 6-month post-intervention between the two groups (MD: -16.37, 95%CI: -20.64,-12.11, P <0.00001) .
Other indicators for outcome evaluation
The following studies were meta-analyzed for the outcome of patients, including 2[16,27] appraising the TQ score 1-week post-intervention, 2 [16,27] of the TQ score 1-month post-intervention, 2 [15,27] of the TQ score 6-month post-intervention, 3 [16,19] (1 [19] containing two RCTs) of the mean change in TQ scores 1-week post-intervention, 2 [17,27] of the VAS score 1-month post-intervention, and 2 [16,17] of tinnitus loudness 1-month post-intervention. There was a statistically significant difference in the TQ score 1-week post-intervention between the rTMS and sham-rTMS groups (P =0.02). Non-signficant differences in other outcomes were found between the two groups (MD: -6.53, 95%CI: -11.40,-1.66, P =0.009) (Table.2).
Adverse events
Fifteen studies[5,15,17,19,20,23,27,27-31,36,39] reporting adverse events after rTMS sessions were meta-analyzed using a fixed-effect model, with nonsignificant heterogeneity among the studies (I2 = 37%, P = 0.13). The results showed a nonsignificant difference in the incidence of adverse events between the rTMS and sham-rTMS groups (12.55% vs. 13.38%, OR: 1.11, 95%CI: 0.51-2.42, P = 0.79) (Fig.7). Among these adverse events, 21 patients reported headache, 7 worsening of tinnitus, and 5 sleep disturbance. Facial muscle discomfort, back pain, and muscle hardening, and ENT-symptoms (e.g., rhinitis, otitis media) occurred in 3 patients; neck and shoulder stiffness and jaw spasms in 2; increased sensitivity to noise, painful sensation in the affected ear, and anxiety and panic attacks in 1 patient. Nine cases reported other events.
Sensitivity analyses
Sensitivity analyses were performed for the selected studies to identify outliers that affected the overall results. There was a nonsignificant difference in the stability of the results (Fig.8), which validated the rationality and reliability of our meta-analysis.
Evaluation of publication bias
Visual inspection of funnel plots was adopted in the estimation (Fig.9). Egger᾽s and Begg᾽s analyses[16,17,20,22,24,25,27] showed no publication bias in our meta-analysis (P = 0.925).