Association of Central Noninvasive Brain Stimulation Interventions With Efficacy and Safety in Tinnitus Management: A Meta-analysis | Otolaryngology | JAMA Otolaryngology–Head & Neck Surgery | JAMA Network
[Skip to Navigation]
Figure 1.  Flowchart of the Present Network Meta-analysis
Flowchart of the Present Network Meta-analysis
Figure 2.  The Network Structure of Changes of Severity of Tinnitus
The Network Structure of Changes of Severity of Tinnitus

The lines between nodes represent direct comparisons in various trials, and the size of each circle is proportional to the size of the population involved in each specific treatment. The thickness of the lines is proportional to the number of trials connected to the network. a-tDCS indicates anodal transcranial direct current stimulation; cTBS, continuous theta-burst stimulation; c-tDCS, cathodal tDCS; dTMS, deep transcranial magnetic stimulation; F3, left dorsolateral prefrontal cortex (DLPFC); F4, right DLPFC; Fp2, right supraorbital area; HF, high-frequency; iTBS, intermittent TBS; LF, low-frequency; rTMS, repetitive TMS; T3, left auditory cortex; T4, right auditory cortex; and tRNS, transcranial random noise stimulation.

Figure 3.  Forest Plot of the Changes of Severity of Tinnitus
Forest Plot of the Changes of Severity of Tinnitus

When the effect size is less than zero, it indicated the specified treatment was associated with higher improvement in severity of tinnitus than controls. a-tDCS indicates anodal transcranial direct current stimulation; cTBS, continuous theta-burst stimulation; c-tDCS, cathodal tDCS; dTMS, deep transcranial magnetic stimulation; F3, over the left dorsolateral prefrontal cortex (DLPFC); F4, over the right DLPFC; F3F4, over the bilateral DLPFC; Fp2, over the right supraorbital area; HF, high-frequency; iTBS, intermittent TBS; LF, low-frequency; rTMS, repetitive TMS; SMD, standardized mean difference; T3, over the left auditory cortex; T4, over the right auditory cortex; T3T4, over the bilateral auditory cortices; and tRNS, transcranial random noise stimulation.

1.
Bauer  CA.  Tinnitus.   N Engl J Med. 2018;378(13):1224-1231. doi:10.1056/NEJMcp1506631 PubMedGoogle ScholarCrossref
2.
Panov  F, Kopell  BH.  Use of cortical stimulation in neuropathic pain, tinnitus, depression, and movement disorders.   Neurotherapeutics. 2014;11(3):564-571. doi:10.1007/s13311-014-0283-0 PubMedGoogle ScholarCrossref
3.
Eggermont  JJ, Roberts  LE.  The neuroscience of tinnitus.   Trends Neurosci. 2004;27(11):676-682. doi:10.1016/j.tins.2004.08.010 PubMedGoogle ScholarCrossref
4.
Weisz  N, Müller  S, Schlee  W, Dohrmann  K, Hartmann  T, Elbert  T.  The neural code of auditory phantom perception.   J Neurosci. 2007;27(6):1479-1484. doi:10.1523/JNEUROSCI.3711-06.2007 PubMedGoogle ScholarCrossref
5.
Vanneste  S, Plazier  M, der Loo  Ev, de Heyning  PV, Congedo  M, De Ridder  D.  The neural correlates of tinnitus-related distress.   Neuroimage. 2010;52(2):470-480. doi:10.1016/j.neuroimage.2010.04.029 PubMedGoogle ScholarCrossref
6.
De Ridder  D, De Mulder  G, Walsh  V, Muggleton  N, Sunaert  S, Møller  A.  Magnetic and electrical stimulation of the auditory cortex for intractable tinnitus: case report.   J Neurosurg. 2004;100(3):560-564. doi:10.3171/jns.2004.100.3.0560 PubMedGoogle ScholarCrossref
7.
Formánek  M, Migaľová  P, Krulová  P,  et al.  Combined transcranial magnetic stimulation in the treatment of chronic tinnitus.   Ann Clin Transl Neurol. 2018;5(7):857-864. doi:10.1002/acn3.587 PubMedGoogle ScholarCrossref
8.
Forogh  B, Yazdi-Bahri  SM, Ahadi  T, Fereshtehnejad  SM, Raissi  GR.  Comparison of two protocols of transcranial magnetic stimulation for treatment of chronic tinnitus: a randomized controlled clinical trial of burst repetitive versus high-frequency repetitive transcranial magnetic stimulation.   Neurol Sci. 2014;35(2):227-232. doi:10.1007/s10072-013-1487-5 PubMedGoogle ScholarCrossref
9.
Lorenz  I, Müller  N, Schlee  W, Langguth  B, Weisz  N.  Short-term effects of single repetitive TMS sessions on auditory evoked activity in patients with chronic tinnitus.   J Neurophysiol. 2010;104(3):1497-1505. doi:10.1152/jn.00370.2010 PubMedGoogle ScholarCrossref
10.
Faber  M, Vanneste  S, Fregni  F, De Ridder  D.  Top down prefrontal affective modulation of tinnitus with multiple sessions of tDCS of dorsolateral prefrontal cortex.   Brain Stimul. 2012;5(4):492-498. doi:10.1016/j.brs.2011.09.003 PubMedGoogle ScholarCrossref
11.
To  WT, Ost  J, Hart  J  Jr, De Ridder  D, Vanneste  S.  The added value of auditory cortex transcranial random noise stimulation (tRNS) after bifrontal transcranial direct current stimulation (tDCS) for tinnitus.   J Neural Transm (Vienna). 2017;124(1):79-88. doi:10.1007/s00702-016-1634-2 PubMedGoogle ScholarCrossref
12.
Milev  RV, Giacobbe  P, Kennedy  SH,  et al; CANMAT Depression Work Group.  Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4, neurostimulation treatments.   Can J Psychiatry. 2016;61(9):561-575. doi:10.1177/0706743716660033 PubMedGoogle ScholarCrossref
13.
Horvath  JC, Carter  O, Forte  JD.  Transcranial direct current stimulation: five important issues we aren’t discussing (but probably should be).   Front Syst Neurosci. 2014;8:2. doi:10.3389/fnsys.2014.00002 PubMedGoogle ScholarCrossref
14.
Hoare  DJ, Adjamian  P, Sereda  M.  Electrical stimulation of the ear, head, cranial nerve, or cortex for the treatment of tinnitus: a scoping review.   Neural Plast. 2016;2016:5130503. doi:10.1155/2016/5130503 PubMedGoogle Scholar
15.
Song  JJ, Vanneste  S, Van de Heyning  P, De Ridder  D.  Transcranial direct current stimulation in tinnitus patients: a systemic review and meta-analysis.   ScientificWorldJournal. 2012;2012:427941. doi:10.1100/2012/427941 PubMedGoogle Scholar
16.
Soleimani  R, Jalali  MM, Hasandokht  T.  Therapeutic impact of repetitive transcranial magnetic stimulation (rTMS) on tinnitus: a systematic review and meta-analysis.   Eur Arch Otorhinolaryngol. 2016;273(7):1663-1675. doi:10.1007/s00405-015-3642-5 PubMedGoogle ScholarCrossref
17.
Kreuzer  PM, Lehner  A, Schlee  W,  et al.  Combined rTMS treatment targeting the anterior cingulate and the temporal cortex for the treatment of chronic tinnitus.   Sci Rep. 2015;5:18028. doi:10.1038/srep18028 PubMedGoogle ScholarCrossref
18.
Meng  Z, Liu  S, Zheng  Y, Phillips  JS.  Repetitive transcranial magnetic stimulation for tinnitus.   Cochrane Database Syst Rev. 2011;(10):CD007946.PubMedGoogle Scholar
19.
Higgins  JP, Welton  NJ.  Network meta-analysis: a norm for comparative effectiveness?   Lancet. 2015;386(9994):628-630. doi:10.1016/S0140-6736(15)61478-7 PubMedGoogle ScholarCrossref
20.
Hsieh  MT, Tseng  PT, Wu  YC,  et al.  Effects of different pharmacologic smoking cessation treatments on body weight changes and success rates in patients with nicotine dependence: a network meta-analysis.   Obes Rev. 2019;20(6):895-905. doi:10.1111/obr.12835 PubMedGoogle ScholarCrossref
21.
Tu  YK, Faggion  CM  Jr.  A primer on network meta-analysis for dental research.   ISRN Dent. 2012;2012:276520. doi:10.5402/2012/276520 PubMedGoogle Scholar
22.
Wu  YC, Tseng  PT, Tu  YK,  et al.  Association of delirium response and safety of pharmacological interventions for the management and prevention of delirium: a network meta-analysis.   JAMA Psychiatry. 2019;76(5):526-535. doi:10.1001/jamapsychiatry.2018.4365 PubMedGoogle ScholarCrossref
23.
Zeng  BS, Lin  SY, Tu  YK,  et al.  Prevention of postdental procedure bacteremia: a network meta-analysis.   J Dent Res. 2019;98(11):1204-1210. doi:10.1177/0022034519870466 PubMedGoogle ScholarCrossref
24.
Huang  SW, Tsai  CY, Tseng  CS,  et al.  Comparative efficacy and safety of new surgical treatments for benign prostatic hyperplasia: systematic review and network meta-analysis.   BMJ. 2019;367:5919. doi:10.1136/bmj.l5919 PubMedGoogle ScholarCrossref
25.
Yang  CP, Tseng  PT, Pei-Chen Chang  J, Su  H, Satyanarayanan  SK, Su  KP.  Melatonergic agents in the prevention of delirium: a network meta-analysis of randomized controlled trials.   Sleep Med Rev. 2020;50:101235. doi:10.1016/j.smrv.2019.101235 PubMedGoogle Scholar
26.
Tseng  PT, Yang  CP, Su  KP,  et al.  The association between melatonin and episodic migraine: a pilot network meta-analysis of randomized controlled trials to compare the prophylactic effects with exogenous melatonin supplementation and pharmacotherapy.   J Pineal Res. Published online April 29, 2020.PubMedGoogle Scholar
27.
Higgins  JGS.  Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2. The Cochrane Collaboration; 2009.
28.
Tu  YK.  Use of generalized linear mixed models for network meta-analysis.   Med Decis Making. 2014;34(7):911-918. doi:10.1177/0272989X14545789 PubMedGoogle ScholarCrossref
29.
Liu  Y, Wang  W, Zhang  AB, Bai  X, Zhang  S.  Epley and Semont maneuvers for posterior canal benign paroxysmal positional vertigo: A network meta-analysis.   Laryngoscope. 2016;126(4):951-955. doi:10.1002/lary.25688PubMedGoogle ScholarCrossref
30.
Salanti  G, Ades  AE, Ioannidis  JP.  Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial.   J Clin Epidemiol. 2011;64(2):163-171. doi:10.1016/j.jclinepi.2010.03.016 PubMedGoogle ScholarCrossref
31.
Higgins  JP, Del Giovane  C, Chaimani  A, Caldwell  DM, Salanti  G.  Evaluating the quality of evidence from a network meta-analysis.   Value Health. 2014;17(7):A324. doi:10.1016/j.jval.2014.08.572 PubMedGoogle ScholarCrossref
32.
Anders  M, Dvorakova  J, Rathova  L,  et al.  Efficacy of repetitive transcranial magnetic stimulation for the treatment of refractory chronic tinnitus: a randomized, placebo controlled study.   Neuro Endocrinol Lett. 2010;31(2):238-249.PubMedGoogle Scholar
33.
Bilici  S, Yigit  O, Taskin  U, Gor  AP, Yilmaz  ED.  Medium-term results of combined treatment with transcranial magnetic stimulation and antidepressant drug for chronic tinnitus.   Eur Arch Otorhinolaryngol. 2015;272(2):337-343. doi:10.1007/s00405-013-2851-zPubMedGoogle ScholarCrossref
34.
Chung  HK, Tsai  CH, Lin  YC,  et al.  Effectiveness of theta-burst repetitive transcranial magnetic stimulation for treating chronic tinnitus.   Audiol Neurootol. 2012;17(2):112-120. doi:10.1159/000330882PubMedGoogle ScholarCrossref
35.
Folmer  RL, Theodoroff  SM, Casiana  L, Shi  Y, Griest  S, Vachhani  J.  Repetitive transcranial magnetic stimulation treatment for chronic tinnitus: a randomized clinical trial.   JAMA Otolaryngol Head Neck Surg. 2015;141(8):716-722. doi:10.1001/jamaoto.2015.1219PubMedGoogle ScholarCrossref
36.
Forogh  B, Mirshaki  Z, Raissi  GR, Shirazi  A, Mansoori  K, Ahadi  T.  Repeated sessions of transcranial direct current stimulation for treatment of chronic subjective tinnitus: a pilot randomized controlled trial.   Neurol Sci. 2016;37(2):253-259. doi:10.1007/s10072-015-2393-9PubMedGoogle ScholarCrossref
37.
Hoekstra  CE, Versnel  H, Neggers  SF, Niesten  ME, van Zanten  GA.  Bilateral low-frequency repetitive transcranial magnetic stimulation of the auditory cortex in tinnitus patients is not effective: a randomised controlled trial.   Audiol Neurootol. 2013;18(6):362-373. doi:10.1159/000354977PubMedGoogle ScholarCrossref
38.
James  GA, Thostenson  JD, Brown  G,  et al.  Neural activity during attentional conflict predicts reduction in tinnitus perception following rTMS.   Brain Stimul. 2017;10(5):934-943. doi:10.1016/j.brs.2017.05.009PubMedGoogle ScholarCrossref
39.
Khedr  EM, Rothwell  JC, Ahmed  MA, El-Atar  A.  Effect of daily repetitive transcranial magnetic stimulation for treatment of tinnitus: comparison of different stimulus frequencies.   J Neurol Neurosurg Psychiatry. 2008;79(2):212-215. doi:10.1136/jnnp.2007.127712PubMedGoogle ScholarCrossref
40.
Kreuzer  PM, Landgrebe  M, Schecklmann  M,  et al.  Can temporal repetitive transcranial magnetic stimulation be enhanced by targeting affective components of tinnitus with frontal rTMS? a randomized controlled pilot trial.   Front Syst Neurosci. 2011;5:88. doi:10.3389/fnsys.2011.00088PubMedGoogle ScholarCrossref
41.
Kyong  JS, Noh  TS, Park  MK, Oh  SH, Lee  JH, Suh  MW.  Phantom perception of sound and the abnormal cortical inhibition system: an electroencephalography (EEG) study.   Ann Otol Rhinol Laryngol. 2019;128(6_suppl):84S-95S. doi:10.1177/0003489419837990Google Scholar
42.
Landgrebe  M, Hajak  G, Wolf  S,  et al.  1-Hz rTMS in the treatment of tinnitus: A sham-controlled, randomized multicenter trial.   Brain Stimul. 2017;10(6):1112-1120. doi:10.1016/j.brs.2017.08.001PubMedGoogle ScholarCrossref
43.
Langguth  B, Kleinjung  T, Frank  E,  et al.  High-frequency priming stimulation does not enhance the effect of low-frequency rTMS in the treatment of tinnitus.   Exp Brain Res. 2008;184(4):587-591. doi:10.1007/s00221-007-1228-1PubMedGoogle ScholarCrossref
44.
Langguth  B, Landgrebe  M, Frank  E,  et al.  Efficacy of different protocols of transcranial magnetic stimulation for the treatment of tinnitus: Pooled analysis of two randomized controlled studies.   World J Biol Psychiatry. 2014;15(4):276-285. doi:10.3109/15622975.2012.708438PubMedGoogle ScholarCrossref
45.
Lehner  A, Schecklmann  M, Greenlee  MW, Rupprecht  R, Langguth  B.  Triple-site rTMS for the treatment of chronic tinnitus: a randomized controlled trial.   Sci Rep. 2016;6:22302. doi:10.1038/srep22302 PubMedGoogle ScholarCrossref
46.
Marcondes  RA, Sanchez  TG, Kii  MA,  et al.  Repetitive transcranial magnetic stimulation improve tinnitus in normal hearing patients: a double-blind controlled, clinical and neuroimaging outcome study.   Eur J Neurol. 2010;17(1):38-44. doi:10.1111/j.1468-1331.2009.02730.xPubMedGoogle ScholarCrossref
47.
Noh  TS, Kyong  JS, Chang  MY,  et al.  Comparison of treatment outcomes following either prefrontal cortical-only or dual-site repetitive transcranial magnetic stimulation in chronic tinnitus patients: a double-blind randomized study.   Otol Neurotol. 2017;38(2):296-303.PubMedGoogle Scholar
48.
Pal  N, Maire  R, Stephan  MA, Herrmann  FR, Benninger  DH.  Transcranial direct current stimulation for the treatment of chronic tinnitus: a randomized controlled study.   Brain Stimul. 2015;8(6):1101-1107. doi:10.1016/j.brs.2015.06.014PubMedGoogle ScholarCrossref
49.
Piccirillo  JF, Garcia  KS, Nicklaus  J,  et al.  Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus.   Arch Otolaryngol Head Neck Surg. 2011;137(3):221-228. doi:10.1001/archoto.2011.3PubMedGoogle ScholarCrossref
50.
Piccirillo  JF, Kallogjeri  D, Nicklaus  J,  et al.  Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus: four-week stimulation trial.   JAMA Otolaryngol Head Neck Surg. 2013;139(4):388-395. doi:10.1001/jamaoto.2013.233PubMedGoogle ScholarCrossref
51.
Plewnia  C, Reimold  M, Najib  A, Reischl  G, Plontke  SK, Gerloff  C.  Moderate therapeutic efficacy of positron emission tomography-navigated repetitive transcranial magnetic stimulation for chronic tinnitus: a randomised, controlled pilot study.   J Neurol Neurosurg Psychiatry. 2007;78(2):152-156. doi:10.1136/jnnp.2006.095612PubMedGoogle ScholarCrossref
52.
Plewnia  C, Vonthein  R, Wasserka  B,  et al.  Treatment of chronic tinnitus with θ burst stimulation: a randomized controlled trial.   Neurology. 2012;78(21):1628-1634. doi:10.1212/WNL.0b013e3182574ef9 PubMedGoogle ScholarCrossref
53.
Rossi  S, De Capua  A, Ulivelli  M,  et al.  Effects of repetitive transcranial magnetic stimulation on chronic tinnitus: a randomised, crossover, double blind, placebo controlled study.   J Neurol Neurosurg Psychiatry. 2007;78(8):857-863. doi:10.1136/jnnp.2006.105007PubMedGoogle ScholarCrossref
54.
Sahlsten  H, Virtanen  J, Joutsa  J,  et al.  Electric field-navigated transcranial magnetic stimulation for chronic tinnitus: a randomized, placebo-controlled study.   Int J Audiol. 2017;56(9):692-700. doi:10.1080/14992027.2017.1313461PubMedGoogle ScholarCrossref
55.
Schecklmann  M, Giani  A, Tupak  S,  et al.  Neuronavigated left temporal continuous theta burst stimulation in chronic tinnitus.   Restor Neurol Neurosci. 2016;34(2):165-175. doi:10.3233/RNN-150518PubMedGoogle Scholar
56.
Smith  JA, Mennemeier  M, Bartel  T,  et al.  Repetitive transcranial magnetic stimulation for tinnitus: a pilot study.   Laryngoscope. 2007;117(3):529-534. doi:10.1097/MLG.0b013e31802f4154PubMedGoogle ScholarCrossref
57.
Yilmaz  M, Yener  MH, Turgut  NF, Aydin  F, Altug  T.  Effectiveness of transcranial magnetic stimulation application in treatment of tinnitus.   J Craniofac Surg. 2014;25(4):1315-1318. doi:10.1097/SCS.0000000000000782PubMedGoogle ScholarCrossref
58.
Van Doren  J, Langguth  B, Schecklmann  M.  Electroencephalographic effects of transcranial random noise stimulation in the auditory cortex.   Brain Stimul. 2014;7(6):807-812. doi:10.1016/j.brs.2014.08.007 PubMedGoogle ScholarCrossref
59.
Vanneste  S, Fregni  F, De Ridder  D.  Head-to-head comparison of transcranial random noise stimulation, transcranial AC stimulation, and transcranial DC stimulation for tinnitus.   Front Psychiatry. 2013;4:158. doi:10.3389/fpsyt.2013.00158 PubMedGoogle ScholarCrossref
60.
Lang  N, Siebner  HR, Ernst  D,  et al.  Preconditioning with transcranial direct current stimulation sensitizes the motor cortex to rapid-rate transcranial magnetic stimulation and controls the direction of after-effects.   Biol Psychiatry. 2004;56(9):634-639. doi:10.1016/j.biopsych.2004.07.017 PubMedGoogle ScholarCrossref
61.
Vanneste  S, De Ridder  D.  Bifrontal transcranial direct current stimulation modulates tinnitus intensity and tinnitus-distress-related brain activity.   Eur J Neurosci. 2011;34(4):605-614. doi:10.1111/j.1460-9568.2011.07778.x PubMedGoogle ScholarCrossref
62.
Meeus  O, Blaivie  C, Ost  J, De Ridder  D, Van de Heyning  P.  Influence of tonic and burst transcranial magnetic stimulation characteristics on acute inhibition of subjective tinnitus.   Otol Neurotol. 2009;30(6):697-703. doi:10.1097/MAO.0b013e3181b05023 PubMedGoogle ScholarCrossref
63.
De Ridder  D, van der Loo  E, Van der Kelen  K, Menovsky  T, van de Heyning  P, Moller  A.  Do tonic and burst TMS modulate the lemniscal and extralemniscal system differentially?   Int J Med Sci. 2007;4(5):242-246. doi:10.7150/ijms.4.242 PubMedGoogle ScholarCrossref
64.
Poreisz  C, Paulus  W, Moser  T, Lang  N.  Does a single session of theta-burst transcranial magnetic stimulation of inferior temporal cortex affect tinnitus perception?   BMC Neurosci. 2009;10:54. doi:10.1186/1471-2202-10-54 PubMedGoogle ScholarCrossref
65.
Kleinjung  T, Eichhammer  P, Landgrebe  M,  et al.  Combined temporal and prefrontal transcranial magnetic stimulation for tinnitus treatment: a pilot study.   Otolaryngol Head Neck Surg. 2008;138(4):497-501. doi:10.1016/j.otohns.2007.12.022 PubMedGoogle ScholarCrossref
66.
Lehner  A, Schecklmann  M, Poeppl  TB,  et al.  Multisite rTMS for the treatment of chronic tinnitus: stimulation of the cortical tinnitus network—a pilot study.   Brain Topogr. 2013;26(3):501-510. doi:10.1007/s10548-012-0268-4 PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    Original Investigation
    July 9, 2020

    Association of Central Noninvasive Brain Stimulation Interventions With Efficacy and Safety in Tinnitus Management: A Meta-analysis

    Author Affiliations
    • 1Department of Neurology, E-Da Cancer Hospital, Kaohsiung, Taiwan
    • 2Prospect Clinic for Otorhinolaryngology and Neurology, Kaohsiung City, Taiwan
    • 3Department of Internal Medicine, E-Da Hospital, Kaohsiung, Taiwan
    • 4Department of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
    • 5Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Department of Psychological Medicine, London, United Kingdom
    • 6Physiotherapy Department, South London and Maudsley NHS (National Health Service) Foundation Trust, London, United Kingdom
    • 7Positive Ageing Research Institute (PARI), Faculty of Health, Social Care Medicine and Education, Anglia Ruskin University, Chelmsford, United Kingdom
    • 8Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
    • 9Centre for Addiction and Mental Health, Toronto, Ontario, Canada
    • 10Service of Interdisciplinary Neuromodulation, Department and Institute of Psychiatry, Laboratory of Neurosciences (LIM-27), University of Sao Paulo, Sao Paulo, Brazil
    • 11Interdisciplinary Center for Applied Neuromodulation, University Hospital, University of Sao Paulo, Sao Paulo, Brazil
    • 12Department of Psychiatry and Mind-Body Interface Laboratory, China Medical University Hospital, Taichung, Taiwan
    • 13College of Medicine, China Medical University, Taichung, Taiwan
    • 14An-Nan Hospital, China Medical University, Tainan, Taiwan
    • 15Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
    • 16Department of Dentistry, National Taiwan University Hospital, Taipei, Taiwan
    • 17Department of Sports Medicine, Landseed International Hospital, Taoyuan, Taiwan
    • 18Department of Psychiatry, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan
    • 19Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan
    • 20Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
    • 21Institute for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
    • 22Department of Psychiatry, Beitou Branch, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, Taipei, Taiwan
    • 23Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
    • 24Department of Neurology, E-Da Hospital/School of Medicine, I-Shou University, Kaohsiung, Taiwan
    • 25Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan
    • 26Division of Psychiatry, School of Medicine, National Yang-Ming University, Taipei, Taiwan
    • 27Institute of Brain Science and Brain Research Center, School of Medicine, National Yang-Ming University, Taipei, Taiwan
    JAMA Otolaryngol Head Neck Surg. 2020;146(9):801-809. doi:10.1001/jamaoto.2020.1497
    Key Points

    Question  Which noninvasive brain stimulation treatment was associated with the best efficacy and acceptability in tinnitus management?

    Findings  In this meta-analysis of 32 unique studies including 1458 unique participants, the 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 both tinnitus severity and quality of life. Continuous theta-burst stimulation over both auditory cortices ranked more favorably than that over the left auditory cortex only.

    Meaning  Regarding the efficacy and acceptability for tinnitus treatment, these findings suggest that the cathodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex combined with transcranial random noise stimulation over the bilateral auditory cortex is preferable.

    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.

    Introduction

    Quiz Ref IDIn the adult population, tinnitus has a prevalence of 10% to 25%,1,2 and 6% to 25% of these persons suggest that these symptoms are severely debilitating and have an adverse effect on quality of life.3 Tinnitus is recognized as a difficult disease to identify and manage because of controversy regarding its definition and treatment. Tinnitus usually results from heterogeneous causes: (1) the auditory system (usually peripheral, rarely central), (2) the somatosensory system (head and neck), or (3) a combination of these. The condition results when the interactivity of the auditory and somatosensory systems exceeds the individual’s tinnitus threshold. Treatments to reduce tinnitus severity and tinnitus-related distress include cognitive behavioral therapy, acoustic stimulation, and educational counseling. Although somatic treatments can be effective in cases of tinnitus with a specific origin (eg, palatal myoclonus, deafferentation of the auditory system, loss of cochlear hair cells, and ototoxic drugs), no specific interventions have been proven to be effective in treating tinnitus without a specific cause.2

    With the help of functional brain imaging studies, abnormal hyperactivity has been detected in the whole brain area, especially in both auditory cortices,4 the anterior cingulate cortex,5 and the insula.5Quiz Ref ID Therefore, suppression of abnormal brain hyperactivity through central noninvasive brain stimulation (NIBS) has been proposed as a tinnitus management strategy.6 The central NIBS techniques include repetitive transcranial magnetic stimulation (rTMS),7 the rTMS variant theta-burst stimulation (TBS),8,9 and transcranial electrical stimulation, such as transcranial direct current stimulation (tDCS)10 and transcranial random noise stimulation (tRNS).11 Based on the frequency applied, rTMS can induce different changes in brain activity in patients with tinnitus. For example, high-frequency rTMS induces higher brain activity, whereas low-frequency rTMS suppresses hyperactivity in the cerebral cortex.12 Transcranial DCS, in which a weak direct electrical current is passed through the brain cortex, has a similar suppressing or enhancing effect on brain activity. Similarly, tDCS has been found to have a modulating effect on the stimulated brain cortex, although the suppressing or enhancing effect due to the polarity of tDCS is still debated.8,13 The suppression of hyperactivity in the temporoparietal cortex (ie, the primary or secondary auditory cortex) through the use of rTMS or tDCS was considered a reasonable NIBS method in the management of tinnitus.14

    Pairwise meta-analyses have indicated significant efficacy of tDCS15 and rTMS16 vs sham treatment in improving the severity of tinnitus. However, these meta-analyses were based on only 2 to 4 randomized clinical trials (RCTs), resulting in poor evidence of efficacy. In addition, different combination protocols of NIBS interventions have been developed for tinnitus management, including different brain stimulation targets and stimulation parameters. Specifically, additive stimulation over the prefrontal cortex (often dorsolateral prefrontal cortex [DLPFC]), also termed the priming procedure, has been reported to have an enhancing effect on tinnitus management.7,17 However, the most recent meta-analyses have not provided conclusive results relevant to clinical practice.15,16,18 In addition, traditional pairwise meta-analyses cannot provide further information about the relative efficacy of interventions that have not been directly compared in head-to-head trials, which is an essential aspect when judging the therapeutic value of an intervention. Considering these issues, we conducted a network meta-analysis of the currently published RCTs to estimate the association between different central NIBS interventions and relative efficacy and acceptability in patients with tinnitus.19

    Methods

    The present study did not receive any ethics committee approval or informed consent from the participants because we did not approach any specific participants or report any detailed information of specific participants. Our previous project was approved by the institutional review board of the Tri-Service General Hospital, National Defense Medical Center. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline (eTable 1 in the Supplement).

    Detailed information regarding the methods and materials is presented in the eMethods in the Supplement. We searched the ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, and Web of Science databases 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. We included RCTs with sham-controlled, waiting list–controlled, or active-controlled design conducted in patients with tinnitus. The detailed categorization of the targets of comparison arms were listed in the node definition section of the eMethods in the Supplement.

    Following the flowchart used in previous network meta-analyses,20-26 we extracted the relevant information from the RCTs and evaluated the risk of bias in the included studies. Two authors (J.J.C. and B.S.Z.) independently screened the studies, extracted the relevant information from the manuscripts, and evaluated the risk of bias in the included studies. In cases of discrepancy, a third author (P.T.T.) became involved. If manuscript data were not available, the corresponding authors or coauthors were approached to obtain the original data. We only extracted data on central NIBS and not peripheral stimulation.

    The primary outcome was change in the severity of tinnitus after NIBS in patients with tinnitus, which could be rated using a different tinnitus questionnaire (described in the Results section) (outcomes in eMethods in the Supplement). The secondary outcomes were change in quality of life and response rate related to the NIBS method in patients with tinnitus. The detailed definition of response rate and quality of life had been presented in the outcomes in eMethods in the Supplement. Finally, the safety profile was calculated using the dropout rate, which was defined as the percentage of patients leaving the study before its conclusion for any reason.

    The risk of bias was evaluated according to the Cochrane risk-of-bias tool.27 The current network meta-analysis was conducted under the frequentist model and generalized linear mixed models to make direct and indirect comparisons.28 In our analysis, the mvmeta command was applied in the STATA program, version 14.0.29 We estimated the standardized mean difference (SMD) with 95% CI for continuous variables (ie, the primary outcome of tinnitus severity and the secondary outcome of quality of life). We evaluated categorical values with the rate ratio and 95% CI (ie, the secondary outcome of response and safety of dropout) and applied a 0.5 zero-cell correction during the meta-analysis procedure. Heterogeneity among the included studies was evaluated using the τ value, which is the estimated SD of the association across the included studies.

    To provide additional information for clinical applications, we calculated the surface under the cumulative ranking curve (SUCRA), which indicates the relative ranking probabilities of the treatment effects for the target outcomes.30 We conducted meta-regression to determine the associations between change in tinnitus severity and participant characteristics, such as mean age and the sex distribution. Finally, we evaluated the potential inconsistencies between the direct and indirect evidence within the network by using the loop-specific approach and identified local inconsistencies by using the node-splitting method. The design-by-treatment model was used to evaluate global inconsistencies across the entire network meta-analysis.31

    Results

    After the initial screening procedure, 104 articles were considered for full-text review (Figure 1). However, 72 were excluded for various reasons (eTable 2 in the Supplement). Finally, 32 articles7-11,17,32-57 were included in the current study (eTable 3 in the Supplement). Figure 2 depicts the entire geometric distribution of the treatment arms. The detailed categorization of the treatment arms is provided in eTable 4 in the Supplement.

    Characteristics of the Included Studies

    A total of 1458 participants were included. The mean age of the participants was 49.6 years (range, 40.0-62.8 years; median, 49.8 [interquartile range (IQR), 48.1-52.4] years); the mean female proportion was 34.4% (range, 0%-81.2%; median, 30.3% [IQR, 24.7%-40.9%]), and the mean male proportion was 65.6% (range, 18.8%-100%; median, 69.7% [IQR, 59.1%-75.3%]). The mean duration of central NIBS treatment was 16.9 weeks (range, 2-54 weeks; median, 12 [IQR, 4-24] weeks). The baseline characteristics of the included participants are summarized in eTable 3 in the Supplement. The definition of response varied among the recruited studies as patient self-rated global impression, Tinnitus Handicap Inventory score reduction of greater than 7 or 10 points, Tinnitus Handicap Inventory score reduction of greater than 20% of the baseline score, and Tinnitus Questionnaire score reduction of greater than 5 or 10 points.

    Primary Outcome: Change in Tinnitus Severity

    The network meta-analysis revealed that only the cathodal tDCS over the left DLPFC (F3) plus anodal tDCS over the right DLPFC (F4) plus tRNS of the left auditory cortex (T3) combination (SMD, −1.89 [95% CI, −3.00 to −0.78]), continuous TBS (cTBS) over the bilateral auditory cortices (T3T4) (SMD, −0.79 [95% CI, −1.57 to −0.01]), and high-frequency rTMS-F3 plus low-frequency rTMS-T3T4 combination (SMD, −0.70 [95% CI, −1.38 to −0.02]) were associated with significant improvement in the severity of tinnitus compared with the control (eTable 5 in the Supplement and Figure 3). The associations between an NIBS method and the change in tinnitus severity were ranked according to the SUCRA, where lower values indicate superior outcomes of tinnitus severity. In brief, the combination of cathodal tDCS-F3 plus anodal tDCS-F4 plus tRNS-T3 was associated with the largest improvement, followed by deep TMS bilateral medial frontal cortex plus low-frequency rTMS-T3 and cTBS-T3T4. In addition, rTMS with a priming procedure (ie, rTMS over the frontal lobe followed by rTMS over the auditory cortex, such as high-frequency rTMS-F3 plus low-frequency rTMS-T3T4 (SUCRA, 36.6), high-frequency rTMS-F3 plus low-frequency rTMS-T3 (SUCRA, 38.8), low-frequency rTMS-F3 plus low-frequency rTMS-T3 (SUCRA, 48.3), and low-frequency rTMS-F4 plus low-frequency rTMS-T3 (SUCRA, 38.1) was ranked more highly than rTMS without priming (ie, rTMS over the auditory cortex alone, such as low-frequency rTMS-T3 (SUCRA, 62.9), low-frequency rTMS-T3T4 (SUCRA, 54.0), and high-frequency rTMS-T3T4; SUCRA, 56.5). Finally, bilateral cTBS (ie, cTBS-T3T4; SUCRA, 32.7) was ranked more highly than unilateral cTBS (ie, cTBS-T3; SUCRA, 64.1) and intermittent TBS (iTBS) (ie, iTBS-T3; SUCRA, 53.4) (eTable 6A in the Supplement). A meta-regression using the restricted maximum likelihood estimator was performed to examine the potential association of age and sex with the change in tinnitus severity. The results reveal a nonsignificant association with the change in tinnitus severity when using the moderating variables age and sex (eTable 7A in the Supplement).

    Secondary Outcomes
    Change in Quality of Life

    The network meta-analysis revealed that the cathodal tDCS-F3 plus anodal tDCS-F4 plus tRNS-T3 combination (SMD, −1.24 [95% CI, −2.02 to −0.45]), low-frequency rTMS-T3T4 (SMD, −0.52 [95% CI, −0.83 to −0.20]), and high-frequency rTMS-T3 (SMD, −0.49 [95% CI, −0.93 to −0.04]) were associated with significant improvements in the quality of life of patients with tinnitus in comparison to the sham control (eTable 8A, eFigure 1A, and eFigure 2A in the Supplement). The associations between NIBS method and change in quality of life were ranked according to the SUCRA. In brief, the combination cathodal tDCS-F3 plus anodal tDCS-F4 plus tRNS-T3 was associated with the largest improvement in quality of life (SUCRA, 5.0), followed by cTBS-T3 (SUCRA, 28.8) and low-frequency rTMS-T3T4 (SUCRA, 33.4) (eTable 6B in the Supplement). The results of this meta-regression revealed a nonsignificant association with change in quality of life when using the moderating variables age and sex (eTable 7B in the Supplement).

    Response Rate

    The network meta-analysis revealed that none of the investigated NIBS methods were associated with significantly better response rates than the sham control (eTable 8B, eFigure 1B, and eFigure 2B in the Supplement). The associations between the NIBS methods and change in quality of life were ranked according to the SUCRA. In brief, high-frequency rTMS-T3 was associated with the highest response rate (SUCRA, 27.5) (eTable 6C in the Supplement). The results of this meta-regression revealed a nonsignificant association with the response rate when using the moderating variables age and sex (eTable 7C in the Supplement).

    Safety Profile: Tolerability Reflected by Dropout Rate

    In the network meta-analysis, none of the investigated NIBSs were associated with significantly different dropout rates when compared with the sham control (eTable 6D, eTable 8C, eFigure 1C, and eFigure 2C in the Supplement). The results of this meta-regression reveal a nonsignificant association with the dropout rate when using the moderating variables age and sex (eTable 7D in the Supplement).

    Risk of Bias and Publication Bias

    Among the included studies, we found that 134 of 224 items (59.8%) had a low risk of bias; 69 of 224 items (30.8%), an unclear risk of bias; and 21 of 224 items (9.4%), a high risk of bias. Unclear reporting of the allocation procedure or blinding of the studies further contributed to the risk of bias (eFigure 3A-B in the Supplement).

    Funnel plots of the publication bias (eFigure 4A-H in the Supplement) revealed general symmetry, and the results of the Egger test indicated no significant publication bias among the articles included in the network meta-analysis. In general, the analysis did not demonstrate inconsistencies in terms of local inconsistencies, as assessed using the loop-specific approach and node-splitting method, or global inconsistencies, as determined using the design-by-treatment method except for the situation mentioned below. Overall inconsistencies were detected in the outcomes of severity of tinnitus and quality of life (eTables 9 and 10 in the Supplement).

    Discussion

    To our knowledge, the current study is the first comprehensive network meta-analysis performed to investigate the association between central NIBS interventions and efficacy and acceptability in patients with tinnitus. Quiz Ref IDEvidence from this network meta-analysis revealed that cathodal tDCS-F3 plus anodal tDCS-F4 plus tRNS-T3 was associated with significantly greater improvement in both tinnitus severity and quality of life than the sham control and the largest improvement in both tinnitus severity and quality of life. In addition, cTBS-T3T4 was ranked more highly than cTBS-T3 or iTBS. Repetitive TMS with a priming procedure may be better at improving the severity of tinnitus. Noninvasive brain stimulation using high-frequency rTMS as the priming intervention (ie, high-frequency rTMS-F3 plus low-frequency rTMS-T3T4) was associated with significantly greater improvement in tinnitus severity than the sham control. Finally, most of the investigated NIBS methods were suggested by the dropout rate to be well tolerated.

    The first main finding of this study was that the cathodal tDCS-F3 plus anodal tDCS-F4 plus tRNS-T3 combination was associated with significantly greater improvement in both tinnitus severity and quality of life than the sham control and was also associated with the greatest improvement in both the severity of tinnitus and quality of life. The cathodal tDCS-F3 plus anodal tDCS-F4 plus tRNS-T3 combination involved cathodal tDCS-F3 and tRNS-T3. Transcranial RNS is a modification of transcranial alternating current stimulation with random oscillations (ranging from 0.1-640.0 Hz).58 In 1 RCT,10 the effect of cathodal tDCS-F3 on tinnitus intensity was demonstrated. However, in a head-to-head trial,59 tRNS was proven to be superior to tDCS in suppressing tinnitus intensity and decreasing distress after a single session. Furthermore, the findings of the current network meta-analysis supported the superiority of continuous sessions of a combination of cathodal tDCS-F3, anodal tDCS-F4, and tRNS-T3 for tinnitus intensity. Based on the findings of hyperactivity detected in both auditory cortices,4 the anterior cingulate cortex,5 and the insula5 in functional brain imaging studies (ie, magnetoencephalography, functional magnetic resonance imaging, or brain positron emission tomography) for patients with tinnitus, the rationale of a combination of stimulation types over these sites is a reasonable strategy.11 Furthermore, the hypothesis of the preconditioning phenomenon can be a valid explanation of the importance of sequence of stimulation.60 According to this hypothesis, the beneficial effect of the second stimulation targeting another region (ie, the auditory cortex) of the tinnitus network is enhanced by the priming stimulation (ie, over the frontal region).61 However, only 1 RCT with waiting list controls has reported the additive effect of tRNS in patients with tinnitus recruited for this network meta-analysis.11 Although significant inconsistency was not detected within the comparison of treatment arms of cathodal tDCS-F3 plus anodal tDCS-F4, cathodal tDCS-F3 plus anodal tDCS-F4 plus tRNS-T3, and controls, which were treatment arms applied in that RCT,11 according to the side-splitting inconsistency model (side-splitting inconsistency model in eTable 7 in the Supplement), the clinicians should pay special attention when applying this result in their clinical practice. Further large-scale RCTs are required to support or refute the results of this study.

    Another remarkable finding of the present network meta-analysis was that cTBS-T3T4 resulted in superior outcomes to cTBS-T3 or iTBS-T3 only. Moreover, the potential benefit of cTBS regarding severity of tinnitus has been proven in many trials, both in a single session62,63 and multiple sessions.8,52 Continuous TBS, which is reported to better suppress both pure-tone tinnitus and white noise than tonic TMS,63 had a more powerful effect on tinnitus relief than high-frequency rTMS.8 In addition, according to reports, cTBS was suggested to be able to modulate both the extralemniscal and lemniscal systems, the systems that mainly manage the sensory input to the central nervous system, whereas tonic TMS modulates only the lemniscal system.63,64 Furthermore, another RCT8 demonstrated that bilateral cTBS was more effective than unilateral stimulation. However, because bilateral cTBS (cTBS-T3T4) in patients with tinnitus was reported only in 2 RCTs included in the current network meta-analysis,8,52 future large-scale RCTs are required to support or refute this study’s results.

    Finally, the present network meta-analysis identified rTMS with priming procedure as more beneficial to tinnitus severity than such stimulation without priming. Specifically, rTMS in combination with stimulation over the frontal lobe and then over the auditory cortex was superior compared with rTMS over the auditory cortex only, either in high frequency or low frequency. Furthermore, NIBS using high-frequency rTMS as the priming intervention (ie, high-frequency rTMS-F3 plus low-frequency rTMS-T3T4) was associated with significantly greater improvement in tinnitus severity than in the sham control. These findings correspond with the results of clinical brain imaging studies in which patients with tinnitus were demonstrated to have hyperactivity in multiple brain regions, including both the auditory cortex and DLPFC.4,5 In addition, the hypothesis of the preconditioning phenomenon supports multiple site interventions applied in a sequence.60 This hypothesis of the priming effect is also supported by previous clinical reports demonstrating a superior prolonged beneficial effect on tinnitus severity when a priming rTMS protocol was used in such patients for long-term follow-up compared with rTMS without priming, especially for stimulation at higher frequency.7,45,65,66 Therefore, the present network meta-analysis result can be considered as further essential evidence of the preconditioning phenomenon hypothesis. However, because of limited RCTs addressing the potential benefit of a priming procedure, future large-scale RCTs are required to support or refute the results of the current network meta-analysis.

    Limitations

    Several potential limitations should be considered for this network meta-analysis. Quiz Ref IDFirst, this analysis may have been underpowered owing to the heterogeneity of the participants (eg, comorbidities, mood disorder, baseline severity of tinnitus, history of tinnitus onset, commercial machine used in each study, and follow-up duration), variety in the definition of response, and variety in tinnitus severity or quality-of-life rating scales. Although meta-regression analyses were performed to reduce the heterogeneity, some differences did exist between the included RCTs, which were attributed to other unknown factors. Second, although most of the RCTs included a sham control in their study design, the blindness of those RCTs may not have been complete because of the limitation of the commercial machine used. Third, given the relatively small number of patients and RCTs, the main results of this network meta-analysis should perhaps be conservatively applied in clinical practice. Specifically, the potential effect of additive tRNS, the priming procedure, and bilateral cTBS should be carefully interpreted because only a few RCTs reported the results of these NIBS methods (1 trial for additive tRNS,11 7 trials for priming procedure,7,17,40,41,44,45,47 and 2 trials for bilateral cTBS8,52). In addition, the relatively small number of patients and RCTs would limit the potential benefit of NIBS interventions in some outcomes. For example, although most of the NIBS interventions were associated with relatively better response than the sham or control group, the variation and CIs ranged widely, which would result in an insignificant outcome (eFigure 2B in the Supplement). Future larger-scale RCTs are warranted to support or refute the result of the present network meta-analysis. Quiz Ref IDFinally, we detected significant inconsistency in some of the outcomes (ie, severity of tinnitus and quality of life). Clinicians should pay attention when applying these results in their clinical practice.

    Conclusions

    This study showed that the cathodal tDCS-F3 plus anodal tDCS-F4 plus tRNS-T3 combination was associated with the greatest improvement in tinnitus severity and quality of life. A specific central NIBS protocol (ie, bilateral cTBS and priming with high-frequency rTMS or tDCS) was also associated with superior improvement in tinnitus severity. All central NIBS methods had similar tolerability in terms of the dropout rate compared with the sham control. However, because some of the intervention comparisons were based on only a few RCTs, clinicians should select specific treatments with caution and avoid the one-size-fits-all treatment for all clinical conditions.

    Back to top
    Article Information

    Accepted for Publication: May 5, 2020.

    Corresponding Authors: Ping-Tao Tseng, MD, Prospect Clinic for Otorhinolaryngology and Neurology, No. 252, Nanzixin Road, Nanzi District, Kaohsiung City 81166, Taiwan (ducktseng@gmail.com), and Cheng-Ta Li, MD, PhD, Division of Community and Rehabilitation Psychiatry, Department of Psychiatry, Taipei Veterans General Hospital, Taiwan, No. 201, Section 2, Shipai Road, Beitou District, Taipei City 11267, Taiwan (on5083@msn.com).

    Published Online: July 9, 2020. doi:10.1001/jamaoto.2020.1497

    Author Contributions: Drs J.-J. Chen and Zeng contributed equally as co–first authors, Drs Y-W Chen and Tseng had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: J.-J. Chen, Zeng, C.-N. Wu, Su, Tu, T.-Y. Chen, Liang, C.-W. Hsu, S.-P. Hsu, Kuo, Y.-W. Chen, Tseng.

    Acquisition, analysis, or interpretation of data: J.-J. Chen, Zeng, Stubbs, Carvalho, Brunoni, Tu, Y.-C. Wu, T.-Y. Chen, Lin, Liang, Tseng, Li.

    Drafting of the manuscript: J.-J. Chen, Zeng, Stubbs, Carvalho, Tu.

    Critical revision of the manuscript for important intellectual content: C.-N. Wu, Stubbs, Carvalho, Brunoni, Su, Tu, Y.-C. Wu, T.-Y. Chen, Lin, Liang, C.-W. Hsu, S.-P. Hsu, Kuo, Y.-W. Chen, Tseng, Li.

    Statistical analysis: J.-J. Chen, Carvalho, Tu, Liang, Y.-W. Chen, Tseng, Li.

    Administrative, technical, or material support: J.-J. Chen, Zeng, Stubbs, T.-Y. Chen, Kuo, Tseng, Li.

    Supervision: Stubbs, Brunoni, Su, Tu, Y.-C. Wu, Tseng, Li.

    Conflict of Interest Disclosures: Dr Brunoni reported receiving academic support in the form of financial fees, outside the submitted work, from the University of Sao Paulo Medical School and the National Council for Scientific and Technological Development, and being a medical adviser for Flow Neuroscience with a small equity of the company (he receives no personal fees from the company). No other disclosures were reported.

    Funding/Support: This study was supported by Clinical Lectureship ICA-CL-2017-03-001 jointly funded by Health Education England and the National Institute for Health Research (NIHR) (Dr Stubbs); the NIHR Biomedical Research Centre at South London and Maudsley NHS (National Health Service) Foundation Trust (Dr Stubbs); Maudsley Charity, King’s College London and the NIHR South London Collaboration for Leadership in Applied Health Research and Care funding (Dr Stubbs); grants MOST 106-2314-B-039-027-MY3, 107-2314-B-039-005, 108-2320-B-039-048, and 108-2314-B-039-016 from the Ministry of Science and Technology, Taiwan (Dr Su); grants DMR-107-091, DRM-108-091, CRS-108-048, CMU108-SR-106, DMR-108-216, CMRC-CMA-3, and DMR-109-102 from the Chinese Medicine Research Center from the China Medical University, Taiwan (Dr Su); grants MOST 106-2314-B-182A-085-MY2 and MOST 105-2314-B-182A-057 from the Ministry of Science and Technology, Taiwan (Dr Lin); grants CMRPG8F1371 and CMRPG8E1061F from Kaohsiung Chang Gung Memorial Hospital, Taiwan (Dr Lin); grant 106-2314-B-002-098-MY3 from the Ministry of Science and Technology, Taiwan (Dr Tu); grant MOST 108-2321-B-075-004-MY2) from the Ministry of Science and Technology; and grant 108BRC-B502 from the Brain Research Center within the framework of the Higher Education Sprout Project by the Ministry of Education in Taiwan (National Yang-Ming University from The Featured Areas Research Center Program).

    Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: The views expressed in this publication are those of the authors and not necessarily those of the acknowledged institutions.

    Additional Contributions: This article was edited by Wallace Academic Editing. The work was not funded by any source of funding.

    References
    1.
    Bauer  CA.  Tinnitus.   N Engl J Med. 2018;378(13):1224-1231. doi:10.1056/NEJMcp1506631 PubMedGoogle ScholarCrossref
    2.
    Panov  F, Kopell  BH.  Use of cortical stimulation in neuropathic pain, tinnitus, depression, and movement disorders.   Neurotherapeutics. 2014;11(3):564-571. doi:10.1007/s13311-014-0283-0 PubMedGoogle ScholarCrossref
    3.
    Eggermont  JJ, Roberts  LE.  The neuroscience of tinnitus.   Trends Neurosci. 2004;27(11):676-682. doi:10.1016/j.tins.2004.08.010 PubMedGoogle ScholarCrossref
    4.
    Weisz  N, Müller  S, Schlee  W, Dohrmann  K, Hartmann  T, Elbert  T.  The neural code of auditory phantom perception.   J Neurosci. 2007;27(6):1479-1484. doi:10.1523/JNEUROSCI.3711-06.2007 PubMedGoogle ScholarCrossref
    5.
    Vanneste  S, Plazier  M, der Loo  Ev, de Heyning  PV, Congedo  M, De Ridder  D.  The neural correlates of tinnitus-related distress.   Neuroimage. 2010;52(2):470-480. doi:10.1016/j.neuroimage.2010.04.029 PubMedGoogle ScholarCrossref
    6.
    De Ridder  D, De Mulder  G, Walsh  V, Muggleton  N, Sunaert  S, Møller  A.  Magnetic and electrical stimulation of the auditory cortex for intractable tinnitus: case report.   J Neurosurg. 2004;100(3):560-564. doi:10.3171/jns.2004.100.3.0560 PubMedGoogle ScholarCrossref
    7.
    Formánek  M, Migaľová  P, Krulová  P,  et al.  Combined transcranial magnetic stimulation in the treatment of chronic tinnitus.   Ann Clin Transl Neurol. 2018;5(7):857-864. doi:10.1002/acn3.587 PubMedGoogle ScholarCrossref
    8.
    Forogh  B, Yazdi-Bahri  SM, Ahadi  T, Fereshtehnejad  SM, Raissi  GR.  Comparison of two protocols of transcranial magnetic stimulation for treatment of chronic tinnitus: a randomized controlled clinical trial of burst repetitive versus high-frequency repetitive transcranial magnetic stimulation.   Neurol Sci. 2014;35(2):227-232. doi:10.1007/s10072-013-1487-5 PubMedGoogle ScholarCrossref
    9.
    Lorenz  I, Müller  N, Schlee  W, Langguth  B, Weisz  N.  Short-term effects of single repetitive TMS sessions on auditory evoked activity in patients with chronic tinnitus.   J Neurophysiol. 2010;104(3):1497-1505. doi:10.1152/jn.00370.2010 PubMedGoogle ScholarCrossref
    10.
    Faber  M, Vanneste  S, Fregni  F, De Ridder  D.  Top down prefrontal affective modulation of tinnitus with multiple sessions of tDCS of dorsolateral prefrontal cortex.   Brain Stimul. 2012;5(4):492-498. doi:10.1016/j.brs.2011.09.003 PubMedGoogle ScholarCrossref
    11.
    To  WT, Ost  J, Hart  J  Jr, De Ridder  D, Vanneste  S.  The added value of auditory cortex transcranial random noise stimulation (tRNS) after bifrontal transcranial direct current stimulation (tDCS) for tinnitus.   J Neural Transm (Vienna). 2017;124(1):79-88. doi:10.1007/s00702-016-1634-2 PubMedGoogle ScholarCrossref
    12.
    Milev  RV, Giacobbe  P, Kennedy  SH,  et al; CANMAT Depression Work Group.  Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 clinical guidelines for the management of adults with major depressive disorder: section 4, neurostimulation treatments.   Can J Psychiatry. 2016;61(9):561-575. doi:10.1177/0706743716660033 PubMedGoogle ScholarCrossref
    13.
    Horvath  JC, Carter  O, Forte  JD.  Transcranial direct current stimulation: five important issues we aren’t discussing (but probably should be).   Front Syst Neurosci. 2014;8:2. doi:10.3389/fnsys.2014.00002 PubMedGoogle ScholarCrossref
    14.
    Hoare  DJ, Adjamian  P, Sereda  M.  Electrical stimulation of the ear, head, cranial nerve, or cortex for the treatment of tinnitus: a scoping review.   Neural Plast. 2016;2016:5130503. doi:10.1155/2016/5130503 PubMedGoogle Scholar
    15.
    Song  JJ, Vanneste  S, Van de Heyning  P, De Ridder  D.  Transcranial direct current stimulation in tinnitus patients: a systemic review and meta-analysis.   ScientificWorldJournal. 2012;2012:427941. doi:10.1100/2012/427941 PubMedGoogle Scholar
    16.
    Soleimani  R, Jalali  MM, Hasandokht  T.  Therapeutic impact of repetitive transcranial magnetic stimulation (rTMS) on tinnitus: a systematic review and meta-analysis.   Eur Arch Otorhinolaryngol. 2016;273(7):1663-1675. doi:10.1007/s00405-015-3642-5 PubMedGoogle ScholarCrossref
    17.
    Kreuzer  PM, Lehner  A, Schlee  W,  et al.  Combined rTMS treatment targeting the anterior cingulate and the temporal cortex for the treatment of chronic tinnitus.   Sci Rep. 2015;5:18028. doi:10.1038/srep18028 PubMedGoogle ScholarCrossref
    18.
    Meng  Z, Liu  S, Zheng  Y, Phillips  JS.  Repetitive transcranial magnetic stimulation for tinnitus.   Cochrane Database Syst Rev. 2011;(10):CD007946.PubMedGoogle Scholar
    19.
    Higgins  JP, Welton  NJ.  Network meta-analysis: a norm for comparative effectiveness?   Lancet. 2015;386(9994):628-630. doi:10.1016/S0140-6736(15)61478-7 PubMedGoogle ScholarCrossref
    20.
    Hsieh  MT, Tseng  PT, Wu  YC,  et al.  Effects of different pharmacologic smoking cessation treatments on body weight changes and success rates in patients with nicotine dependence: a network meta-analysis.   Obes Rev. 2019;20(6):895-905. doi:10.1111/obr.12835 PubMedGoogle ScholarCrossref
    21.
    Tu  YK, Faggion  CM  Jr.  A primer on network meta-analysis for dental research.   ISRN Dent. 2012;2012:276520. doi:10.5402/2012/276520 PubMedGoogle Scholar
    22.
    Wu  YC, Tseng  PT, Tu  YK,  et al.  Association of delirium response and safety of pharmacological interventions for the management and prevention of delirium: a network meta-analysis.   JAMA Psychiatry. 2019;76(5):526-535. doi:10.1001/jamapsychiatry.2018.4365 PubMedGoogle ScholarCrossref
    23.
    Zeng  BS, Lin  SY, Tu  YK,  et al.  Prevention of postdental procedure bacteremia: a network meta-analysis.   J Dent Res. 2019;98(11):1204-1210. doi:10.1177/0022034519870466 PubMedGoogle ScholarCrossref
    24.
    Huang  SW, Tsai  CY, Tseng  CS,  et al.  Comparative efficacy and safety of new surgical treatments for benign prostatic hyperplasia: systematic review and network meta-analysis.   BMJ. 2019;367:5919. doi:10.1136/bmj.l5919 PubMedGoogle ScholarCrossref
    25.
    Yang  CP, Tseng  PT, Pei-Chen Chang  J, Su  H, Satyanarayanan  SK, Su  KP.  Melatonergic agents in the prevention of delirium: a network meta-analysis of randomized controlled trials.   Sleep Med Rev. 2020;50:101235. doi:10.1016/j.smrv.2019.101235 PubMedGoogle Scholar
    26.
    Tseng  PT, Yang  CP, Su  KP,  et al.  The association between melatonin and episodic migraine: a pilot network meta-analysis of randomized controlled trials to compare the prophylactic effects with exogenous melatonin supplementation and pharmacotherapy.   J Pineal Res. Published online April 29, 2020.PubMedGoogle Scholar
    27.
    Higgins  JGS.  Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2. The Cochrane Collaboration; 2009.
    28.
    Tu  YK.  Use of generalized linear mixed models for network meta-analysis.   Med Decis Making. 2014;34(7):911-918. doi:10.1177/0272989X14545789 PubMedGoogle ScholarCrossref
    29.
    Liu  Y, Wang  W, Zhang  AB, Bai  X, Zhang  S.  Epley and Semont maneuvers for posterior canal benign paroxysmal positional vertigo: A network meta-analysis.   Laryngoscope. 2016;126(4):951-955. doi:10.1002/lary.25688PubMedGoogle ScholarCrossref
    30.
    Salanti  G, Ades  AE, Ioannidis  JP.  Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial.   J Clin Epidemiol. 2011;64(2):163-171. doi:10.1016/j.jclinepi.2010.03.016 PubMedGoogle ScholarCrossref
    31.
    Higgins  JP, Del Giovane  C, Chaimani  A, Caldwell  DM, Salanti  G.  Evaluating the quality of evidence from a network meta-analysis.   Value Health. 2014;17(7):A324. doi:10.1016/j.jval.2014.08.572 PubMedGoogle ScholarCrossref
    32.
    Anders  M, Dvorakova  J, Rathova  L,  et al.  Efficacy of repetitive transcranial magnetic stimulation for the treatment of refractory chronic tinnitus: a randomized, placebo controlled study.   Neuro Endocrinol Lett. 2010;31(2):238-249.PubMedGoogle Scholar
    33.
    Bilici  S, Yigit  O, Taskin  U, Gor  AP, Yilmaz  ED.  Medium-term results of combined treatment with transcranial magnetic stimulation and antidepressant drug for chronic tinnitus.   Eur Arch Otorhinolaryngol. 2015;272(2):337-343. doi:10.1007/s00405-013-2851-zPubMedGoogle ScholarCrossref
    34.
    Chung  HK, Tsai  CH, Lin  YC,  et al.  Effectiveness of theta-burst repetitive transcranial magnetic stimulation for treating chronic tinnitus.   Audiol Neurootol. 2012;17(2):112-120. doi:10.1159/000330882PubMedGoogle ScholarCrossref
    35.
    Folmer  RL, Theodoroff  SM, Casiana  L, Shi  Y, Griest  S, Vachhani  J.  Repetitive transcranial magnetic stimulation treatment for chronic tinnitus: a randomized clinical trial.   JAMA Otolaryngol Head Neck Surg. 2015;141(8):716-722. doi:10.1001/jamaoto.2015.1219PubMedGoogle ScholarCrossref
    36.
    Forogh  B, Mirshaki  Z, Raissi  GR, Shirazi  A, Mansoori  K, Ahadi  T.  Repeated sessions of transcranial direct current stimulation for treatment of chronic subjective tinnitus: a pilot randomized controlled trial.   Neurol Sci. 2016;37(2):253-259. doi:10.1007/s10072-015-2393-9PubMedGoogle ScholarCrossref
    37.
    Hoekstra  CE, Versnel  H, Neggers  SF, Niesten  ME, van Zanten  GA.  Bilateral low-frequency repetitive transcranial magnetic stimulation of the auditory cortex in tinnitus patients is not effective: a randomised controlled trial.   Audiol Neurootol. 2013;18(6):362-373. doi:10.1159/000354977PubMedGoogle ScholarCrossref
    38.
    James  GA, Thostenson  JD, Brown  G,  et al.  Neural activity during attentional conflict predicts reduction in tinnitus perception following rTMS.   Brain Stimul. 2017;10(5):934-943. doi:10.1016/j.brs.2017.05.009PubMedGoogle ScholarCrossref
    39.
    Khedr  EM, Rothwell  JC, Ahmed  MA, El-Atar  A.  Effect of daily repetitive transcranial magnetic stimulation for treatment of tinnitus: comparison of different stimulus frequencies.   J Neurol Neurosurg Psychiatry. 2008;79(2):212-215. doi:10.1136/jnnp.2007.127712PubMedGoogle ScholarCrossref
    40.
    Kreuzer  PM, Landgrebe  M, Schecklmann  M,  et al.  Can temporal repetitive transcranial magnetic stimulation be enhanced by targeting affective components of tinnitus with frontal rTMS? a randomized controlled pilot trial.   Front Syst Neurosci. 2011;5:88. doi:10.3389/fnsys.2011.00088PubMedGoogle ScholarCrossref
    41.
    Kyong  JS, Noh  TS, Park  MK, Oh  SH, Lee  JH, Suh  MW.  Phantom perception of sound and the abnormal cortical inhibition system: an electroencephalography (EEG) study.   Ann Otol Rhinol Laryngol. 2019;128(6_suppl):84S-95S. doi:10.1177/0003489419837990Google Scholar
    42.
    Landgrebe  M, Hajak  G, Wolf  S,  et al.  1-Hz rTMS in the treatment of tinnitus: A sham-controlled, randomized multicenter trial.   Brain Stimul. 2017;10(6):1112-1120. doi:10.1016/j.brs.2017.08.001PubMedGoogle ScholarCrossref
    43.
    Langguth  B, Kleinjung  T, Frank  E,  et al.  High-frequency priming stimulation does not enhance the effect of low-frequency rTMS in the treatment of tinnitus.   Exp Brain Res. 2008;184(4):587-591. doi:10.1007/s00221-007-1228-1PubMedGoogle ScholarCrossref
    44.
    Langguth  B, Landgrebe  M, Frank  E,  et al.  Efficacy of different protocols of transcranial magnetic stimulation for the treatment of tinnitus: Pooled analysis of two randomized controlled studies.   World J Biol Psychiatry. 2014;15(4):276-285. doi:10.3109/15622975.2012.708438PubMedGoogle ScholarCrossref
    45.
    Lehner  A, Schecklmann  M, Greenlee  MW, Rupprecht  R, Langguth  B.  Triple-site rTMS for the treatment of chronic tinnitus: a randomized controlled trial.   Sci Rep. 2016;6:22302. doi:10.1038/srep22302 PubMedGoogle ScholarCrossref
    46.
    Marcondes  RA, Sanchez  TG, Kii  MA,  et al.  Repetitive transcranial magnetic stimulation improve tinnitus in normal hearing patients: a double-blind controlled, clinical and neuroimaging outcome study.   Eur J Neurol. 2010;17(1):38-44. doi:10.1111/j.1468-1331.2009.02730.xPubMedGoogle ScholarCrossref
    47.
    Noh  TS, Kyong  JS, Chang  MY,  et al.  Comparison of treatment outcomes following either prefrontal cortical-only or dual-site repetitive transcranial magnetic stimulation in chronic tinnitus patients: a double-blind randomized study.   Otol Neurotol. 2017;38(2):296-303.PubMedGoogle Scholar
    48.
    Pal  N, Maire  R, Stephan  MA, Herrmann  FR, Benninger  DH.  Transcranial direct current stimulation for the treatment of chronic tinnitus: a randomized controlled study.   Brain Stimul. 2015;8(6):1101-1107. doi:10.1016/j.brs.2015.06.014PubMedGoogle ScholarCrossref
    49.
    Piccirillo  JF, Garcia  KS, Nicklaus  J,  et al.  Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus.   Arch Otolaryngol Head Neck Surg. 2011;137(3):221-228. doi:10.1001/archoto.2011.3PubMedGoogle ScholarCrossref
    50.
    Piccirillo  JF, Kallogjeri  D, Nicklaus  J,  et al.  Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus: four-week stimulation trial.   JAMA Otolaryngol Head Neck Surg. 2013;139(4):388-395. doi:10.1001/jamaoto.2013.233PubMedGoogle ScholarCrossref
    51.
    Plewnia  C, Reimold  M, Najib  A, Reischl  G, Plontke  SK, Gerloff  C.  Moderate therapeutic efficacy of positron emission tomography-navigated repetitive transcranial magnetic stimulation for chronic tinnitus: a randomised, controlled pilot study.   J Neurol Neurosurg Psychiatry. 2007;78(2):152-156. doi:10.1136/jnnp.2006.095612PubMedGoogle ScholarCrossref
    52.
    Plewnia  C, Vonthein  R, Wasserka  B,  et al.  Treatment of chronic tinnitus with θ burst stimulation: a randomized controlled trial.   Neurology. 2012;78(21):1628-1634. doi:10.1212/WNL.0b013e3182574ef9 PubMedGoogle ScholarCrossref
    53.
    Rossi  S, De Capua  A, Ulivelli  M,  et al.  Effects of repetitive transcranial magnetic stimulation on chronic tinnitus: a randomised, crossover, double blind, placebo controlled study.   J Neurol Neurosurg Psychiatry. 2007;78(8):857-863. doi:10.1136/jnnp.2006.105007PubMedGoogle ScholarCrossref
    54.
    Sahlsten  H, Virtanen  J, Joutsa  J,  et al.  Electric field-navigated transcranial magnetic stimulation for chronic tinnitus: a randomized, placebo-controlled study.   Int J Audiol. 2017;56(9):692-700. doi:10.1080/14992027.2017.1313461PubMedGoogle ScholarCrossref
    55.
    Schecklmann  M, Giani  A, Tupak  S,  et al.  Neuronavigated left temporal continuous theta burst stimulation in chronic tinnitus.   Restor Neurol Neurosci. 2016;34(2):165-175. doi:10.3233/RNN-150518PubMedGoogle Scholar
    56.
    Smith  JA, Mennemeier  M, Bartel  T,  et al.  Repetitive transcranial magnetic stimulation for tinnitus: a pilot study.   Laryngoscope. 2007;117(3):529-534. doi:10.1097/MLG.0b013e31802f4154PubMedGoogle ScholarCrossref
    57.
    Yilmaz  M, Yener  MH, Turgut  NF, Aydin  F, Altug  T.  Effectiveness of transcranial magnetic stimulation application in treatment of tinnitus.   J Craniofac Surg. 2014;25(4):1315-1318. doi:10.1097/SCS.0000000000000782PubMedGoogle ScholarCrossref
    58.
    Van Doren  J, Langguth  B, Schecklmann  M.  Electroencephalographic effects of transcranial random noise stimulation in the auditory cortex.   Brain Stimul. 2014;7(6):807-812. doi:10.1016/j.brs.2014.08.007 PubMedGoogle ScholarCrossref
    59.
    Vanneste  S, Fregni  F, De Ridder  D.  Head-to-head comparison of transcranial random noise stimulation, transcranial AC stimulation, and transcranial DC stimulation for tinnitus.   Front Psychiatry. 2013;4:158. doi:10.3389/fpsyt.2013.00158 PubMedGoogle ScholarCrossref
    60.
    Lang  N, Siebner  HR, Ernst  D,  et al.  Preconditioning with transcranial direct current stimulation sensitizes the motor cortex to rapid-rate transcranial magnetic stimulation and controls the direction of after-effects.   Biol Psychiatry. 2004;56(9):634-639. doi:10.1016/j.biopsych.2004.07.017 PubMedGoogle ScholarCrossref
    61.
    Vanneste  S, De Ridder  D.  Bifrontal transcranial direct current stimulation modulates tinnitus intensity and tinnitus-distress-related brain activity.   Eur J Neurosci. 2011;34(4):605-614. doi:10.1111/j.1460-9568.2011.07778.x PubMedGoogle ScholarCrossref
    62.
    Meeus  O, Blaivie  C, Ost  J, De Ridder  D, Van de Heyning  P.  Influence of tonic and burst transcranial magnetic stimulation characteristics on acute inhibition of subjective tinnitus.   Otol Neurotol. 2009;30(6):697-703. doi:10.1097/MAO.0b013e3181b05023 PubMedGoogle ScholarCrossref
    63.
    De Ridder  D, van der Loo  E, Van der Kelen  K, Menovsky  T, van de Heyning  P, Moller  A.  Do tonic and burst TMS modulate the lemniscal and extralemniscal system differentially?   Int J Med Sci. 2007;4(5):242-246. doi:10.7150/ijms.4.242 PubMedGoogle ScholarCrossref
    64.
    Poreisz  C, Paulus  W, Moser  T, Lang  N.  Does a single session of theta-burst transcranial magnetic stimulation of inferior temporal cortex affect tinnitus perception?   BMC Neurosci. 2009;10:54. doi:10.1186/1471-2202-10-54 PubMedGoogle ScholarCrossref
    65.
    Kleinjung  T, Eichhammer  P, Landgrebe  M,  et al.  Combined temporal and prefrontal transcranial magnetic stimulation for tinnitus treatment: a pilot study.   Otolaryngol Head Neck Surg. 2008;138(4):497-501. doi:10.1016/j.otohns.2007.12.022 PubMedGoogle ScholarCrossref
    66.
    Lehner  A, Schecklmann  M, Poeppl  TB,  et al.  Multisite rTMS for the treatment of chronic tinnitus: stimulation of the cortical tinnitus network—a pilot study.   Brain Topogr. 2013;26(3):501-510. doi:10.1007/s10548-012-0268-4 PubMedGoogle ScholarCrossref
    ×