Jiann-Jy Chen1,2, Bing-Syuan Zeng3, Ching-Nung Wu4, Brendon Stubbs5,6,7, Andre F Carvalho8,9, Andre R Brunoni10,11, Kuan-Pin Su5,12,13,14, Yu-Kang Tu15,16, Yi-Cheng Wu17, Tien-Yu Chen18,19, Pao-Yen Lin20,21, Chih-Sung Liang22,23, Chih-Wei Hsu20, Shih-Pin Hsu24, Hung-Chang Kuo24, Yen-Wen Chen2, Ping-Tao Tseng2, Cheng-Ta Li25,26,27. 1. Department of Neurology, E-Da Cancer Hospital, Kaohsiung, Taiwan. 2. Prospect Clinic for Otorhinolaryngology and Neurology, Kaohsiung City, Taiwan. 3. Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan. 4. Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. 5. Institute of Psychiatry, Psychology and Neuroscience, King's College London, Department of Psychological Medicine, London, United Kingdom. 6. Physiotherapy Department, South London and Maudsley NHS (National Health Service) Foundation Trust, London, United Kingdom. 7. Positive Ageing Research Institute (PARI), Faculty of Health, Social Care Medicine and Education, Anglia Ruskin University, Chelmsford, United Kingdom. 8. Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada. 9. Centre for Addiction and Mental Health, Toronto, Ontario, Canada. 10. Service of Interdisciplinary Neuromodulation, Department and Institute of Psychiatry, Laboratory of Neurosciences (LIM-27), University of Sao Paulo, Sao Paulo, Brazil. 11. Interdisciplinary Center for Applied Neuromodulation, University Hospital, University of Sao Paulo, Sao Paulo, Brazil. 12. Department of Psychiatry and Mind-Body Interface Laboratory, China Medical University Hospital, Taichung, Taiwan. 13. College of Medicine, China Medical University, Taichung, Taiwan. 14. An-Nan Hospital, China Medical University, Tainan, Taiwan. 15. Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan. 16. Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan. 17. Department of Sports Medicine, Landseed International Hospital, Taoyuan, Taiwan. 18. Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan. 19. Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan. 20. Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. 21. Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. 22. Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan. 23. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan. 24. Department of Neurology, E-Da Hospital/School of Medicine, I-Shou University, Kaohsiung, Taiwan. 25. Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan. 26. Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan. 27. Institute of Brain Science and Brain Research Center, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
Abstract
Importance: Tinnitus has a prevalence of 10% to 25% and is frequently associated with numerous complications, such as neuropsychiatric disease. Traditional treatments have failed to meet the needs of patients with tinnitus. Noninvasive brain stimulation (NIBS) can focally modify cortical functioning and has been proposed as a strategy for reducing tinnitus severity. However, the results have been inconclusive. Objective: To evaluate the association between different central NIBS therapies and efficacy and acceptability for treatment of tinnitus. Data Sources: ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, and Web of Science databases were searched from inception to August 4, 2019. No language restriction was applied. Manual searches were performed for potentially eligible articles selected from the reference lists of review articles and pairwise meta-analyses. Study Selection: Randomized clinical trials (RCTs) examining the central NIBS method used in patients with unilateral or bilateral tinnitus were included in the current network meta-analysis. The central NIBS method was compared with sham, waiting list, or active controls. Studies that were not clinical trials or RCTs and did not report the outcome of interest were excluded. Data Extraction and Synthesis: Two authors independently screened the studies, extracted the relevant information, and evaluated the risk of bias in the included studies. In cases of discrepancy, a third author became involved. If manuscript data were not available, the corresponding authors or coauthors were approached to obtain the original data. This network meta-analysis was based on the frequentist model. Main Outcomes and Measures: The primary outcome was change in the severity of tinnitus. Secondary outcomes were changes in quality of life and the response rate related to the NIBS method in patients with tinnitus. Results: Overall, 32 unique RCTs were included with 1458 unique participants (mean female proportion, 34.4% [range, 0%-81.2%]; mean age, 49.6 [range, 40.0-62.8] years; median age, 49.8 [interquartile range, 48.1-52.4] years). The results of the network meta-analysis revealed that cathodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex combined with transcranial random noise stimulation over the bilateral auditory cortex was associated with the greatest improvement in tinnitus severity (standardized mean difference [SMD], -1.89; 95% CI, -3.00 to -0.78) and quality of life (SMD, -1.24; 95% CI, -2.02 to -0.45) compared with the controls. Improvement in tinnitus severity ranked more favorably for continuous theta-burst stimulation (cTBS) over both auditory cortices (SMD, -0.79; 95% CI = -1.57 to -0.01) than cTBS over only the left auditory cortex (SMD, -0.30; 95% CI, -0.87 to 0.28), compared with controls. Repetitive transcranial magnetic stimulation with priming had a superior beneficial association with tinnitus severity compared with the strategies without priming. None of the investigated NIBS types had a significantly different dropout rate compared with that of the control group. Conclusions and Relevance: This network meta-analysis suggests a potential role of NIBS interventions in tinnitus management. Future large-scale RCTs focusing on longer follow-up and different priming procedure NIBS are warranted to confirm these findings.
Importance: Tinnitus has a prevalence of 10% to 25% and is frequently associated with numerous complications, such as neuropsychiatric disease. Traditional treatments have failed to meet the needs of patients with tinnitus. Noninvasive brain stimulation (NIBS) can focally modify cortical functioning and has been proposed as a strategy for reducing tinnitus severity. However, the results have been inconclusive. Objective: To evaluate the association between different central NIBS therapies and efficacy and acceptability for treatment of tinnitus. Data Sources: ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, and Web of Science databases were searched from inception to August 4, 2019. No language restriction was applied. Manual searches were performed for potentially eligible articles selected from the reference lists of review articles and pairwise meta-analyses. Study Selection: Randomized clinical trials (RCTs) examining the central NIBS method used in patients with unilateral or bilateral tinnitus were included in the current network meta-analysis. The central NIBS method was compared with sham, waiting list, or active controls. Studies that were not clinical trials or RCTs and did not report the outcome of interest were excluded. Data Extraction and Synthesis: Two authors independently screened the studies, extracted the relevant information, and evaluated the risk of bias in the included studies. In cases of discrepancy, a third author became involved. If manuscript data were not available, the corresponding authors or coauthors were approached to obtain the original data. This network meta-analysis was based on the frequentist model. Main Outcomes and Measures: The primary outcome was change in the severity of tinnitus. Secondary outcomes were changes in quality of life and the response rate related to the NIBS method in patients with tinnitus. Results: Overall, 32 unique RCTs were included with 1458 unique participants (mean female proportion, 34.4% [range, 0%-81.2%]; mean age, 49.6 [range, 40.0-62.8] years; median age, 49.8 [interquartile range, 48.1-52.4] years). The results of the network meta-analysis revealed that cathodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex combined with transcranial random noise stimulation over the bilateral auditory cortex was associated with the greatest improvement in tinnitus severity (standardized mean difference [SMD], -1.89; 95% CI, -3.00 to -0.78) and quality of life (SMD, -1.24; 95% CI, -2.02 to -0.45) compared with the controls. Improvement in tinnitus severity ranked more favorably for continuous theta-burst stimulation (cTBS) over both auditory cortices (SMD, -0.79; 95% CI = -1.57 to -0.01) than cTBS over only the left auditory cortex (SMD, -0.30; 95% CI, -0.87 to 0.28), compared with controls. Repetitive transcranial magnetic stimulation with priming had a superior beneficial association with tinnitus severity compared with the strategies without priming. None of the investigated NIBS types had a significantly different dropout rate compared with that of the control group. Conclusions and Relevance: This network meta-analysis suggests a potential role of NIBS interventions in tinnitus management. Future large-scale RCTs focusing on longer follow-up and different priming procedure NIBS are warranted to confirm these findings.
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