Repetitive Transcranial Magnetic Stimulation (RTMS) on Chronic Tinnitus: a Systematic Review and Meta-Analysis

Background:Although the clinical ecacy and safety of repeated transcranial magnetic stimulation(rTMS)on the treatment of chronic tinnitushave been frequently reported, the results remain controversial.Therefore, its relatedclinical ecacy and safety were systematically evaluated and meta-classied in this study. Methods:Literature on repeated transcranial magnetic stimulation(rTMS)on chronic tinnitus was retrieved in PubMed, Embase and Cochrane Library due April 2020.Review Manager 5.3 software was appliedto data synthesis, and Stata 13.0 software was adopted for analyses of publication bias and sensitivity. Results:A total of 29randomized studies with 1,228 patients were included. Compared with sham rTMS, rTMSshowed statistical signicance in tinnitus handicap inventory(THI) scores 1 week after intervention (MD-7.92, 95% condidence interval [CI] -14.18,-1.66), THI scores 1month after intervention (MD-8.52, 95% CI -12.49,-4.55),THI scores 6months after intervention (MD-6.53, 95% CI -11.406,-1.66), TQ scores 1 week after intervention (MD-8.54, 95% CI -15.56,-1.52),mean change in THI scores 1month after intervention(MD-14.86, 95% CI -21.42,-8.29) and mean change in THI scores 6months after intervention(MD-16.37, 95% CI -20.64,-12.11) .There was no statistical difference between rTMS and sham rTMS in THI scores 2 week after intervention (MD-1.51, 95% CI -13.42,-10.40),tinnitus questionnaire(TQ) scores 1 month after intervention (MD-8.97, 95% CI -20.41,2.48),TQ scores 6 months after intervention (MD-7.02, 95% CI -18.18,4.13) , mean change in TQ scores 1months after intervention(MD-3.67, 95% CI -8.56,1.22) and adverse events (OR 1.11,


Background
Tinnitus is a common auditory symptom that can cause severe stress when co-existing with other symptoms.Studies have shown that the incidence of tinnitus in adults ranges from 10 to 19 percent [1][2] ,characterized by an abnormal auditory perception in the brain or ear in the absence of external acoustic or electrical stimulation.In the 2019 European multidisciplinary tinnitus guidelines, tinnitus lasting more than 6 months is de ned as chronic tinnitus [3] .Long-term tinnitus not only brings the in uence of noise to patients, but also is often accompanied by varying degrees of mood disorders.Studies have found that tinnitus seriously damages the quality of life of 1-2% of people [4] .According to the neurophysiological model of tinnitus, tinnitus is the abnormal electrical activity of neurons in the peripheral and central auditory pathways (including the cerebral cortex), reshaping the detection and perception process of the cortex or subcortical center, and thus causing tinnitus [5] .
In recent years, the incidence of tinnitus has increased year by year,and in most cases, there is no cure, and there is a lack of effective standardized treatment.In recent years, several studies have shown that repetitive transcranial stimulation is effective in the treatment of chronic tinnitus [6][7] .Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that enables electromagnetic pulses to reach the scalp and brain to cause changes in neuronal excitability and neurotransmitter systems [8][9] .In other words, it is through repetitive rTMS and different frequency of stimulation, the auditory neurons are adjusted, reduce the abnormal electrical activity of hearing central neurons, reduce the occurrence of tinnitus, thus to achieve the treatment of tinnitus.The clinical e cacy and safety of rTMS on the treatment of chronic tinnitus have been reported by many lately, but the results of studies are divergent and even controversial.So far,a Cochrane review included 5 randomized studies and concluded that rTMS was useful for tinnitus, but the sample size is relatively small and the safety of rTMS treatment was not reported in ve studies [10] .The most recent of these,a systematic review of 15 studies showed that rTMS therapy had a signi cant effect on tinnitus, but large-scale experimental studies were lacking [11] .
In this study, we retrieved the published literature on rTMS on the treatment of chronic tinnitus, extracted high-relevant data for a systematic review and meta-analysis to evaluated the e cacy and safety, in a bid to provide a reference for the prevention and treatment of chronic tinnitus.

Search strategies
This study was executed in line with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [12] and reported based on the guidelines developed by the Meta-Analysis of Observational Studies in Epidemiology group [13] . Because all the analyses were performed on the basis of previous published studies, no ethical approval or patient consent was required. In the initial screening, 2 investigators (Z-RL and GC) conducted the main search in the electronic databases of PubMed, Embase and Cochrane Library to retrieve eligible randomized controlled trial articles about rTMS on the treatment of chronic tinnitus from the inception of the databases to April 2020, without restrictions to languages or regions.

Study Selection Criteria
Two independent investigators (Z-RL and GC) analyzed the initially selected articles to verify their relevance with the topic of rTMS on the treatment of chronic tinnitus. Studies had to ful ll the following criteria for inclusion: outcome was clinical e cacy and safety of rTMS on the treatment of chronic tinnitus;study design was randomized controlled trial;participants were selected without limitations to regions, ages or social status.Trials were excluded according to following identi cations: non-randomized controlled, trialduplicate or overlapping data, animal experiments, conference abstracts, letters and review articles. In case of any disagreement the results were discussed and uni ed by senior authors .

Data Extraction
Data from the included studies were extracted and independently categorized by 2 of the authors (Z-RL and GC) in a prede ned data extraction form. All disagreements were resolved by discussion. Design information, baseline population characteristics (mean age, sample size,course of the disease and country), interventions, clinical e cacy score, adverse events, etc from all included studies were strati ed into a standardized evidence table. All the data were rechecked to ensure accuracy. Study selections were shown in a PRISMA ow diagram.

Methodological Quality Assessment
The methodological quality of the included studies was evaluated by 2 independent reviewers (Z-RL and GC) based on the Cochrane Handbook Version 5.3 that include Random sequence generation; Allocation concealment; The blinding of participants, Personnel and outcome assessor; Incomplete outcome data; Selective reporting and other sources of bias.

Statistical Analysis
The meta-analysis and statistical analysis were performed using Cochrane Collaboration Review Manager software (RevMan version 5.3, Nordic Cochrane center, Copenhagen, Denmark).For Dichotomous data, we used the risk ratios (RRs) or odds ratios (ORs) as the analysis of statistics.
For continuous data, we used the weighted mean difference (WMD) as the analysis of statistics. The I-square (I 2 ) test was adopted to evaluate the in uence of heterogeneity on the output of metaanalysis. I 2 values of 0%, 25%, 50% and 75% represented no, low, medium and high heterogeneity, respectively. According to the Cochrane review guidelines, severe heterogeneity of I 2 ≥ 50% required the utilization of random-effect models. Otherwise, the xed effect model was approved. P value less than 0.05 was accepted as statistical signi cance. Sensitivity analysis [14] was conducted by study removal approach to evaluate the quality and consistency of the results. Funnel plots were visually checked, and Egger and Begg linear regression tests of publication bias were carried out by Stata 13.0 software.

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 ow chart describing the selection process of the study was shown in Fig. 1.

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.

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 signi cant heterogeneity among the studies (I 2 = 72%, P = 0.03). The results exhibited no statistically signi cant 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)

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 signi cant statistical heterogeneity among the studies (I 2 = 21%, P = 0.28) and the xed effect model was utilized. It was found that the difference in THI scores 6 months after intervention was signi cant between the two patient groups (MD: -6.53, 95%CI: -11.40,-1.66, P = 0.009). (Fig. 7)

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 signi cant heterogeneity among the studies (I 2 = 56%, P = 0.08). The results exhibited a statistically signi cant 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 signi cant statistical heterogeneity among the studies (I 2 = 0%, P = 0.87) and the xed effect model was utilized. It was found that the difference in mean change in THI scores 6 months after intervention was signi cant between the two patient groups (MD: -16.37, 95%CI: -20.64,-12.11, P < 0.00001). (Fig. 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 nonsigni cant difference in the stability of the results (Fig. 11), which validated the rationality and reliability of our analysis.

Evaluation Of Publication Bias
Visual inspection of funnel plots was adopted in the estimation (Fig. 12). Speci cally, 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 metaanalysis (P = 0.925). (Figs. 13 and 14) 4. Discussion In this study,We report results of a systematic review and meta-analysis of 29 selected RCTs of rTMS to reduce chronic tinnitus.In order to ensure reliable conclusions, we retrieved, reviewed and summarized the previously published studies on rTMS in the treatment of chronic tinnitus to achieve high levels, good compliance, and high quality to answer various clinical questions about this disease.Overall, our results suggest that repeated transcranial magnetic stimulation is effective in the treatment of chronic tinnitus.Group analysis showed that repeated transcranial magnetic stimulation for the treatment of chronic tinnitus was statistically signi cant among the participants.The treament of rTMS was safe at the intension: serious adverse events were evenly distributed between participants randomly assigned to rTMS versus sham rTMS.
Tinnitus heterogeneity and with a high incidence in the crowd, though many treatments have been used in the treatment of tinnitus, but because most of the low level of evidence therapeutic strategy, there is a lack of widely agreed to be able to reduce tinnitus loudness, reduce the impact of tinnitus and can be copied to verify the effective treatment of tinnitus methods [41] .This presents a huge challenge for the ear, nose and throat doctor.Landgrebe et al found that by repeated low-frequency rTMS stimulation on a daily basis, its biological effects had a stacking effect, which not only caused synaptic inhibition and changes in the plasticity of auditory cortex nucleus, but also affected the series changes of hemodynamics in the auditory region, showing a signi cant effect in the treatment of chronic tinnitus [15] .Our ndings from analysing the study population as a whole are consistent with those of recent aggregate data metaanalysis of RCTs of rTMS for the chronic tinnitus [42] .
Our study has several strengths.The included studies were of publication of the protocol, detailed and predefned sensitivity and subgroup analyses, comprehensive assessment of the risk of systematic and random errors, and assessment of the quality of evidence Secondly, the rationality and reliability of our meta-analysis have been prudently and signi cantly improved in that the overall comprehensive estimation is based on a large sample size. In addition, su cient sensitivity analysis has been carried out to ensure the reliability of this study.
However, our review also has some limitations.On the one hand, despite the inclusion of recent large randomized trials, our analytical capabilities are still very low, because repeated transcranial magnetic stimulation has not been widely used in the clinic,the total sample of patients included in this study is still small,resulting in the loss of statistical signi cance in some outcome indicators.On the other hand,this study contains only English references, which leads to lost data from those in other languages.In addition, Egger s and Begg s analyses of publication bias showed that publication bias did not exist in our meta-analysis,however, because few studies were included in the analysis, false negatives cannot be excluded.

Conclusion
In summary, our systematic review and meta-analysis suggests that rTMS on chronic tinnitus has certain clinical curative effect and high safety,however, due to the lack of included studies and the small sample size, more large-sample, multi-center, randomized double-blind trials are needed for further veri cation.
Abbreviations rTMS repeated transcranial magnetic stimulation,CI = condidence interval,THI = tinnitus handicap inventory,TQ = tinnitus questionnaire,PRISMA = Preferred Reporting Items for Systematic Reviews and Meta- Figure 1 The ow diagram of literature selection.

Figure 2
The risk of bias graph.

Figure 3
The risk of bias summary Figure 4 Meta-analysis results of the THI scores 1 week after intervention Meta-analysis results of the THI scores 2 week after intervention Figure 6 Meta-analysis results of the THI scores 1 month after intervention Meta-analysis results of the THI scores 6 months after intervention Meta-analysis results of the mean change in THI scores 1month after intervention Meta-analysis results of the mean change in THI scores 6months after intervention Figure 10 Meta-analysis results of the adverse events after intervention Figure 11 In uence analysis of included studies.

Figure 12
Funnel plot ofthe THI scores 1 month after intervention Figure 13 Egger's funnel plot Figure 14 Begg's funnel plot