3.1. Study selection process
As a result, 897 references were initially retrieved, 524 were left after eliminating duplicate literature; and then 477 without high-relevant to our topic were discarded by reading titles and abstracts, and 47 studies remained. Finally, 18 full-text articles were abandoned because of the following reasons: 4 studies on irrelevant topics; 1 study was viewpoint; 2 studies were protocol;8 studies were no randomized controlled trial; 3 studies without free online full-text materials.Therefore, 29 randomized controlled studies with 1,228 patients were included in the A Systematic Review and Meta-Analysis. The flow chart describing the selection process of the study was shown in Fig. 1.
3.2. Study Characteristics And Methodological Quality
-
The 29 included references were randomized controlled studies, with the publication years differing from 2004 to 2017. 3 were conducted in China (including 1 in Taiwan), 4 in Germany,3 in Turkey, 3 in South Korea,6 in USA,2 in Czech Republic and 1 in Italy, Egypt, Brazil, Australia, Netherlands, Finland, UK,Belgium,respectively. In the selected clinical trials, the sample sizes varied between 8 and 146 participants.The mean duration of tinnitus in these studies ranged from 6 to 420 months.The mean treatment Course in these studies ranged from 5 to 20 days.The basic characteristics of the 29 of them were shown in Table 2 and Table 3. In addition, the methodological quality graph (Figs. 2 and 3) presents each item for each included study as well as each item presented as percentages across all included trails according to our established quality evaluation standard.
Table 2
Characteristics of the Included Studies
Inclued trials | Country | Study design | Gender(male/female) | | Age(yeas) | | Duration of tinnitus(month) |
T | C | | T | C | | T | C |
Landgrebe M 2017[15] | Germany | Sham-controlled, randomized multicenter tria | 54/17 | 51/24 | | 48.1 ± 12.5 | 49.9 ± 13.2 | | 6.2 ± 5.3 | 8.1 ± 8.4 |
Formánek M 2018[6] | Czech Republic | Randomized double-blinded controlled trial | 13/7 | 10/2 | | 47.9 ± 14.31 | 51.8 ± 10.34 | | 53.4 ± 61.89 | 76.8 ± 76.85 |
Chung HK 2012[16] | China | Parallel randomized control study | 11/1 | 11/1 | | 53.83 ± 18.4 | 51.90 ± 15.5 | | 6−240 | 6−240 |
Yilmaz 2014[17] | Turkey | Randomized controlled trial | 27/33 | 27/33 | | 49.8 ± 8.03(36–66) | 49.8 ± 8.03(36–66) | | > 6 | > 6 |
Rossi S 2007[18] | Italy | Randomised,double blind, crossover, placebo controlled trial | 7/1 | 4/2 | | 52.63(35–72) | 52.33(37–62) | | 12–300 | 12–300 |
langguth B 2014(1)[4] | Germany | Randomized,double-blind, parallel-group,controlled clinical trial | 35/13 | 31/14 | | 44.9 ± 11.5 | 50.3 ± 12.9 | | 68.0 ± 97.0 | 74.4 ± 74.2 |
langguth B 2014(2)[4] | Germany | Randomized,double-blind, parallel-group,controlled clinical trial | 32/16 | 31/14 | | 50.4 ± 12.5 | 50.3 ± 12.9 | | 78.3 ± 64.9 | 78.3 ± 64.9 |
Bilici S 2015[19] | Turkey | Randomised,double-blind, placebo-controlled study | 33/42 | 33/42 | | 40 ± 13.2(20–62) | 40 ± 13.2(20–62) | | > 12 | > 12 |
Khedr EM 2009[20] | Egypt | Randomized controlled trial | Unclear | Unclear | | Unclear | Unclear | | Unclear | Unclear |
Marcondes RA 2010[21] | Brazil | Randomised,double-blind, parallel design, study | Unclear | Unclear | | > 18 | > 18 | | > 6 | > 6 |
Folmer RL 2015[22] | USA | A randomized, participantand clinician or observer–blinded, placebo-controlled clinical trial | 25/7 | 26/6 | | 58.3 ± 9.5 | 62.8 ± 8.3 | | > 12 | > 12 |
Li LPH 2019[23] | Taiwan,China | Randomized controlled trial | 7/5 | 7/5 | | 57 ± 10.1 | 54 ± 7.5 | | > 6 | > 6 |
Noh TS 2019[24] | South Korea | Double-blind randomized controlled trial | 14/3 | 7/6 | | 51.9 ± 12.4 | 55.8 ± 6.9 | | 76.1 ± 129.3 | 70.1 ± 70.4 |
Anders M 2010[25] | Czech Republic | Randomized,placebo controlled study | 12/10 | 17/3 | | 48.09 | 50.1 | | 106.8 ± 81.6 | 88.4 ± 67.5 |
Hoekstra CEL 2013[26] | The Netherlands | Randomised,double-blind placebo-controlled clinical trial | 26/0 | 15/9 | | 50 ± 12 | 50 ± 12 | | 58(8-240) | 38(12–420) |
Sahlsten H 2017[27] | Finland | Randomized,placebo-controlled study | 13/6 | 14/6 | | 48.9 ± 13.1 | 51.5 ± 10.7 | | > 6 | > 6 |
Wang H 2016[28] | China | Randomized controlled trial | 6/8 | 3/7 | | 62.1 ± 9.81 | 56.4 ± 11.8 | | 6–72 | 6–72 |
Cacace AT 2017[29] | USA | Randomized single-blinded sham-controlled cross-over study | 30/0 | 30/0 | | 54.2 ± 14.2 | 54.2 ± 14.2 | | Unclear | Unclear |
Piccirillo JF 2013[30] | USA | Crossover,double-blind, randomized controlled trial | 9/5 | 9/5 | | Median 42(22–59) | Median 42(22–59) | | 6−360 | 6−360 |
James G 2018[31] | USA | Double-blind, randomized clinical trial with participant crossover | 9/3 | 9/3 | | 49.2 ± 15.3 | 49.2 ± 15.3 | | > 6 | > 6 |
Kyong JS 2019(1)[32] | Korea | Randomized controlled trial | 4/4 | 6/2 | | 56 ± 4.9 | 50.9 ± 7.1 | | > 6 | > 6 |
Kyong JS 2019(2)[32] | Korea | Randomized controlled trial | 6/2 | 6/2 | | 50.9 ± 7.1 | 50.9 ± 7.1 | | > 6 | > 6 |
Roland LT 2016[33] | USA | Randomized, double-blind, controlled clinical trial | 11/5 | 10/4 | | Median 50 | Median 53 | | > 6 | > 6 |
Barwood CHS 2013[34] | Australia | Singleblind,randomized controlled trial | 2/2 | 2/2 | | 29–58 | | | > 12 | > 12 |
Godbehere J 2019[35] | UK | A two-arm, single-blind, randomized controlled trial | Unclear | Unclear | | Unclear | Unclear | | Unclear | Unclear |
Mennemeier M 2011[36] | USA | Randomized, sham-controlled crossover | Unclear | Unclear | | 28–75 | 28–75 | | > 6 | > 6 |
Lee1 HY 2013[37] | Korea | Randomized controlled trial | 8/7 | 8/7 | | 53 | 53 | | Mean 48 | Mean 48 |
Lorenz I 2013[38] | Germany | Randomized,single-blind, sham-controlled trial | 7/3 | 7/3 | | 49.8 | 49.8 | | Mean 21.6 | Mean 21.6 |
Vanneste S 2012[39] | Belgium | Randomized controlled trial | Unclear | Unclear | | 50.05 ± 11.77 | 50.05 ± 11.77 | | > 12 | > 12 |
Plewnia C 2012(1)[40] | Germany | Randomized controlled trial | 10/6 | 8/8 | | 46.4 ± 13.0 | 45.6 ± 10.3 | | 27 ± 14 | 22 ± 14 |
Plewnia C 2012(2)[40] | Germany | Randomized controlled trial | 7/9 | 8/8 | | 55.8 ± 9.7 | 45.6 ± 10.3 | | 28 ± 13 | 22 ± 14 |
Table 3
Characteristics of the Included Studies
Inclued trials | Interventions | | Position | Treatment Course(days) | Follow up | Conclusion by author |
T | C | |
Landgrebe M 2017[15] | 1-Hz-rTMS (2000 stimuli, 110% motor threshold) | sham rTMS | | The left temporal cortex | 10d | 6 months | No significant |
Formanek M 2018[6] | 1-Hz-rTMS (1000 stimuli, 110% motor threshold,the left side and primary auditory cortex on both sides );25-Hz-rTMS (300 stimuli,80% motor threshold,the dorsolateral prefrontal cortex ) | sham rTMS | | The dorsolateral prefrontal cortex or the left side and primary auditory cortex on both sides | 5d | 6 months | No significant |
Chung HK 2012[16] | 5-Hz-rTMS (900 stimuli, 80% motor threshold) | sham rTMS | | The temporoparietal | 10d | 1 month | Significant |
Yilmaz 2014[17] | 1-Hz-rTMS (1800 stimuli, motor threshold:unclear) | sham rTMS | | Unclear | 10d | 1 month | Significant |
Rossi S 2007[18] | 1-Hz-rTMS (1200 stimuli, 120% motor threshold) | sham rTMS | | The left temporoparietal region | 5d | 6 weeks | Significant |
langguth B 2014(1)[4] | 1-Hz-rTMS (2000 stimuli, 110% motor threshold) | sham rTMS | | PET-based neuronavigated | 10d | 11 weeks | No significant |
langguth B 2014(2)[4] | 1-Hz-rTMS (2000 stimuli, 110% motor threshold) | sham rTMS | | The left auditory cortex | 10d | 11 weeks | No significant |
Bilici S 2015(1)[19] | 1-Hz-rTMS (900 stimuli, 110% motor threshold) | sham rTMS | | The left temporoparietal region | 10d | 6 months | Significant |
Bilici S 2015(2)[19] | 10-Hz-rTMS (600 stimuli, 110% motor threshold) | sham rTMS | | The left temporoparietal region | 10d | 6 months | Significant |
Khedr EM 2009(1)[20] | 1-Hz-rTMS (1500 stimuli, 100% motor threshold) | sham rTMS | | The left temporoparietal region | 10d | 12 months | No significant |
Khedr EM 2009(2)[20] | 10-Hz-rTMS (1500 stimuli, 100% motor threshold) | sham rTMS | | The left temporoparietal region | 10d | 12 months | Significant |
Khedr EM 2009(3)[20] | 25-Hz-rTMS (1500 stimuli, 100% motor threshold) | sham rTMS | | The left temporoparietal region | 10d | 12 months | Significant |
Marcondes RA 2010[21] | 1-Hz-rTMS (1020 stimuli, 110% motor threshold) | sham rTMS | | Thel eft temporoparietal region | 5d | 6 months | Significant |
Folmer RL 2015[22] | 1-Hz-rTMS (2000 stimuli, 110% or lower motor threshold) | sham rTMS | | The auditory cortex | 10d | 6 months | Significant |
Li LPH 2019[23] | 1-Hz-rTMS (1800 stimuli, 110% or lower motor threshold) | sham rTMS | | The left primary auditory cortex | 5d | 1 month | Significant |
Noh TS 2019[24] | 1-Hz-rTMS (2,000 pulses over the AC and 1,000 pulses over the DLPFC, 110% or lower motor threshold ) | sham rTMS | | The left primary auditory cortex(AC) and left dorsolateral prefrontal cortex(DLPFC) | 4d | 8 weeks | Significant |
Anders M 2010[25] | 1-Hz-rTMS (1500 stimuli, 110% or lower motor threshold) | sham rTMS | | The left primary auditory cortex | 10d | 6 months | Significant |
Hoekstra CEL 2013[26] | 1-Hz-rTMS (2000 stimuli, 110% motor threshold) | sham rTMS | | The auditory cortex | 5d | 6 months | No significant |
Sahlsten H 2017[27] | 1-Hz-rTMS (4000 stimuli, 100% motor threshold) | sham rTMS | | The left superior temporal gyrus | 10d | 6 months | No significant |
Wang H 2016[28] | 1-Hz-rTMS (1000 stimuli, 110% motor threshold) | sham rTMS | | The left temporoparietal region | 10d | Unclear | Significant |
Cacace AT 2017[29] | 1-Hz-rTMS (1200 stimuli, 110% motor threshold) | sham rTMS | | The temporal cortex of the left hemisphere | 5d | Unclear | Significant |
Piccirillo JF 2013[30] | 1-Hz-rTMS (1650 stimuli, 110% motor threshold) | sham rTMS | | The left temporoparietal area | 20d | > 4 weeks | No significant |
James G 2018[31] | 1 OR 10-Hz-rTMS (1800 stimuli, 110% motor threshold) | sham rTMS | | The posterior superior temporal gyrus | 5d | Unclear | Significant |
Kyong JS 2019(1)[32] | 1-Hz-rTMS (stimuli:unclear,motor threshold:unclear) | sham rTMS | | The auditory temporal cortex | Unclear | Unclear | No significant |
Kyong JS 2019(2)[32] | 1-Hz-rTMS (stimuli:unclear,motor threshold:unclear) | sham rTMS | | The auditory temporal and the frontal regions | Unclear | Unclear | Significant |
Roland LT 2016[33] | 1-Hz-rTMS (stimuli:unclear:, 110 motor threshold) | sham rTMS | | The motor cortex | 10d or 20d | 4 weeks | No significant |
Barwood CHS 2013[34] | 1-Hz-rTMS (2000 stimuli, 110% motor threshold) | sham rTMS | | The left primary auditory cortex | 10d | 3 months | Significant |
Godbehere J 2019[35] | 5-Hz-rTMS (1200 stimuli, 80% motor threshold) | sham rTMS | | The temporal-parietal region of the scalp, overlying the auditory cortex | 5d | 4 weeks | No significant |
Mennemeier M 2011[36] | 1-Hz-rTMS (1800 stimuli, 110% motor threshold) | sham rTMS | | The temporal cortex | 5d | Unclear | Significant |
Lee1 HY 2013[37] | 1-Hz-rTMS (1200 stimuli, 100% motor threshold) | sham rTMS | | The motor cortex | 5d | Unclear | Significant |
Lorenz I 2013[38] | 1-Hz-rTMS (1000 stimuli, 110% motor threshold) | sham rTMS | | The auditory cortex | 5d | Unclear | Significant |
Vanneste S 2012[39] | 1 or 10 Hz-rTMS (900 stimuli, 120% motor threshold) | sham rTMS | | The left ventrolateral prefrontal cortex | 5d | 12 months | Significant(for 10 Hz) |
Plewnia C 2012(1)[40] | 5-Hz-rTMS (2400 stimuli, 80% motor threshold) | sham rTMS | | The secondary auditory cortex | 20d | 12 weeks | No significant |
Plewnia C 2012(2)[40] | 5-Hz-rTMS (2400 stimuli, 80% motor threshold) | sham rTMS | | The temporoparietal association cortex | 20d | 12 weeks | No significant |
rTMS = repeated transcranial magnetic stimulation,AC = auditory cortex,DLPFC = dorsolateral prefrontal cortex |
Table 4
Meta-analysis results of other outcome evaluation indicators
Outcome | Included studies(n) | Included patients(T/C,n) | Heterogeneity | MD,95%CI | P |
TQ scores 1 week after intervention | 2 | 38/34 | P = 0.55, I2 = 0% | −8.54(−15.56,−1.52) | 0.02 |
TQ scores 1 month after intervention | 2 | 38/34 | P = 0.15, I2 = 53% | −8.97(−20.41,2.48) | 0.12 |
TQ scores 6 months after intervention | 2 | 97/99 | P = 0.03, I2 = 79% | -−7.02(−18.18,4.13) | 0.22 |
Mean change in TQ scores 1 week after intervention | 3 | 108/100 | P = 0.04, I2 = 69% | −3.67(−8.56,1.22) | 0.14 |
VAS scores 1 month after intervention | 2 | 56/54 | P = 0.07, I2 = 69% | −0.64(−1.77,0.48) | 0.26 |
Tinnitus loudness 1 month after intervention | 2 | 42/40 | P = 0.71, I2 = 0% | −1.13(−7.13,4.87) | 0.71 |
TQ = tinnitus questionnaire,VAS = visual analogue scale,CI = condidence interval |
3.3. The clinical efficacy and safety of rTMS on the treatment of chronic tinnitus
3.3.1. Thi Scores 1 Week After Intervention
Of the 29 included studies, 3 reported[16, 24, 26] the THI scores 1 week after intervention.Because of nonsignificant heterogeneity among the studies, the fixed effect model was utilized (I2 = 0%, P = 0.57). The outcome manifested a statistically significant difference in the item between the two patient groups (MD: -7.92, 95%CI: -14.18,-1.66, P = 0.01). (Fig. 4)
3.3.2. Thi Scores 2 Week After Intervention
Three studies[15,24,25,] containing statistics on the THI scores 1 week after intervention were available for the analysis using the random effect model, with significant heterogeneity among the studies (I2 = 72%, P = 0.03). The results exhibited no statistically significant differences in THI scores 1 week after intervention between the two patient groups (MD:-1.51, 95%CI: -13.42,10.40, P = 0.80). (Fig. 5)
3.3.3. Thi Scores 1 Month After Intervention
Seven studies[16,17,19,21,23,24,26,] reporting statistics on the THI scores 1 month after intervention were involved in meta-analysis. There was no significant statistical heterogeneity among the studies (I2 = 0%, P = 0.53) and the fixed effect model was utilized. It was found that the difference in THI scores 1 month after intervention was significant between the two patient groups (MD: -8.52, 95%CI: -12.49,-4.55, P < 0.0001). (Fig. 6)
3.3.4. Thi Scores 6 Months After Intervention
Four studies[15, 19, 21, 26] reporting statistics on the THI scores 6 months after intervention were involved in meta-analysis. There was no significant statistical heterogeneity among the studies (I2 = 21%, P = 0.28) and the fixed effect model was utilized. It was found that the difference in THI scores 6 months after intervention was significant between the two patient groups (MD: -6.53, 95%CI: -11.40,-1.66, P = 0.009). (Fig. 7)
3.3.5. Mean change in THI scores 1 month after intervention
Three studies[19, 21, 23] containing statistics on mean change in THI scores 1 month after intervention were available for the analysis using the random effect model, with significant heterogeneity among the studies (I2 = 56%, P = 0.08). The results exhibited a statistically significant differences in THI scores 1 month after intervention between the two patient groups (MD:-14.86, 95%CI: -21.42,-8.29, P < 0.00001). (Fig. 8)
3.3.6.mean Change In Thi Scores 6 Months After Intervention
Two studies[19, 21] reporting statistics on mean change in THI scores 6 months after intervention were involved in meta-analysis. There was no significant statistical heterogeneity among the studies (I2 = 0%, P = 0.87) and the fixed effect model was utilized. It was found that the difference in mean change in THI scores 6 months after intervention was significant between the two patient groups (MD: -16.37, 95%CI: -20.64,-12.11, P < 0.00001). (Fig. 9)
3.3.7. Other Outcome Evaluation Indicators
Two studies[16, 26] reporting statistics on TQ scores 1 week after intervention,2 studies[16, 26] reporting statistics on TQ scores 1 month after intervention were involved in meta-analysis,2 studies[15, 26] reporting statistics on TQ scores 6 months after intervention, 3 studies[4, 16] (One study[4] included two RCTs) reporting statistics on mean change in TQ scores 1 week after intervention,2 studies[17, 26] reporting statistics on VAS scores 1 month after intervention and 2 studies[16, 17] reporting statistics on tinnitus loudness 1 month after intervention were involved in meta-analysis,The results exhibited a statistically significant differences in TQ scores 1 week after intervention between the two patient groups (P = 0.02).However, It was found that the difference in other outcome after intervention were no significant between the two patient groups (MD: -6.53, 95%CI: -11.40,-1.66, P = 0.009). (Table.4)
3.3.8. Adverse Events
Data on adverse events were available for the meta-analysis from 15 studies[4, 6, 15, 17, 19, 22, 23, 26–30, 35, 38], and nonsignificant heterogeneity was presented among the studies (I2 = 37%, P = 0.13). Therefore, the fixed effect model was applied. However, differences in adverse events between the two patient groups were still nonsignificant (OR: 1.11, 95%CI: 0.51–2.42, P = 0.79). (Fig. 10)
3.3.9. Sensitivity Analyses
The sensitivity analysis was performed on the selected studies to assess whether individual studies would affect the overall results. The results showed that there was a nonsignificant difference in the stability of the results (Fig. 11), which validated the rationality and reliability of our analysis.
3.3.10. Evaluation Of Publication Bias
Visual inspection of funnel plots was adopted in the estimation(Fig. 12). Specifically, Egger᾽s and Begg᾽s analyses[16,17,19,21,23,24,26,] of publication bias showed that publication bias did not exist in our meta-analysis (P = 0.925). (Figs. 13 and 14)