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Non-invasive neuromodulation for tinnitus: A meta-analysis and modeling studies

  • Mathilde Lefebvre-Demers
    Affiliations
    CERVO Brain Research Centre, Institut Universitaire En Santé Mentale de Québec, Centre Intégré Universitaire De Santé Et De Services Sociaux De La Capitale-Nationale, Canada

    Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Canada
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  • Nicolas Doyon
    Affiliations
    CERVO Brain Research Centre, Institut Universitaire En Santé Mentale de Québec, Centre Intégré Universitaire De Santé Et De Services Sociaux De La Capitale-Nationale, Canada

    Faculty of Science and Engineering, Université Laval, Canada
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  • Shirley Fecteau
    Correspondence
    Corresponding author. CERVO Brain Research Centre, Institut Universitaire En Santé Mentale de Québec, Centre Intégré Universitaire De Santé Et De Services Sociaux De La Capitale-Nationale, Canada.
    Affiliations
    CERVO Brain Research Centre, Institut Universitaire En Santé Mentale de Québec, Centre Intégré Universitaire De Santé Et De Services Sociaux De La Capitale-Nationale, Canada

    Department of Psychiatry and Neurosciences, Faculty of Medicine, Université Laval, Canada
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Open AccessPublished:November 30, 2020DOI:https://doi.org/10.1016/j.brs.2020.11.014

      Highlights

      • Active as compared to sham rTMS reduced tinnitus, but not tDCS.
      • RTMS over the auditory cortex was the most beneficial protocol to reduce tinnitus.
      • RTMS over the auditory cortex generated a stronger electric field in the insula.
      • RTMS can reduce tinnitus up to 6 months after the end of the rTMS regimen.
      • Women are more likely than men to benefit from rTMS for tinnitus relief.

      Abstract

      Background

      Patients with tinnitus often have poor quality of life, as well as severe anxiety and depression. New approaches to treat tinnitus are needed.

      Objective

      Evaluate the effects of non-invasive neuromodulation on tinnitus through a metaanalysis and modeling study. The main hypothesis was that real as compared to sham neuromodulation that decreases tinnitus will modulate regions in line with the neurobiological models of tinnitus.

      Methods and results

      The systematic review, conducted from Pubmed, Cochrane and PsycINFO databases, showed that active as compared to sham repetitive transcranial magnetic stimulation (rTMS) reduced tinnitus, but active and sham transcranial direct current stimulation did not significantly differ. Further, rTMS over the auditory cortex was the most effective protocol. The modeling results indicate that this rTMS protocol elicited the strongest electric fields in the insula. Also, rTMS was particularly beneficial in women. Finally, the placebo effects were highly variable, highlighting the importance of conducting sham-controlled trials.

      Conclusion

      In sum, neuromodulation protocols that target the auditory cortex and the insula may hold clinical potential to treat tinnitus.

      Keywords

      Introduction

      There is no curative treatment for tinnitus, affecting from 5.1 to 42,7% of the world population [
      • McCormack A.
      • Edmondson-Jones M.
      • Somerset S.
      • Hall D.
      A systematic review of the reporting of tinnitus prevalence and severity.
      ]. Tinnitus is characterized by a sensation of ringing in the ears, despite no external sound [
      • Eggermont J.J.
      Tinnitus: neurobiological substrates.
      ,
      • Eggermont J.J.
      The auditory cortex and tinnitus - a review of animal and human studies.
      ,
      • Jastreboff P.J.
      Phantom auditory perception (tinnitus): mechanisms of generation and perception.
      ]. The prevalence of depressive disorders in this population can be high, ranging between 10 and 90% [
      • Ziai K.
      • Moshtaghi O.
      • Mahboubi H.
      • Djalilian H.R.
      Tinnitus patients suffering from anxiety and depression: a review.
      ]. Efficacy of pharmacological and behavioral interventions remains limited (e.g., Ref. [
      • Pichora-Fuller M.K.
      • Santaguida P.
      • Hammill A.
      • Oremus M.
      • Westerberg B.
      • Ali U.
      • et al.
      Evaluation and treatment of tinnitus: comparative effectiveness.
      ]) so there is a need to develop new approaches. Noninvasive neuromodulation holds promise partly because it can target the neurobiological substrates involved in this condition. For instance, rTMS is believed to modulate synaptic plasticity by increasing or decreasing synaptic connections in a way that is similar to long term potentiation or depression described in animals [
      • Klomjai W.
      • Katz R.
      • Lackmy-Vallée A.
      Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS).
      ,
      • Bliss T.V.P.
      • Gardner-Medwin A.R.
      Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path.
      ]. In this way, rTMS may modulate abnormal activity in the neural regions affected by tinnitus [
      • To W.T.
      • De Ridder D.
      • Hart Jr., J.
      • Vanneste S.
      Changing brain networks through non-invasive neuromodulation.
      ].
      As for electrical modulation (tDCS, tRNS, tACS), the stochastic resonance theory has been proposed as an interesting model for tinnitus. In this model, the electric field applied is considered as an unspecific « neural noise » that brings neurons closer to their thresholds [
      • Fertonani A.
      • Miniussi C.
      Transcranial electrical stimulation.
      ,
      • McDonnell M.D.
      • Abbott D.
      What is stochastic resonance? Definitions, misconceptions, debates, and its relevance to biology.
      ]. In this way, electrical modulation may reinforce cerebral regions to compensate for the abnormal activity in regions affected by tinnitus [
      • McDonnell M.D.
      • Abbott D.
      What is stochastic resonance? Definitions, misconceptions, debates, and its relevance to biology.
      ]. Some studies reported that neuromodulation decreased tinnitus symptoms [
      • To W.T.
      • De Ridder D.
      • Hart Jr., J.
      • Vanneste S.
      Changing brain networks through non-invasive neuromodulation.
      ], but they employed various protocols (e.g., brain sites). It is thus difficult to offer specific approaches to treat tinnitus.
      Our aim was two-fold: 1) to evaluate the effects of noninvasive neuromodulation on tinnitus by conducting a meta-analysis and 2) to assess how neuromodulation may reduce global score of tinnitus from standardized questionnaires by performing modeling work. The main hypotheses were that 1) real as compared to sham neuromodulation will decrease tinnitus and 2) the most effective neuromodulation approaches will modulate regions in line with the neurobiological models of tinnitus. There are two main tendencies for models of tinnitus (e.g., Ref. [
      • De Ridder D.
      • Vanneste S.
      • Weisz N.
      • Londero A.
      • Schlee W.
      • Elgoyhen A.B.
      • et al.
      An integrative model of auditory phantom perception: tinnitus as a unified percept of interacting separable subnetworks.
      ,
      • Henry J.A.
      • Roberts L.E.
      • Caspary D.M.
      • Theodoroff S.M.
      • Salvi R.J.
      Underlying mechanisms of tinnitus: review and clinical implications.
      ]). One relates tinnitus to impaired auditory information processing involving the primary and secondary auditory cortex (AC) and connections with the insula and parahippocampal gyrus (e.g., Ref. [
      • Maudoux A.
      • Lefebvre P.
      • Cabay J.-E.
      • Demertzi A.
      • Vanhaudenhuyse A.
      • Laureys S.
      • et al.
      Auditory resting-state network connectivity in tinnitus: a functional MRI study.
      ]). Another relates tinnitus to impaired sensory and emotional processing involving the frontal regions and connections with the amygdala (e.g., Ref. [
      • Burton H.
      • Wineland A.
      • Bhattacharya M.
      • Nicklaus J.
      • Garcia K.S.
      • Piccirillo J.F.
      Altered networks in bothersome tinnitus: a functional connectivity study.
      ,
      • Mirz F.
      • Gjedde A.
      • Ishizu K.
      • Pedersen C.
      Cortical networks subserving the perception of tinnitus - a PET study.
      ]). Based on these works, we predicted that modeling will indicate that 1) neuromodulation over the AC will decrease tinnitus by modulating activity involved in auditory information processing, such as the primary and secondary AC, the insula, and the parahipoccampus; and 2) neuromodulation over the frontal cortex will decrease tinnitus by modulating activity involved in sensory and emotional factors including the frontal regions (dorsolateral prefrontal cortex (dlPFC), anterior cingulate cortex (ACC)), the parahippocampus, and the amygdala.
      Studies using neuroimaging to characterize the impact of rTMS and tCS with direct current (tDCS) on brain activity in patients with tinnitus remain scarce, but some data support our hypotheses. It has been reported that rTMS over the AC modulated activity in the contralateral AC [
      • Andoh J.
      • Zatorre R.J.
      Mapping interhemispheric connectivity using functional MRI after transcranial magnetic stimulation on the human auditory cortex.
      ] and tDCS over the AC modulated activity in the primary AC and insula, among others (e.g., somatosensory, motor areas; [
      • Minami S.B.
      • Oishi N.
      • Watabe T.
      • Uno K.
      • Kaga K.
      • Ogawa K.
      Auditory resting-state functional connectivity in tinnitus and modulation with transcranial direct current stimulation.
      ]). In regard to the frontal cortex, rTMS modulated activity in the ACC, the parahippocampus, and the AC in patients with tinnitus [
      • De Ridder D.
      • Song J.-J.
      • Vanneste S.
      Frontal cortex TMS for tinnitus.
      ]. tDCS over the frontal cortex modulated activity in frontal regions and the subgenual ACC [
      • Vanneste S.
      • Focquaert F.
      • Van de Heyning P.
      • De Ridder D.
      Different resting state brain activity and functional connectivity in patients who respond and not respond to bifrontal tDCS for tinnitus suppression.
      ,
      • Vanneste S.
      • De Ridder D.
      Bifrontal transcranial direct current stimulation modulates tinnitus intensity and tinnitus-distress-related brain activity.
      ]. Based on this, we predict that rTMS over the frontal cortex will reduce the most tinnitus as it modulates both networks of auditory and sensory/emotional processes [
      • De Ridder D.
      • Song J.-J.
      • Vanneste S.
      Frontal cortex TMS for tinnitus.
      ,
      • Baeken C.
      • De Raedt R.
      • Van Schuerbeek P.
      • Vanderhasselt M.A.
      • De Mey J.
      • Bossuyt A.
      • et al.
      Right prefrontal HF-rTMS attenuates right amygdala processing of negatively valenced emotional stimuli in healthy females.
      ].

      Meta-analysis of noninvasive neuromodulation on tinnitus

      Literature search

      We performed a systematic literature search using PRISMA guidelines [
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      ] in 3 databases (PubMed, Cochrane Database of Systematic Review, and PsycINFO) using search strings of “Hearing disease” OR Tinnitus OR Audition OR Auditory AND “noninvasive brain stimulation” OR tDCS OR tACS OR rTMS OR tRNS OR “transcranial direct current stimulation” OR “transcranial alternating current stimulation” OR “repetitive transcranial magnetic stimulation” OR “transcranial random noise stimulation” on articles published up to January 3rd, 2020. One author (M.L.D) performed the search and 2 investigators (M.L.D., S.F.) screened and examined all records. We further examined records referring to clinical trials, congress presentations and posters to find additional publications.

      Selection criteria and study selection

      Two authors (M.L.D., S.F.) independently screened the studies on the inclusion criteria. A third party (Marilyne Joyal) was available in case of disagreement. The inclusion criteria were that the records a) included patients with tinnitus, b) used noninvasive neuromodulation with a therapeutic objective, c) were peer-reviewed, d) were published in English, e) included original clinical scores of standardized tinnitus questionnaires, and f) included a sham treatment condition.

      Data extraction

      One author (M.L.D.) extracted the following data: a) study design, b) number of participants, c) women percentage, d) mean age, e) mean tinnitus duration, f) mean tinnitus severity at baseline, g) types of standardized tinnitus questionnaire h) tinnitus score changes (mean, standard deviations, SD) for active and sham neuromodulation, i) neuromodulation types, j) neuromodulation sites, k) neuromodulation frequencies and amplitudes, l) number of neuromodulation sessions, m) tinnitus score changes at first follow up assessment, and n) depression and anxiety score changes. Another author (S.F.) confirmed the process. Differences in opinion were resolved by consensus.

      Outcome assessment

      The main outcome measure was the mean change in tinnitus scores before and after neuromodulation assessed by standardized questionnaires. These were the Tinnitus Handicap Inventory (THI), the Tinnitus Questionnaire (TQ), the Tinnitus Functional Index (TFI), and the Tinnitus Severity Index (TSI). The TQ and TFI have good convergent validity with the THI [
      • Henry J.A.
      • Griest S.
      • Thielman E.
      • McMillan G.
      • Kaelin C.
      • Carlson K.F.
      Tinnitus Functional Index: development, validation, outcomes research, and clinical application.
      ,
      • Zeman F.
      • Koller M.
      • Schecklmann M.
      • Langguth B.
      • Landgrebe M.
      Tinnitus assessment by means of standardized self-report questionnaires: psychometric properties of the Tinnitus Questionnaire (TQ), the Tinnitus Handicap Inventory (THI), and their short versions in an international and multi-lingual sample.
      ]. When a study reported multiple questionnaires, we used THI scores when available. Effect sizes were computed using the mean change in tinnitus score, the SD, and the number of participants for each treatment group. We used the raw data to compute the mean change and SD of the change. When this was not possible, we computed the mean change and SD from the mean scores and the SD pre- and post-treatment (using the test-retest correlation coefficient of the questionnaire), the mean change, and confidence interval at 95% (using the formula for paired data) or the quartiles reported (estimation based on the model by Ref. [
      • Wan X.
      • Wang W.
      • Liu J.
      • Tong T.
      Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range.
      ]). We used a random-effects model to evaluate the standardized mean difference between active and sham treatments and also computed the Hedges’ g of the active treatment.
      The use of the standardized mean difference to compute the effect size allowed us to combine the data provided by multiple questionnaires. Indeed, the standardized mean difference is computed by dividing the mean difference between active and sham groups in each study by the pooled standard deviation of the two groups of the study. This allows us to combine the studies that used different questionnaires and therefore to obtain a pooled standardized mean difference. In other words, we standardize the outcomes and make them comparable since they are all expressed in term of the same unit: the standard deviation [
      • Murad M.H.
      • Wang Z.
      • Chu H.
      • Lin L.
      When continuous outcomes are measured using different scales: guide for meta-analysis and interpretation.
      ].
      Secondary outcomes were 1) mean change in tinnitus scores at follow-up assessment to explore whether the neuromodulation effects last and 2) mean change in symptoms of depression and anxiety to explore whether neuromodulation alleviate these symptoms as they are highly associated with tinnitus symptoms [
      • Bhatt J.M.
      • Bhattacharyya N.
      • Lin H.W.
      Relationships between tinnitus and the prevalence of anxiety and depression.
      ,
      • Krog N.H.
      • Engdahl B.
      • Tambs K.
      The association between tinnitus and mental health in a general population sample: results from the HUNT Study.
      ]. For the follow-up assessment, we calculated the mean change in tinnitus score before neuromodulation and at the first follow-up visit. For depression and anxiety, we calculated the mean change in anxiety and/or depression scores from standardized questionnaires (Beck Depression Inventory, BDI-I, BDI-II; Beck Anxiety Inventory, BAI; Hospital Anxiety and Depression Scale, HADS). These questionnaires have been validated [
      • Smarr K.L.
      Measures of depression and depressive symptoms: the Beck depression inventory (BDI), center for epidemiological studies-depression scale (CES-D), geriatric depression scale (GDS), hospital anxiety and depression scale (HADS), and primary care evaluation o.
      ,
      • Smarr K.L.
      • Keefer A.L.
      Measures of depression and depressive symptoms: Beck depression inventory-II (BDI-II), center for epidemiologic studies depression scale (CES-D), geriatric depression scale (GDS), hospital anxiety and depression scale (HADS), and patient health questionna.
      ] and share a strong correlation (r = 0.714, HADS depression subscale and BDI [
      • Falavigna A.
      • Righesso O.
      • Teles A.R.
      • Baseggio N.
      • Velho M.C.
      • Ruschel L.G.
      • et al.
      Depression subscale of the hospital anxiety and depression scale applied preoperatively in spinal surgery.
      ]). The BAI mildly correlates with the HADS [
      • Beck A.T.
      • Epstein N.
      • Brown G.
      • Steer R.A.
      An inventory for measuring clinical anxiety: psychometric properties.
      ].
      Statistics were computed using the R software version 3.5.3 [
      • Viechtbauer W.
      Conducting meta-analyses in R with the metafor package.
      ]. We applied the Bonferroni correction for multiple comparisons when hypotheses where formulated.

      Results of the literature search

      The literature search lead to 2478 articles (Fig. 1). There was one additional record [
      • Ghossaini S.N.
      • Spitzer J.B.
      • Mackins C.C.
      • Zschommler A.
      • Diamond B.E.
      • Wazen J.J.
      High-frequency pulsed electromagnetic energy in tinnitus treatment.
      ] identified through [
      • Soleimani R.
      • Jalali M.M.
      • Hasandokht T.
      Therapeutic impact of repetitive transcranial magnetic stimulation (rTMS) on tinnitus: a systematic review and meta-analysis.
      ]. We then excluded 666 duplicates. We screened the remaining 1813 articles according to the inclusion criteria cited above, leaving 29 eligible articles [
      • Ghossaini S.N.
      • Spitzer J.B.
      • Mackins C.C.
      • Zschommler A.
      • Diamond B.E.
      • Wazen J.J.
      High-frequency pulsed electromagnetic energy in tinnitus treatment.
      ,
      • Anders M.
      • Dvorakova J.
      • Rathova L.
      • Havrankova P.
      • Pelcova P.
      • Vaneckova M.
      • et al.
      Efficacy of repetitive transcranial magnetic stimulation for the treatment of refractory chronic tinnitus: a randomized, placebo controlled study.
      ,
      • Hyvärinen P.
      • Mäkitie A.
      • Aarnisalo A.A.
      Self-administered domiciliary tDCS treatment for tinnitus: a double-blind sham-controlled study.
      ,
      • Landgrebe M.
      • Hajak G.
      • Wolf S.
      • Padberg F.
      • Klupp P.
      • Fallgatter A.J.
      • et al.
      1-Hz rTMS in the treatment of tinnitus: a sham-controlled, randomized multicenter trial.
      ,
      • Langguth B.
      • Landgrebe M.
      • Frank E.
      • Schecklmann M.
      • Sand P.G.
      • Vielsmeier V.
      • et al.
      Efficacy of different protocols of transcranial magnetic stimulation for the treatment of tinnitus: pooled analysis of two randomized controlled studies.
      ,
      • Lee H.Y.
      • Yoo S.D.
      • Ryu E.W.
      • Byun J.Y.
      • Yeo S.G.
      • Park M.S.
      Short term effects of repetitive transcranial magnetic stimulation in patients with catastrophic intractable tinnitus: preliminary report.
      ,
      • Li L.P.H.
      • Shiao A.S.
      • Li C.T.
      • Lee P.L.
      • Cheng C.M.
      • Chou C.C.
      • et al.
      Steady-state auditory evoked fields reflect long-term effects of repetitive transcranial magnetic stimulation in tinnitus.
      ,
      • Marcondes R.A.
      • Sanchez T.G.
      • Kii M.A.
      • Ono C.R.
      • Buchpiguel C.A.
      • Langguth B.
      • et al.
      Repetitive transcranial magnetic stimulation improve tinnitus in normal hearing patients: a double-blind controlled, clinical and neuroimaging outcome study.
      ,
      • Noh T.-S.
      • Kyong J.-S.
      • Park M.K.
      • Lee J.H.
      • Oh S.H.
      • Chung C.K.
      • et al.
      Treatment outcome of auditory and frontal dual-site rTMS in tinnitus patients and changes in magnetoencephalographic functional connectivity after rTMS: double-blind randomized controlled trial.
      ,
      • Pal N.
      • Maire R.
      • Stephan M.A.
      • Herrmann F.R.
      • Benninger D.H.
      Transcranial direct current stimulation for the treatment of chronic tinnitus: a randomized controlled study.
      ,
      • Piccirillo J.F.
      • Garcia K.S.
      • Nicklaus J.
      • Pierce K.
      • Burton H.
      • Vlassenko A.G.
      • et al.
      Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus.
      ,
      • Piccirillo J.F.
      • Kallogjeri D.
      • Nicklaus J.
      • Wineland A.
      • Spitznagel E.L.
      • Vlassenko A.G.
      • et al.
      Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus: four-week stimulation trial.
      ,
      • Barwood C.H.S.
      • Wilson W.J.
      • Malicka A.N.
      • McPherson B.
      • Lloyd D.
      • Munt K.
      • et al.
      The effect of rTMS on auditory processing in adults with chronic, bilateral tinnitus: a placebo-controlled pilot study.
      ,
      • Plewnia C.
      • Vonthein R.
      • Wasserka B.
      • Arfeller C.
      • Naumann A.
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      • et al.
      Treatment of chronic tinnitus with theta burst stimulation: a randomized controlled trial.
      ,
      • Sahlsten H.
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      • Joutsa J.
      • Niinivirta-Joutsa K.
      • Löyttyniemi E.
      • Johansson R.
      • et al.
      Electric field-navigated transcranial magnetic stimulation for chronic tinnitus: a randomized, placebo-controlled study.
      ,
      • Schecklmann M.
      • Giani A.
      • Tupak S.
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      • Raab V.
      • Polak T.
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      Neuronavigated left temporal continuous theta burst stimulation in chronic tinnitus.
      ,
      • Shekhawat G.S.
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      ,
      • Smith J.A.
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      • et al.
      Repetitive transcranial magnetic stimulation for tinnitus: a pilot study.
      ,
      • Wang H.
      • Li B.
      • Feng Y.
      • Cui B.
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      • et al.
      A pilot study of EEG source analysis based repetitive transcranial magnetic stimulation for the treatment of tinnitus.
      ,
      • Yadollahpour A.
      • Bayat A.
      • Rashidi S.
      • Saki N.
      • Karimi M.
      Dataset of acute repeated sessions of bifrontal transcranial direct current stimulation for treatment of intractable tinnitus: a randomized controlled trial.
      ,
      • Yadollahpour A.
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      • Saki N.
      • Rashidi S.
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      A chronic protocol of bilateral transcranial direct current stimulation over auditory cortex for tinnitus treatment: dataset from a double-blinded randomized controlled trial [version 1; referees: 2 approved].
      ,
      • Yilmaz M.
      • Yener M.H.
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      Effectiveness of transcranial magnetic stimulation application in treatment of tinnitus.
      ,
      • Bilici S.
      • Yigit O.
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      Medium-term results of combined treatment with transcranial magnetic stimulation and antidepressant drug for chronic tinnitus.
      ,
      • Chung H.-K.
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      • Lin Y.-C.
      • Chen J.-M.
      • Tsou Y.-A.
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      • et al.
      Effectiveness of theta-burst repetitive transcranial magnetic stimulation for treating chronic tinnitus.
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      • Forogh B.
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      ].
      Fig. 1
      Fig. 1Flow chart for the systematic review and meta-analysis.

      Characteristics of the studies

      There were 28 datasets from 22 rTMS studies and 9 datasets from 7 tDCS studies and we analyzed both techniques separately (Table 1, Table 2). Most studies were randomized controlled trials (29 datasets), the others were crossover trials (6 datasets) and pilot studies (2 datasets).
      Table 1Characteristics of the rTMS studies. RCT: Randomized Controlled Trial, Pilot: Pilot study, THI: Tinnitus Handicap Inventory, TFI: Tinnitus Functional Index, TSI: Tinnitus Severity Index, rTMS: repetitive Transcranial Magnetic Stimulation, AC: Auditory Cortex, TPJ: Temporoparietal Junction, dlPFC: dorsolateral Prefrontal Cortex, SAC: Secondary Auditory Cortex, BAI: Beck Anxiety Inventory, BDI: Beck Depression Inventory, BDI-II: Beck Depression Inventory version 2, ∗Number of subjects in the sham group adjusted for arms (N = Nsham/number of arms) ∗∗:missing data, ∗∗∗:median, +:could not be accessed because of design.
      #First author, publication yearStudy designNumber of participants% WomenMean age (years)Mean Tinnitus duration (years)Mean Tinnitus severity at baseline (THI)Standardized questionnaire used for outcomesChange in tinnitus score after active (mean ± SD)Neuromodulation siteNeuromodulation frequencyNumber of neuromodulation sessionsFirst follow up assessment (number of days/weeks/months after)Depression/anxiety questionnaire extractedChange in depression/anxiety score after active (mean ± SD)
      1Wang 2015 ARCT10∗57.1452.144.152.22THI−17.78Frontal (highest activity)1Hz102wk
      2Li 2019RCT2441.755.5475.67THI−28.5lPAC1Hz5
      3Barwood 2013Pilot85039.881421.77THI−4.41lPAC1Hz101 m
      4Wang 2015 BRCT10∗64.2952.932.4852.22THI−8.89lTPJ1Hz102wk
      5Chung 2012RCT229.0952.966.5739.27THI−8.33lAC50Hz10
      6Bilici 2015 ARCT22∗63.3348.95>142.55THI−9.1lTPJ10Hz106 mBAI−0.7
      7Bilici 2015 BRCT22∗53.3350.8>150.55THI−18lTPJ1Hz106 mBAI−1.7
      8Noh 2019 ARCT303053.596.1348.09THI−7lAC, ldlPFC1Hz42wk
      9Yilmaz 2014RCT605549.8>0.552.11THI−8.36AC1Hz10
      10Lee 2013Cross-over1546.753492.8THI−18.84lAC1Hz10
      11Noh 2019 BRCT55054.025.2351.23THI−8.2lAC, ldlPFC1Hz42wk
      12Marcondes 2010RCT19>18>0.2529.37THI−10.4lTPJ1Hz56 m
      13Formanek 2018RCT3128.1349.365.18THI−4.5dlPFC, l and r PAC25Hz, 1Hz56 mBDI−0.5
      14Langguth 2014 ARCT62∗31.5251.536.8537.07TQ−3.32L temporal, ldlPFC20Hz, 1Hz1025d
      15Smith 2007Cross-over4030 to 60>0.528.5TSI−2.25PAC (highest activity)1Hz104wk+
      16Folmer 2015RCT6420.360.61 to >2042.7TFI−5.2l or r AC1Hz101wk
      17Hoekstra 2013RCT5018523.8345THI−4l and r AC1Hz51wk
      18Piccirillo 2013Cross-over143641.2511.5357.5THI−6.9lTPJ1Hz204wk+
      19Langguth 2014 BRCT63∗32.2650.356.3737.44TQ−2L temporal1Hz1025d
      20Langguth 2014CRCT63∗29.0347.515.9237.08TQ−1.88AC (highest activity)1Hz1025d
      21Ghossaini 2004RCT37∗∗59.1914.3836.64THI−4.351-inch lateral to the auricle27,12 MHz12
      22Anders 2010RCT4230.9549.078.1331.83THI−5.27lPAC1Hz106wk
      23Piccirillo 2011Cross- over142951.258.151∗∗∗THI−7lTPJ1Hz104wk+
      24Landgrebe 2017RCT14628.08497.1550.84THI−1lPAC1Hz1026wkBDI-II−1.3
      25Plewnia 2012 ARCT24∗53.1350.72.0827TQ−2.34Both TPJs50Hz204wk
      26Plewnia 2012 BRCT24∗43.75462.0429TQ−2Both SACs50Hz204wk
      27Schecklmann 2016Pilot2339.1347.356.9143.75TQ−6.17lPAC50Hz101wk
      28Sahlsten 2017RCT3930.7750,35.129.37THI−6.67L temporal1Hz101 mBDI-II−3
      Mean33.8237.3350.736.4844.17−7.6010−1.44
      SD29.0416.064.453.3915.226.274.200.99
      Table 2Characteristics of the tDCS studies. RCT: Randomized Controlled Trial, THI: Tinnitus Handicap Inventory, TFI: Tinnitus Functional Index, AC: Auditory Cortex, dlPFC: dorsolateral Prefrontal Cortex, TPJ: Temporoparietal Junction, BDI-II: Beck Depression Inventory 2, HADS: Hospital Anxiety Scale, BDI-I: Beck Depression Inventory version I, BDI: Beck Depression Inventory (version not specified), ∗Number of subjects in the sham group adjusted for arms (N = Nsham/number of arms).
      #First author, publication yearStudy designNumber of participants% WomenMean age (years)Mean Tinnitus duration (years)Mean Tinnitus severity at baseline (THI)Standardized questionnaire used for outcomesChange in tinnitus score after active (mean ± SD)Neuromodulation site (10–20 International System or 10-10 International system)Neuromodulation amplitudeNumber of neuromodulation sessionsFirst follow up assessment (number of weeks/months after)Depression/anxiety questionnaire extractedChange in depression/anxiety score after active (mean ± SD)
      1Yadollahpour 2018RCT405547.587.5371.9THI−24.88Anode: L AC (T3-T7) Cathode: R AC (T4-F8)2 mA101 m
      2Yadollahpour 2017RCT4254.7647.117.9669.86THI−22.64Anode: R dlPFC (F4)

      Cathode: L dlPFC (F3)
      2 mA101 mBDI-II−12.16
      3Pal 2015RCT424349.85.5946.55THI−6.1Anode: PFC (F3-Fz-F4)

      Cathodes: L AC (T3) and R AC (T4)
      2 mA51 mHADS−2.2
      4Hyvarinen 2016 ARCT14∗5054.5>0.548THI−6Anode: L frontal Cathode: R frontal2 mA10BDI-I0.2
      5Forogh 2016RCT2036.3648.227.7756.16THI0Anode: L TPJ (C3-T5)

      Cathode: R supraorbital area
      2 mA52wk
      6Shekhawat 2014RCT401059.1818.17TFI−6.25Anode: L temporal (C3-T5)

      Cathode: R temporal (F8-T4)
      2 mA53 m
      7Hyvarinen 2016 BRCT15∗28.5746.33>0.546.19THI−4.4Anode: L temporal Cathode: R frontal2 mA10BDI-I−0.3
      8Garin 2011 ACross-over202050.90.67 to >1042TQ−3.26Anode: L TPJ (C3-T5) Cathode: R TPJ (T4-F8)1 mA1BDI−1
      9Garin 2011 BCross-over202050.90.67 to >1042TQ−2.6Anode: R TPJ (T4-F8)

      Cathode: L TPJ (C3-T5)
      1 mA1BDI0
      Mean28.1135.3050.509.4052.83−8.466.33−2.58
      SD12.4316.574.104.9911.998.923.814.77

      Characteristics of rTMS datasets

      The sample size was 34 ± 29 participants, with a ratio of women of 37% ± 16, and an age of 51 ± 4 years. Duration of tinnitus was 6 ± 3 years. Tinnitus severity at baseline was 44/100 ± 15 THI points (indicating severe tinnitus). The questionnaires were the THI (n = 20), the TQ (n = 6), the TFI (n = 1), and the TSI (n = 1). In regards to neuromodulation, frequencies were 1 Hz (n = 20), 10 Hz (n = 1), 50 Hz (cTBS, n = 4), 27,12 MHz (n = 1), or more than one frequency (20 Hz and 1Hz, n = 1; 25 Hz and 1Hz, n = 1). The numbers of sessions ranged from 4 to 20. Studies using rTMS targeted the auditory cortex, the temporoparietal junction (TPJ) or the prefrontal cortex with slight variations. Sixteen datasets targeted the auditory cortex. The exact site targeted was either the left auditory cortex (N = 10), both the right and the left auditory cortex (N = 3), or the auditory cortex with the highest activity (N = 2). The authors of one dataset [
      • Yilmaz M.
      • Yener M.H.
      • Turgut N.F.
      • Aydin F.
      • Altug T.
      Effectiveness of transcranial magnetic stimulation application in treatment of tinnitus.
      ] did not mention which hemisphere was stimulated. Seven datasets targeted the temporoparietal area. The exact site targeted was either the left temporoparietal area (N = 6), or both left and right temporoparietal areas (N = 1). Five datasets targeted the frontal cortex. The exact site targeted was either the left dorsolateral prefrontal cortex and the left auditory cortex (N = 3), the dorsolateral prefrontal cortex and both primary auditory cortices (N = 1), or the frontal cortex with the highest activity (N = 1).

      Results of the rTMS studies

      Main outcome

      Results comparing pre- and post-rTMS indicate a Hedges’ g value of −0.45 (CI = −0.66; −0.24; p < .0001), suggesting a moderate effect size for active as compared to sham rTMS. Mean change of most datasets (n = 23) is situated to the left of the no-effect (0) median line (Fig. 2). The I2 heterogeneity analyses showed moderate total heterogeneity (I2 = 54.9%; Fig. 3). One dataset at the middle left and two datasets at the upper right likely explain the heterogeneity.
      Fig. 2
      Fig. 2Effect sizes of the rTMS studies immediately after treatment.

      Moderation analyses on rTMS sites

      We tested the effects of the rTMS sites (dlPFC, AC, TPJ, “dlPFC/AC” which refers to studies alternatively targeting these two sites in different rTMS sessions but within the same rTMS regimen) (Table 3). There was a difference between the AC and other sites (QM (df = 4): 23.3097, p = .0001) that survived correction for multiple comparisons (p = .02 corrected), indicating that rTMS targeting the AC significantly reduced symptoms. rTMS diminished tinnitus over the AC (g = −0.35, p = .02 corrected) as compared than the other sites: dlPFC (g = −2.02, p = .09 corrected), dlPFC/AC (g = −0.56, p = .17 corrected), or TPJ (g = −0.55, p = .05 corrected).
      Table 3Moderation analyses on the rTMS sites.
      Neuromodulation siteEstimateSEZvalPvalCi.lbCi.ubPval adjusted
      AC−0.35040.1247−2.81000.0050∗∗−0.5948−0.10600.0200∗
      AC + dlPFC−0.55610.2735−2.03320.0420∗−1.0922−0.02000.1680
      Frontal cortex−2.01550.8937−2.25520.0241∗−3.7672−0.26390.0964
      TPJ−0.54650.2196−2.48870.0128∗−0.9769−0.11610.0512
      Signif. codes: ‘∗∗’ 0.01 ‘∗’ 0.05.

      Moderation analyses on patients’ characteristics of the rTMS datasets

      We explored potential impact of patients’ characteristics on tinnitus changes from rTMS. We entered sex, age, tinnitus duration, and tinnitus severity at baseline into a mixed-effects model. Sex had an effect (QM (df = 1): 4.0850, p = .04 uncorrected; Table 4), indicating greater tinnitus decrease for women. Age (QM (df = 1): 0.7032, p = .40 uncorrected), tinnitus duration (QM (df = 1): 0.0002, p = .98 uncorrected), and severity (QM (df = 1): 3.2634, p = .07 uncorrected) had no significant effect.
      Table 4Moderation analyses on sex, age, tinnitus duration, and tinnitus severity for the rTMS studies.
      SexEstimateSEZvalPvalCi.lbCi.ub
      Intercept0.09340.28310.32980.7415−0.46150.6482
      Female %−0.01520.0075−2.02110.0433∗−0.0299−0.0005
      AgeEstimateSEZvalPvalCi.lbCi.ub
      Intercept0.77101.46800.52520.5995−2.10633.6483
      Age−0.02410.0287−0.83860.4017−0.08040.0322
      Tinnitus durationEstimateSEZvalPvalCi.lbCi.ub
      Intercept−0.34160.3125−1.09300.2744−0.95410.2709
      Duration in years0.00070.04350.01520.9879−0.08460.0859
      Tinnitus severityEstimateSEZvalPvalCi.lbCi.ub
      Intercept0.17250.37680.45790.6470−0.56600.9111
      THI score at baseline−0.01430.0079−1.80650.0708−0.02990.0012
      Legend: Signif. codes:‘∗’ 0.05.

      Secondary outcomes

      For the long-term effect of rTMS on tinnitus questionnaires, data from the first follow-up assessment (which vary between 1 week and 6 months, Table 1) of 20 datasets were analyzed. Results indicate a Hedges’ g value of −0.42 (CI = −0.68; −0.15; p = .0024), suggesting a moderate effect size for active as compared to sham rTMS (Fig. 4).
      Fig. 4
      Fig. 4Effect sizes of the rTMS studies at follow-up. Wk: week, m: month, FU: Follow-up.
      The 5 datasets assessing anxiety and depression showed reduced symptom severity with active (mean −1.44 ± 0.99 points) than sham rTMS (mean −0.54 ± 1.20 points), although this difference did not reach statistical significance (g = −0.23; CI = −0.47; 0.006; p = .056) (Fig. 5).
      Fig. 5
      Fig. 5Effect sizes of anxiety and depressive symptoms for the rTMS studies. L: left, r: right, TPJ: Temporoparietal junction, dlPFC: dorsolateral prefrontal cortex, AC: Auditory cortex, %F: percentage of women in the dataset.

      Characteristics of tDCS datasets

      Sample size was 28 ± 12 participants, with women ratio of 35% ± 17 and age of 51 ± 4 years Tinnitus duration was 9 ± 5 years. Tinnitus severity at baseline was 53/100 ± 12 points measured on the THI, indicating severe tinnitus. The tinnitus questionnaires were the THI (n = 6), the TQ (n = 2) and the TFI (n = 1). In regard to the tDCS parameters, amplitudes were 1 mA (n = 2) and 2.0 mA (n = 7). The numbers of tDCS sessions ranged from 1 to 10 (Table 2).

      Results of the tDCS studies

      Main outcome

      Results comparing pre- and post-tDCS indicate a Hedges’ g value of −0.36 (CI = −0.76; 0.04; p = .07), which suggests a small to moderate effect size (Fig. 6). We therefore do not further analyze tDCS effects. Heterogeneity was moderate (I2 = 57.6%; Fig. 7). Most datasets are situated to the right of the graph (n = 7), but 2 were at the middle left, likely explaining the heterogeneity.
      Fig. 6
      Fig. 6Effect sizes of the tDCS studies immediately after treatment.

      Assessment of quality for rTMS and tDCS studies

      No studies were excluded for quality reasons. Most studies had a low risk of bias or some concerns (e.g., a pre-established published protocol was not available, missing data was not justified or accounted for) (Table 5), as defined by the Cochrane RoB 2 tool, the revised tool for assessing risk of bias in randomized trials and crossover trials.
      Table 5Risk of bias in included rTMS and tDCS studies.
      Table thumbnail fx1

      Electric field modeling on the effects of non-invasive neuromodulation on tinnitus

      Simulations

      We used the SimNIBS 2.1.2 software to model the electric field generated by rTMS. It uses T1 and T2 weighted images to create a volume conductor model by segmentation of tissue types: white matter, grey matter, cerebrospinal fluid, scalp and skull [
      • Saturnino G.B.
      • Puonti O.
      • Nielsen J.D.
      • Antonenko D.
      • Madsen K.H.
      • Thielscher A.
      SimNIBS 2.1: a comprehensive pipeline for individualized electric field modelling for transcranial brain stimulation.
      ]. We chose to simulate the effects of non-invasive neuromodulation on an unbiased IRM template brain volume for a normal population. Therefore, we chose the ICBM 2009a Nonlinear Symmetric template [
      • Collins D.L.
      • Zijdenbos A.P.
      • Baaré W.F.C.
      • Evans A.C.
      ANIMAL+INSECT: improved cortical structure segmentation BT - information processing in medical imaging.
      ,
      • Fonov V.
      • Evans A.C.
      • Botteron K.
      • Almli C.R.
      • McKinstry R.C.
      • Collins D.L.
      Unbiased average age-appropriate atlases for pediatric studies.
      ,
      • Fonov V.S.
      • Evans A.C.
      • McKinstry R.C.
      • Almli C.R.
      • Collins D.L.
      Unbiased nonlinear average age-appropriate brain templates from birth to adulthood.
      ] and used the T1 and T2 weighted structural MR images as an input into the SimNIBS pipeline using the headreco command function [
      • Saturnino G.B.
      • Puonti O.
      • Nielsen J.D.
      • Antonenko D.
      • Madsen K.H.
      • Thielscher A.
      SimNIBS 2.1: a comprehensive pipeline for individualized electric field modelling for transcranial brain stimulation.
      ,
      • Nielsen J.D.
      • Madsen K.H.
      • Puonti O.
      • Siebner H.R.
      • Bauer C.
      • Madsen C.G.
      • et al.
      Automatic skull segmentation from MR images for realistic volume conductor models of the head: assessment of the state-of-the-art.
      ]. We used SPM12 (including the CAT12 toolbox) for the segmentation and complete the finite element model tetrahedral mesh using Gmsh [
      • Nielsen J.D.
      • Madsen K.H.
      • Puonti O.
      • Siebner H.R.
      • Bauer C.
      • Madsen C.G.
      • et al.
      Automatic skull segmentation from MR images for realistic volume conductor models of the head: assessment of the state-of-the-art.
      ] and we inspected the model visually with Gmsh. We based the rTMS set-ups on the meta-analysis results (Table 6).
      Table 6rTMS parameters for the modeling study.
      Neuromodulation typeNeuromodulation sitedI/dt (A/s)Coil EEG coordinates (10–20 International System)Coil MNI coordinates (x; y;z)Coil type and shape
      rTMSlAC112,33 × 106Middle btw T3 and C3/T5(-87,62; −14,06; −9,80)Magstim 70 mm

      Fig. 8
      Frontal cortex (BA11)155 × 106(64,62; 68,77; 1,51)MagVenture MC-B70 Fig. 8
      ldlPFC112,33 × 106Middle on F3(-52,49; 74,95; 20,13)Magstim 70 mm

      Fig. 8
      lTPJMiddle btw T3 and P3(-83,42; −36,06; 3,27)
      We tested the rTMS sites from the meta-analysis: left dlPFC, AC and TPJ. We set the distance between the scalp and the coil to 4 mm, the default settings of SimNIBS. The SimNIBS software uses the instantaneous current rate-of-change of (dI/dt). Since the dI/dt depends on the capacitor voltage (Vcap) and the coil inductance (Lcoil), we calculated this value according to Magstim Rapid2 and Magstim D70 coil specifications using these equations:
      dIdt=Vcap/Lcoil


      Using Vcap = 1685 V and Lcoil = 15 μH we get:
      dI/dt=1685V15μH=112,33×106A/s.


      We also tested the rTMS parameters reported by Ref. [
      • Wang H.
      • Li B.
      • Feng Y.
      • Cui B.
      • Wu H.
      • Shi H.
      • et al.
      A pilot study of EEG source analysis based repetitive transcranial magnetic stimulation for the treatment of tinnitus.
      ] since this was the only dataset targeting the frontal cortex alone (Brodmann area 11), using the dI/dt obtained from with the manufacturer.
      For the modeling, we used the SimNIBS standard conductivity values based on previous simulations [
      • Opitz A.
      • Paulus W.
      • Will S.
      • Antunes A.
      • Thielscher A.
      Determinants of the electric field during transcranial direct current stimulation.
      ,
      • Saturnino G.B.
      • Antunes A.
      • Thielscher A.
      On the importance of electrode parameters for shaping electric field patterns generated by tDCS.
      ,
      • Wagner T.A.
      • Zahn M.
      • Grodzinsky A.J.
      • Pascual-Leone A.
      Three-dimensional head model Simulation of transcranial magnetic stimulation.
      ]. The automated SimNIBS pipeline provides values of the norm of the electric field (|E|), the norm of the current density (|J|) and the peak temporal change of the vector potential (dA/dt) in a tetrahedral mesh which can be visualized using either Gmsh or Matlab. rTMS in silico montages are displayed in Fig. 8.
      Fig. 8
      Fig. 8Illustrations of the electric fields generated in rTMS studies. rTMS montage targeting the left AC. From left to right: angle view of the scalp, angle view of brain and coronal cross section view of the brain.

      ROI analyses

      We tested whether the rTMS approaches identified as most effective in the meta-analysis modulate regions in line with the neurobiological models of tinnitus by creating regions of interest (ROIs). Specifically, we tested whether each rTMS site (dlPFC, AC, TPJ) created an electric activity as indicated by the values of |E|, |J| or dA/dt in the following: the left and right ACC, the amygdala, the insula and the parahippocampal gyrus. We included the cerebellum as a control region given that it unlikely plays a role in tinnitus. Results were imported into Matlab. To identify the spatial elements belonging to a ROI, we imported the atlas given in the CONN toolbox [
      • Whitfield-Gabrieli S.
      • Nieto-Castanon A.
      CONN: a functional connectivity toolbox for correlated and anticorrelated brain networks.
      ], a combination of the Harvard-Oxford atlas for cortical and subcortical regions and of the AAL atlas for cerebellum. We extracted the ROIs and excluded the skull and skin from the analysis. We plotted each ROI superimposed to the whole brain for visual confirmation that we analyzed the desired ROI (Fig. 9).
      Fig. 9
      Fig. 9Illustrations of the electric field values for each rTMS site and each ROI for the rTMS studies. Simulation results were imported in Matlab and the figures were also generated in Matlab. Except for the histograms the value of the norm of the electric field (E) is color coded in each panel. The location of the maximal value of E is indicated by a star and the location of the minimal value of E by a red dot. ROIs are indicated in black. We display the amygdalas (top row) and the anterior cingulate cortex (bottom row). The histogram indicates the distribution of E over the grey matter. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)

      Results of the electric field modeling

      The main outcome was the average strength of the electric field in volts per meter for each site (AC, frontal, dlPFC, TPJ) (Table 7). rTMS over the AC generated an average electric field of 16.12 ± 17.56 V/m in the whole brain and was stronger in the insula (13.22 V/m) than in the other ROIs. For rTMS over the frontal cortex [
      • Wang H.
      • Li B.
      • Feng Y.
      • Cui B.
      • Wu H.
      • Shi H.
      • et al.
      A pilot study of EEG source analysis based repetitive transcranial magnetic stimulation for the treatment of tinnitus.
      ], the average electric field was 16.44 ± 23.95 V/m and was stronger in the insula (14.27 V/m). Over the dlPFC, rTMS generated an average electric field of 12.99 ± 15.05 V/m and was stronger in the ACC (9.42 V/m). Finally, rTMS over the TPJ produced an average electric field of 15.25 ± 17.24 V/m and was stronger in the cerebellum (14.57 V/m).
      Table 7Electric field values for each rTMS site and each ROI for the rTMS studies.
      TypeSiteROIElectric Field (V/m)
      Mean in ROIMean in whole brain (SD) (min-max)
      rTMSACInsula13.224116.1185 (17.5619)

      (0.09–163.299)
      Cerebellum11.9560
      Parahippocampus8.3755
      Amygdala8.2580
      ACC5.9609
      Frontal cortex (BA11)Insula14.267616.4436 (23.9466)

      (0.0569–264.3719)
      ACC9.7144
      Amygdala6.5447
      Parahippocampus6.1106
      Cerebellum4.9252
      dlPFCACC9.424712.9857 (15.0463)

      (0.0716–254.5406)
      Insula8.2575
      Parahippocampus6.2762
      Amygdala5.8304
      Cerebellum5.0771
      TPJCerebellum14.565415.2537 (17.2472)

      (0.0742–185.3176)
      We also computed the average current density of the electric field in amperes per meter squared for each site (Table 8). rTMS over the AC generated an average current density of 4.43 ± 4.48 A/m2 in the whole brain and was stronger in the insula (3.64 A/m2) than in the other ROIs. For rTMS over the frontal cortex [
      • Wang H.
      • Li B.
      • Feng Y.
      • Cui B.
      • Wu H.
      • Shi H.
      • et al.
      A pilot study of EEG source analysis based repetitive transcranial magnetic stimulation for the treatment of tinnitus.
      ], the average current density was 4.52 ± 6.59 A/m2 and was stronger in the insula (3.92 A/m2). Over the dlPFC, rTMS generated an average current density of 3.57 ± 4.14 A/m2 and was stronger in the ACC (2.59 V/m). Finally, rTMS over the TPJ produced an average electric field of 4.19 ± 4.74 A/m2 and was stronger in the cerebellum (4.01 A/m2). For the sake of completeness, we added computations of the peak temporal change of the vector potential. Interestingly, this peak temporal change was not always strongest where the electric field or the current density were the strongest. For instance, for rTMS over the TPJ, current density and electric field were strongest in the cerebellum while peak temporal change of the vector potential was strongest in the insula.
      Table 8Current density values and values of the peak temporal change of the vector potential for each rTMS site and each ROI for the rTMS studies.
      TypeSiteROICurrent Density (A/m2)
      Mean in ROIMean in whole brain

      (SD) (Min-Max)
      rTMSACInsula3.63664.4326

      (4.48295)

      (0.0248–44.9072)
      Cerebellum3.2879
      Parahippocampus2.3033
      Amygdala2.2710
      ACC1.6393
      PFC (BA11)Insula3.92364.5220

      (6.5853)

      (0.0157–72.7023)
      ACC2.6715
      Amygdala1.7998
      Parahippocampus1.6804
      Cerebellum1.3544
      dlPFCACC2.59183.5711

      (4.1377)

      (0.0197–69.9987)
      Insula2.2708
      Parahippocampus1.7260
      Amygdala1.6033
      Cerebellum1.3962
      TPJCerebellum4.00554.1948

      (4.7430)

      (0.0204–50.9623)
      Insula2.9220
      Parahippocampus2.5740
      Amygdala2.3568
      ACC1.0760
      TypeSiteROIdA/dt: Peak temporal change of the vector potential. (V/m)
      Mean inROIMean in whole brain

      (SD) (Min-Max)
      rTMSACInsula31.105626.2972

      (28.2140)

      (0.3022–215.4726)

      Amygdala22.4046
      Parahippocampus22.1080
      Cerebellum19.0787
      ACC17.3347
      PFC (BA11)Insula20.205818.1080

      (27.8724)

      (0.0545–262.8243)

      ACC19.4531
      Amygdala8.0828
      Cerebellum5.4652
      Parahippocampus5.2707
      dlPFCACC39.274522.2376

      (25.4881)

      (3.8572–201.7167)

      Insula25.4106
      Amygdala16.6296
      Parahippocampus12.4464
      Cerebellum6.6199
      TPJInsula23.558724.8049

      (27.4142)

      (0.4228–213.8765)

      Amgdala16.3024
      Parahippocampus16.2413
      ACC16.0428
      Cerebellum14.3870

      Discussion

      This work indicates that rTMS is effective to suppress tinnitus, as shown by a significant moderate effect size when comparing active with sham rTMS regimen. Active rTMS resulted in a mean change of tinnitus standardized questionnaires scores of −7.60 (±6,27) which is clinically significant. Indeed, a difference of 6–7 points at the THI [
      • Zeman F.
      • Koller M.
      • Figueiredo R.
      • Aazevedo A.
      • Rates M.
      • Coelho C.
      • et al.
      Tinnitus Handicap inventory for evaluating treatment effects.
      ] or 5 points at the TQ [
      • Adamchic I.
      • Tass P.
      • Langguth B.
      • Hauptmann C.
      • Koller M.
      • Schecklmann M.
      • et al.
      Linking the tinnitus questionnaire and the subjective clinical global impression: which differences are clinically important?.
      ] reflects clinical improvement at the Clinical Global Impression scale. Further, there was an effect of active rTMS at follow up sessions, suggesting that 4 to 20 rTMS sessions can decrease tinnitus over a time period that outlasts the stimulation regimen. We expected that the neuromodulation approaches identified as most effective in the meta-analysis will modulate regions in line with the two main tinnitus neurobiological models [
      • De Ridder D.
      • Vanneste S.
      • Weisz N.
      • Londero A.
      • Schlee W.
      • Elgoyhen A.B.
      • et al.
      An integrative model of auditory phantom perception: tinnitus as a unified percept of interacting separable subnetworks.
      ,
      • Henry J.A.
      • Roberts L.E.
      • Caspary D.M.
      • Theodoroff S.M.
      • Salvi R.J.
      Underlying mechanisms of tinnitus: review and clinical implications.
      ]. Our results suggest that rTMS was the most effective to reduce global score of tinnitus from standardized questionnaires when targeting the AC, as shown by the moderation analysis of the rTMS sites (AC, dlPFC, AC/dlPFC, TPJ). Interestingly, the modeling analysis shows that the strongest electric field induced by rTMS applied over the AC was in the insula among all ROIs (amygdala, ACC, parahippocampus, cerebellum). Our analyses show that the current density was also the strongest in the insula in comparison with the other ROIs. This partially supports the hypothesis that neuromodulation over the AC modulates activity in the insula, supporting the model postulating that tinnitus is related to impaired auditory information processing [
      • Maudoux A.
      • Lefebvre P.
      • Cabay J.-E.
      • Demertzi A.
      • Vanhaudenhuyse A.
      • Laureys S.
      • et al.
      Auditory resting-state network connectivity in tinnitus: a functional MRI study.
      ]. This is also in line with an fMRI study reporting that functional connectivity between the AC and insula was greater in patients with tinnitus than healthy controls [
      • Burton H.
      • Wineland A.
      • Bhattacharya M.
      • Nicklaus J.
      • Garcia K.S.
      • Piccirillo J.F.
      Altered networks in bothersome tinnitus: a functional connectivity study.
      ]. Overall, these results show that rTMS over the AC suppresses tinnitus and such effects may be linked to modulation of insula activity. The insula is known to have functional heterogeneity, from sensorimotor, pain, and socio-emotional processes to high-level attention (e.g., Ref. [
      • Roberts L.E.
      • Husain F.T.
      • Eggermont J.J.
      Role of attention in the generation and modulation of tinnitus.
      ]). Further, insular lesions can cause hyperacusis and central auditory deficits and direct electrical stimulation of the insula can induce auditory illusions and distortions [
      • Uddin L.Q.
      • Nomi J.S.
      • Hébert-Seropian B.
      • Ghaziri J.
      • Boucher O.
      Structure and function of the human insula.
      ].
      We hypothesized that rTMS over the dlPFC would reduce the most tinnitus. This was based on work indicating that tinnitus is linked to impaired sensory and emotional processing [
      • Burton H.
      • Wineland A.
      • Bhattacharya M.
      • Nicklaus J.
      • Garcia K.S.
      • Piccirillo J.F.
      Altered networks in bothersome tinnitus: a functional connectivity study.
      ,
      • Mirz F.
      • Gjedde A.
      • Ishizu K.
      • Pedersen C.
      Cortical networks subserving the perception of tinnitus - a PET study.
      ] and that rTMS applied over the dlPFC can impact brain activity of networks involving the auditory processing such as the AC [
      • De Ridder D.
      • Song J.-J.
      • Vanneste S.
      Frontal cortex TMS for tinnitus.
      ], as well as the sensory and emotional processes including the frontal regions and the parahippocampus [
      • De Ridder D.
      • Song J.-J.
      • Vanneste S.
      Frontal cortex TMS for tinnitus.
      ]. However, our results indicate a large Hedges’ g value that was not statistically significant after correction for multiple comparisons (uncorrected p = .02). Importantly, only one dataset targeted the frontal cortex alone [
      • Wang H.
      • Li B.
      • Feng Y.
      • Cui B.
      • Wu H.
      • Shi H.
      • et al.
      A pilot study of EEG source analysis based repetitive transcranial magnetic stimulation for the treatment of tinnitus.
      ], which showed a stronger electric field and current density in the insula, similarly to rTMS over the AC. This supports the hypothesis that neuromodulation of the frontal can reach limbic structures similar to those reached by neuromodulation over the AC. Other datasets targeted the dlPFC and AC, alternatively within the same regimen or the dlPFC and the temporal area, thus our results do not allow us to conclude on the efficacy of rTMS over the dlPFC. Modeling shows that when rTMS was applied over the dlPFC, the strongest electric field and current density were in the ACC among all ROIs, supporting the idea that rTMS over the dlPFC can target sensory and emotional processes in the frontal regions.
      We also found that 6 studies investigated the impact of rTMS over the TPJ (Table 1). This rTMS regimen had no significant effect on tinnitus and elicited the strongest electric field and current density in the cerebellum among our ROIs. We had no a priori hypothesis on TPJ which is not a key region on the two main neurobiological models of tinnitus (AC, frontal region). Interestingly, Piccirillo et al. [
      • Piccirillo J.F.
      • Garcia K.S.
      • Nicklaus J.
      • Pierce K.
      • Burton H.
      • Vlassenko A.G.
      • et al.
      Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus.
      ,
      • Piccirillo J.F.
      • Kallogjeri D.
      • Nicklaus J.
      • Wineland A.
      • Spitznagel E.L.
      • Vlassenko A.G.
      • et al.
      Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus: four-week stimulation trial.
      ] suggested that rTMS over TPJ may not lead to beneficial effects on tinnitus in part because it might not reach deeper parts of the AC within the Sylvian fissure. Of note, there was one study that delivered 27,12 MHz with a Diapulse device and reported negative results on tinnitus symptoms [
      • Ghossaini S.N.
      • Spitzer J.B.
      • Mackins C.C.
      • Zschommler A.
      • Diamond B.E.
      • Wazen J.J.
      High-frequency pulsed electromagnetic energy in tinnitus treatment.
      ]. This device is typically used to treat inflammation and swelling, but not frequently for neuromodulation.
      Studies on tinnitus often assess depression and anxiety [
      • Ziai K.
      • Moshtaghi O.
      • Mahboubi H.
      • Djalilian H.R.
      Tinnitus patients suffering from anxiety and depression: a review.
      ,
      • Salazar J.W.
      • Meisel K.
      • Smith E.R.
      • Quiggle A.
      • McCoy D.B.
      • Amans M.R.
      Depression in patients with tinnitus: a systematic review.
      ,
      • Loprinzi P.D.
      • Maskalick S.
      • Brown K.
      • Gilham B.
      Association between depression and tinnitus in a nationally representative sample of US older adults.
      ]. Our results suggest that active as compared to sham rTMS applied to treat tinnitus may reduce depression and anxiety (p = .056) and the sample included only 5 datasets. One might expect that these effects could be linked to rTMS applied over the dlPFC, a protocol known to treat depression (e.g.,
      • O’Reardon J.P.
      • Solvason H.B.
      • Janicak P.G.
      • Sampson S.
      • Isenberg K.E.
      • Nahas Z.
      • et al.
      Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial.
      ). However, these 5 datasets targeted various brain regions (TPJ, dlPFC/AC, and AC; Fig. 4). Interestingly, the 2 datasets that had the strongest effect sizes on depressive and anxiety symptoms targeted the left TPJ, an rTMS protocol that was close to significance to reduce global score of tinnitus from standardized questionnaires (uncorrected p = .01). Thus, such impact on depressive and anxiety symptoms cannot clearly be linked to targeting the dlPFC, but may be due to an indirect effect, such that reducing tinnitus diminishes depression and anxiety symptoms.
      Our work also indicates that rTMS had a greater beneficial impact in women. Studies investigating tinnitus in men and women reported that women tend to display greater severity of depressive symptoms [
      • Vanneste S.
      • Joos K.
      • De Ridder D.
      Prefrontal cortex based sex differences in tinnitus perception: same tinnitus intensity, same tinnitus distress, different mood.
      ]. Taking into account this, rTMS may decrease depressive symptoms in patients with tinnitus, which may also in turn partially suppress tinnitus. Interestingly, in studies showing greater decrease in BDI scores (Hedges’s g of −0.86 and −0.44), the percentage of women was over 50%, whereas in studies showing less decrease in BDI scores (Hedges’s g of −0.25, −0.11 and −0.10), the percentage of women was around 30%. Our sample had a mean ratio of women of 37%, consistent with studies reporting greater prevalence of tinnitus in men [
      • McCormack A.
      • Edmondson-Jones M.
      • Somerset S.
      • Hall D.
      A systematic review of the reporting of tinnitus prevalence and severity.
      ,
      • Bhatt J.M.
      • Lin H.W.
      • Bhattacharyya N.
      Prevalence, severity, exposures, and treatment patterns of tinnitus in the United States.
      ]. For tinnitus severity at baseline, results did not reach statistical significance (p = .07) but tend toward that rTMS beneficial effects are greater when tinnitus is more severe prior to treatment. Also, the effects of rTMS on tinnitus were not significantly influenced by age or tinnitus duration. In sum, our findings underline the importance of taking into account sex [
      • Vanneste S.
      • Joos K.
      • De Ridder D.
      Prefrontal cortex based sex differences in tinnitus perception: same tinnitus intensity, same tinnitus distress, different mood.
      ], depressive symptoms, and baseline tinnitus severity.
      This meta-analysis does not support that tDCS diminishes tinnitus symptoms. Our analyses show a small effect size when comparing active with sham tDCS. Although active tDCS resulted in a clinically significant mean change of tinnitus standardized questionnaires scores (−8.46 ± 8.92), it did not reach statistical significance.
      We focused on sham-controlled studies since placebo effects have been reported in rTMS and tDCS trials and placebo effect in patients with tinnitus from various types of treatments is also well documented. For instance, 40% of patients reported a 25% modification (reduction or augmentation) of tinnitus severity in a study using a placebo dose of lidocaine [
      • Duckert L.G.
      • Rees T.S.
      Placebo effect in tinnitus management.
      ]. In our meta-analyses, placebo responses highly vary across studies, from 7% [
      • Piccirillo J.F.
      • Garcia K.S.
      • Nicklaus J.
      • Pierce K.
      • Burton H.
      • Vlassenko A.G.
      • et al.
      Low-frequency repetitive transcranial magnetic stimulation to the temporoparietal junction for tinnitus.
      ] to 67% [
      • Formánek M.
      • Migaľová P.
      • Krulová P.
      • Bar M.
      • Jančatová D.
      • Zakopčanová-Srovnalová H.
      • et al.
      Combined transcranial magnetic stimulation in the treatment of chronic tinnitus.
      ]. Further, sham rTMS yielded a lower placebo effect than sham tDCS (sham rTMS: 1.9 points; sham tDCS 4.4 points).
      There are limitations to address from this work. First, we included only sham-controlled studies that assessed tinnitus with standardized questionnaires which excluded current tRNS and tACS studies [
      • Claes L.
      • Stamberger H.
      • Van de Heyning P.
      • De Ridder D.
      • Vanneste S.
      Auditory cortex tACS and tRNS for tinnitus: single versus multiple sessions.
      ,
      • Joos K.
      • De Ridder D.
      • Vanneste S.
      The differential effect of low- versus high-frequency random noise stimulation in the treatment of tinnitus.
      ,
      • Mohsen S.
      • Mahmoudian S.
      • Talebian S.
      • Pourbakht A.
      Multisite transcranial Random Noise Stimulation (tRNS) modulates the distress network activity and oscillatory powers in subjects with chronic tinnitus.
      ,
      • 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.
      ]. Therefore, our conclusions cannot be generalized to these techniques which may be beneficial to target tinnitus, especially tRNS [
      • Claes L.
      • Stamberger H.
      • Van de Heyning P.
      • De Ridder D.
      • Vanneste S.
      Auditory cortex tACS and tRNS for tinnitus: single versus multiple sessions.
      ,
      • Joos K.
      • De Ridder D.
      • Vanneste S.
      The differential effect of low- versus high-frequency random noise stimulation in the treatment of tinnitus.
      ,
      • Mohsen S.
      • Mahmoudian S.
      • Talebian S.
      • Pourbakht A.
      Multisite transcranial Random Noise Stimulation (tRNS) modulates the distress network activity and oscillatory powers in subjects with chronic tinnitus.
      ,
      • 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.
      ]. Furthermore, generalization of our results is limited by the high heterogeneity present, which likely arises from the various experimental protocols reported. As of today, there is no consensus on the ideal neuromodulation protocol to follow. Also, computation of individual protocols separately would require more data from each experimental setting. This is one of the reasons that motivated our modeling study, namely, to identify protocols that are more likely to generate benefits.
      Second, for the modeling study, we decided to model the rTMS parameters (dI/dt, targeted area) most used in the included studies. Consequently, the results obtained can only be generalized to these parameters. Studies using a dual-site neuromodulation protocol (targeting 2 distinct sites at differential time points) could not be modeled. Third, there can be important variability in the electric field generated with the same rTMS protocol due to physiological variability in features such as skull thickness [
      • Deng Z.-D.
      • Lisanby S.H.
      • Peterchev A.V.
      Effect of anatomical variability on electric field characteristics of electroconvulsive therapy and magnetic seizure therapy: a parametric modeling study.
      ]. For this reason, some guided studies used MRI to target specific brain regions. For other studies, the variability in regions receiving an electric field can be important though impossible to quantify. Experimental protocols reviewed in the present meta-analysis exhibited great variability in the number of treatments, time between treatments, etc. This might be relevant as an often-proposed mechanism of action of rTMS is through modulation of synaptic long-term potentiation (LTP) [
      • Peng Z.
      • Zhou C.
      • Xue S.
      • Bai J.
      • Yu S.
      • Li X.
      • et al.
      Mechanism of repetitive transcranial magnetic stimulation for depression.
      ], which could not be modeled here. We chose to compute the electric fields generated by rTMS since it has been found that even weak electric field (applied at a strength of 80% of the resting motor threshold) can synchronize neurons [
      • Murad M.H.
      • Wang Z.
      • Chu H.
      • Lin L.
      When continuous outcomes are measured using different scales: guide for meta-analysis and interpretation.
      ]. We also computed the current density and the peak temporal change of the vector potential generated by rTMS to complement our electric field results. Indeed, current density results and peak temporal changes of the vector potential mostly support our electric field results (apart from the TPJ simulation) which are that the insula and ACC regions are involved in the reduction of global score of tinnitus from standardized questionnaires.
      However, effects from neuromodulation likely involve other mechanisms, including at the network level, which cannot be evaluated from electric field computation in ROIs alone. Understanding of these mechanisms will require more investigations at the neuronal level and between networks.
      In sum, results of this work partially support our primary hypothesis, that is, active as compared to sham noninvasive neuromodulation suppresses tinnitus. rTMS was effective to reduce global score of tinnitus from standardized questionnaires, whereas effects of tDCS did not reach statistical significance. Results also partially support our secondary hypothesis. We proposed that neuromodulation approaches will modulate regions in line with the neurobiological models of tinnitus. When targeting the AC, rTMS generated a stronger electric field in the insula. On the other hand, rTMS targeting the dlPFC generated a stronger electric field in the ACC. Finally, our moderation analyses indicated that rTMS over the AC is the approach reducing tinnitus scores the most.

      Acknowledgement

      We would like to thank the authors who provided original data included in this meta-analyses, Drs Schecklmann, Piccirillo and Vandermeeren. We would also like to thank Marilyne Joyal for her help with the review procedures. The authors declare no competing interests. Mathilde Lefebvre-Demers was supported by a Canadian Institutes of Health Research Master scholarship and a Fonds de Recherche en Santé du Québec Master scholarship. Shirley Fecteau was supported by the Canada Research Chair in Cognitive Neuroplasticity.

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