Table 2.
Randomized-controlled trials: Summary of characteristics protocols, results, and conclusions in 11 RCTs utilizing rTMS on patients with tinnitus.
| Author | Year | Subjects per Group and Blinding | Primary Baseline Evaluation | rTMS Protocol Group 1 (Session Number, Frequency, Amount of Stimuli) | Protocol Group 2 | Primary Evaluation of Outcomes | Results | Conclusion |
|---|---|---|---|---|---|---|---|---|
| Roland et al. [43] | 2016 | -Group 1 (experimental): 16 patients with nonpulsatile tinnitus -Group 2 (Sham): 14 patients with nonpulsatile tinnitus -Double-blinded |
-Resting state functional connectivity MRI (rs-fcMRI) -THI |
-Group 1: Active treatment was delivered at 1 Hz at 110% of RMT at the temporoparietal junction for 42.5 min (2500 stimuli) with interval stimulation for 2 or 4 weeks. | -Group 2 (sham): same protocol with placebo rTMS | -rs-fcMRI following treatment for 2 or 4 weeks -THI following treatment |
-No statistically significant changes found between pre and post intervention in both the rs-fcMRI and THI | -Concluded both a lack of symptom change and neural connectivity changes -Suggest they may not have had sufficient stimulation to the area of interest or should consider non-auditory brain regions associated with tinnitus |
| Lehner et al. [44] | 2016 | -Group 1: 24 patients with tinnitus (Single site) -Group 2: 25 patients with tinnitus (triple site) -Group 3: 25 patients with tinnitus (placebo) -Double-blinded |
-8 various tinnitus questionnaires | -Group 1 (single site): 3000 pulses/day of the left temporoparietal cortex with low-frequency (1 Hz) rTMS of the left temporoparietal cortex -Group 2 (triple site): 1000 pulses/day of high-frequency 20 Hz stimulation of the left DLPFC, followed by 1000 pulses/day of low-frequency (1 Hz) to both the left and right temporoparietal cortex (3000 pulses total) -Ten sessions total for each group |
Group 3 (placebo): sham coil was localized at the auditory cortex by using a PET-guided neuronavigation system. | -8 tinnitus questionnaires on the last day of treatment (day 12), day 90 and day 180 following treatment | -Both the single site and triple site showed statistically significant reductions in tinnitus severity, but the difference between the two is not significant besides at day 90. | -Study did not find significant differences between one or multi-site rTMS treatment -More work needed on exact protocols for a more effective and individualized treatment |
| Noh et al. [45] | 2017 | -Group 1: 9 patients with tinnitus -Group 2: 13 patients with tinnitus -Blinding not possible |
-THI score -VAS score |
-Group 1: Auditory cortex (AC) and frontal cortex (FC) determined by 10–20 EEG system -rTMS was administered at a frequency of 1 Hz with an intensity of 110% RMT -40 s on and 20 s off -Total of 12,000 pulses: 2000 pulses over the AC, and 1000 pulses over the FC daily for 4 days. |
-Group 2: coil navigated to the primary AC and FC by a MRI neuronavigation system -Same rTMS treatment as group 1 |
-THI weeks 1, 4, and 8 after baseline -VAS at weeks 1, 4, 8, and 12 after baseline |
-Both groups had a significant reduction in THI scores -Group 1 effect lasted 8 weeks and group 2 effect lasted 4 weeks, but the differences were not statistically different -VAS score reduction not statistically significant in group 1 but statistically significant in group 2 up to 12 weeks post treatment -ΔVAS between the groups was not statistically significant |
-Localizing technique for treatment target not a crucial factor in the rTMS outcome of the same locations |
| Noh et al. [46] | 2017 | -Group 1: 9 patients with chronic tinnitus (dual-site) -Group 2: 8 patients with chronic tinnitus (single-site) -Double blinded |
-THI score -VAS score -State-Trait Anxiety Inventory (STAI) -Beck’s Depression Inventory (BDI) -Pittsburgh Sleep Quality Index (PSQI) |
Group 1: Low frequency (1 Hz) treatments with 2000 pulses applied to the AC and 1000 pulses applied to the DLPFC for 4 days (total of 12,000 pulses) | Group 2: Low frequency (1 Hz) treatments with 3000 pulses applied to the DLPFC for 4 days (total of 12,000 pulses). | -THI, VAS, STAI, PSQI at weeks 1, 2, 4, and 12 after treatment | -Group 1 showed significant reductions in THI and VAS scores at all weeks of evaluation, whereas group 2 did not -Group 1 showed significant improvements in STAI at 12 weeks, and PSQI scores at 4 weeks. -Group 2 showed a significant improvement only in STAI at 12 weeks. |
-Targeting both the AC and DLPFC had better outcomes in all areas of evaluation in comparison to just targeting the DLPFC -Non-auditory cortex stimulation only is not sufficient to impact tinnitus |
| James et al. [47] | 2017 | -12 total participants in a crossover study -Half started at 1 Hz, the other half at 10 Hz, with a sham in between crossover -Double-blinded |
-fMRI -Visual Analog Rating (VAR) |
-Both groups received: Sham, 1 Hz, and 10 Hz for four sessions per arm, 1800 pulses per session, delivered at 110% of RMT over the posterior superior temporal gyrus (STG) | -Groups crossed over with a 21-day washout period | -fMRI after final treatment -VAR after final treatment |
-Both 1 Hz and 10 Hz rTMS stimulation showed changes in tinnitus awareness from baseline compared to sham -All three measures of the VAR (awareness, loudness, and annoyance) were improved with 1 Hz. -Higher DLPFC activity at baseline may predict a poorer response to rTMS |
-Using 1 Hz and 10 Hz can lead to similar results, even though they lead to inverse effects on neural excitability -The role of DLPFC plays a role in tinnitus and rTMS responsiveness |
| Cacace et al. [48] | 2017 | -25 total participants with chronic tinnitus -Single-blinded crossover |
-THI for inclusion -Audiogram -Tinnitus Handicap Questionnaire (THQ) -Metabolite levels using magnetic resonance spectroscopy (MRS) |
-Active rTMS: 1 Hz and at a power setting of 110% of RMT over the left AC -20-min sessions with a total of 1200 stimuli -Participants received 5 days of active rTMS and then 5 days of sham rTMS stimulation, sequentially |
-Sham treatment with same time frame | -Audiogram at day 5 -THQ at day 5 -MRS at day 5 |
-Significant decrease in the loudness of tinnitus -Significant reduction in THQ score -Down regulation in the glutamate (excitatory) seen in the left and not the right hemisphere |
-Perceptual, psychoacoustic, and neurochemical analysis of rTMS treatment showed improvement in tinnitus |
| Landgrebe et al. [49] | 2017 | -163 patients with chronic tinnitus -Group 1: 75 patients (experimental) -Group 2: 78 patients (sham) -Patient and rater blinded |
-Tinnitus Questionnaire (TQ) -THI -Tinnitus Severity Scale (TSS) |
-Group 1: 10 sessions active 1-Hz-rTMS (2000 stimuli, 110% RMT) to the left temporal cortex (AC). | -Group 2: Sham rTMS with the same time frame | -TQ, THI, TSS at day 12 | -No statistically significant difference in outcome measures between the active and the sham group | -No effect found in the largest trial testing rTMS of the left AC alone -Larger trials of other protocols should be carried out |
| Sahlsten et al. [50] | 2017 | -39 patients with chronic tinnitus -Group 1: 19 patients (experimental) -Group 2: 20 patients (placebo) -Single-blinded |
-THI -VAS -Audiogram |
-Group 1: 10 sessions over 2 weeks of 4000 pulses at 1 Hz to the left superior temporal gyrus (STG) at 100% of RMT | -Group 2: Placebo rTMS | -THI, VAS after 10 days, at 1 month and at 3 months post treatment | -Significant reduction in THI score in both groups but not between groups -Significant decrease in mean intensity, annoyance and distress VAS scores at 3 months post-treatment but not significant over time -No changes in hearing in both groups |
-Improvement in both VAS and THI in the whole study group but not between groups -May be attributed to too many pulses or placebo effect -Best protocol of rTMS remains uncertain |
| Ciminelli et al. [51] | 2020 | -Group 1 (Experimental): 15 patients with tinnitus -Group 2 (Sham): 14 patients with tinnitus -Single-blinded |
-THI score -VAS score -Tinnitus loudness |
-Group 1 (experimental group): Each session of 10 Hz stimulation applied 3000 pulses to each DMPFC for 15 min each side (6000 pulses total). -5 s on and 10 s off were used, for a total time of 30 min -Treatment was 5 times a week for 4 weeks (20 total sessions) |
-Group 2 (sham) received the same protocol but with a placebo coil -Coil produced the same sound and sensation |
-THI and VAS score at weeks 1, 2, and 4 of treatment and 16 weeks after baseline -Tinnitus loudness following treatment |
-A significant difference of 11.53 in THI (95% confidence interval [CI]: −23.12 to 0.06; p = 0.05) -VAS difference of 0.80 not statistically significant (95% CI, −2.21 to 0.61) -Tinnitus loudness score reduction of 4.46 dB was borderline significant (95% CI: −9.60 to 0.68 dB; p = 0.09). |
-Results show a benefit in 2/3 parameters used to evaluate tinnitus |
| Kreuzer et al. [52] | 2021 | -Exploratory open label study -Randomized, parallel-group design with 80 patients -32 received “standard triple protocol” (Group 1) -38 received “high-frequency triple protocol” (Group 2) |
-Primary baseline: TQ | -“Standard triple” protocol: 20 Hz stimulation of the DLPFC followed by 1 Hz to the left and right temporoparietal cortex with 1000 stimuli for 4 weeks - Total of 3000 stimuli per session -6 patients were treated for only 2 weeks |
-“High-frequency triple” protocol: 20 Hz to the left DLPFC and the left and right temporoparietal junction area with 1000 stimuli for 4 weeks -Total of 3000 stimuli per session -5 patients were treated for only 2 weeks |
-Primary outcome: TQ assessed at baseline, week 2, week 4, week 12 | -Change in TQ from baseline to week 12 was significant (P = 0.016). -No significant interaction effect between measurement time point (2 vs. 4 weeks) and group (standard vs. high-frequency) |
-Due to the pilot nature of the study, clinical relevance remains unknown -4 weeks is a feasible treatment time, but not superior to 2 weeks -High frequency not superior or inferior to the standard therapy |
| Carter et al. [12] | 2021 | -Double-blinded, sham-controlled -19 patients in crossover study -All patients received Sham (Group 1) -All patients received treatment (Group 2) |
-Electro-encephalography (EEG) -VAS and line mark (LM) rating of loudness, annoyance, awareness -THQ |
-Group 1: All participants received sham rTMS first -Three 4-day courses of participants received 1800 pulses at a 110% motor threshold targeted over the posterior, superior temporal gyrus. |
-Group 2: Participants were randomized to either the 1 Hz and 10 Hz and then crossed over to second frequency after completing the first -Three 4-day courses of rTMS participants received 1800 pulses targeted over the posterior, superior temporal gyrus |
-VAR/LM and EEG evaluation at baseline, the end of each treatment week and 2 months following treatment | -No significant change in VAS compared to before and immediately following treatment, during sham, or active 10-Hz treatment -1-Hz treatment led to a significant decrease in both the LM and VAS awareness ratings at days 1–3 with loudness (p = 0.0447), annoyance (p = 0.0195), and awareness (p = 0.0430) -No changes in any EEG frequency band between baseline and sham -EEG after 1 Hz: significant increase in beta and delta coherence -EEG after 10 Hz: increase in theta and beta coherence |
-No immediate effect of rTMS on tinnitus during a single rTMS session -1 Hz was associated with a decrease in tinnitus awareness and was associated with an increase in beta coherence -EEG changes noted in treatment responders but absent in non-responders and sham treatment -Beta coherence is a possible biomarker of the rTMS effect |