Otology & Neurotology 36:1450Y1456 Ó 2015, Otology & Neurotology, Inc.

Difference in Tinnitus Treatment Outcome According to the Pulse Number of Repetitive Transcranial Magnetic Stimulation *Joo Hyun Park, †Tae-Soo Noh, †Jun Ho Lee, †Seung-Ha Oh, ‡June Sic Kim, ‡§Chun Kee Chung, and †Myung-Whan Suh *Department of OtorhinolaryngologyYHead and Neck Surgery, Dongguk University Ilsan Hospital, Goyang; ÞDepartment of OtolaryngologyYHead and Neck Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul; þDepartment of Brain and Cognitive Science, Seoul National University College of Natural Science, Seoul; and §Department of Neurosurgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Korea

Objective: We aimed to compare the treatment result between 6,000 and 12,000 pulses of low-frequency repetitive transcranial magnetic stimulation (rTMS) and to evaluate the correct location of rTMS in Korean brains compared with that of Caucasians. Study Design: Controlled trial. Setting: Tertiary referral center. Patients: Fourteen patients with chronic essential tinnitus were treated with rTMS on the left auditory cortex (AC) and prefrontal cortex (FC). AC targets were determined using the 10-20 electroencephalographic (EEG) method proposed by Langguth in 2006. Six patients received a total of 6,000 pulses rTMS (AC, 1,000; FC, 1,000; 3-d course; Group 1), and eight patients were given 12,000 pulses (AC, 2,000; FC, 1,000; 4-d course; Group 2). Main Outcome Measures: Treatment results were assessed with pretreatment and posttreatment Tinnitus Handicap Inventory (THI) and self-rating Visual Analog Scale (VAS) of awareness,

loudness, annoyance, and effect on daily life of tinnitus at 1, 2, 4, 8, and 12 weeks after treatment. Using the individual subject’s magnetic resonance image and Neuronavigation System, the location of primary AC was determined and compared with that of the 10-20 method in four patients. Results: There was no improvement of THI and VAS in Group 1. On the contrary, a substantial decrease of THI scores and VAS scores for awareness, loudness, and effect on daily life was observed in Group 2. Conclusion: Despite the small number of patients, a beneficial effect of rTMS on tinnitus suppression was found in the 12,000pulse treatment group, whereas no effect was found in the 6,000pulse treatment group. rTMS localization based on the 10-20 EEG method seems to be valid even in Koreans with a shorter anteroposterior skull diameter. Key Words: Coil positioningV TinnitusVTranscranial magnetic stimulation. Otol Neurotol 36:1450Y1456, 2015.

Repetitive transcranial magnetic stimulation (rTMS) is receiving significant attention in a broad range of neuropsychiatric disorders (1). It is particularly notable that rTMS has been approved by the US Food and Drug Administration for management of depression (2). A number of recent studies have reported that rTMS can also be used as a tool to suppress tinnitus. Various stimulation patterns including 1 Hz (3,4), 10 Hz (5,6), and burst stimulation (7,8) have been reported to be effective in tinnitus suppression. In particular, rTMS protocols with a repetition

rate less than 1 Hz are considered to inhibit the neural activity of the auditory cortex (AC), which is suspected to have an increased baseline neural excitability in tinnitus patients (9Y12). A significant reduction in tinnitus loudness has been demonstrated in patients undergoing rTMS through the analysis of several randomized controlled trials comparing the effect of rTMS versus sham rTMS (13). Many medical and behavioral strategies may result in symptomatic relief of tinnitus. Yet, no given modality was able to effectively reduce the intensity of the tinnitus. Cognitive-behavioral therapy (CBT) and tinnitus retraining therapy (TRT) can only improve the tinnitus-related distress and not the tinnitus itself. rTMS is unique and clinically important because it can reduce the patients’ perception or loudness of the tinnitus itself. There is growing evidence that the neural network of both auditory and nonauditory cortical areas such as the

Address correspondence and reprint requests to Myung-Whan Suh, M.D., Ph.D., Department of OtorhinolaryngologyYHead and Neck Surgery, Seoul National University Hospital, YongonYDong, Chongno-Gu, Seoul 110-799, South Korea; E-mail: [email protected] This study was supported by grant 0420140750, 2014-1303 from Seoul National University Hospital. The authors disclose no conflicts of interest.

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TINNITUS TREATMENT OUTCOME DIFFERENCES dorsolateral prefrontal cortex, which is responsible for attentional and emotional processing, is involved in the pathophysiology of chronic subjective tinnitus (14Y17). The left dorsolateral prefrontal cortex (DLPFC) has also been known as the cortex closely related to depression, which is a frequent comorbidity accompanied by tinnitus. Although there are now many publications reporting a positive effect of rTMS on tinnitus suppression, it should be noted that most of the earlier rTMS studies focused on the temporal cortex (the primary and secondary AC). Combined prefrontal and temporal cortex rTMS has recently been reported to be an effective treatment of tinnitus (18Y21). Based on two randomized, double-blind, controlled clinical trials, Langguth et al. (20) reported a higher response rate (43%) of rTMS in tinnitus patients undergoing combined left frontal and temporal rTMS compared with patients undergoing rTMS only on the temporal cortex (38%). Kreuzer et al. (22) also observed a more pronounced reduction of tinnitus in the combined rTMS group (left temporal and right prefrontal cortex) compared with that in the group undergoing temporal rTMS only. As for the repetition number of rTMS stimulation, studies included various amounts of rTMS pulses. Only a small number of rTMS pulses, such as 30 pulses, were applied in some studies (23), whereas others applied more than 1,800 to 2,000 pulses (18). There is no guideline for the number of rTMS stimulations, and more research is needed on this issue. One previous study reported a doseresponseYrelated effect of rTMS and tinnitus suppression in the AC (24). The authors compared the effect of different pulse numbers of rTMS treatments (300, 900, and 1,800 pulses) on tinnitus suppression. According to their results, the treatment outcome was better for patients who received a larger number of stimulations. At least in the AC, it seems that a larger number of rTMS pulses produce a better treatment outcome. However, because combined prefrontal and temporal cortex rTMS has been introduced only recently, the adequate number of pulses for combined prefrontal and temporal cortex rTMS is even more obscure (25,26). In this study, we aimed to elucidate the difference in treatment outcome according to the number of pulses when performing a combined prefrontal and temporal cortex rTMS: we compared the treatment results between 6,000 and 12,000 pulses. To the best of our knowledge, this is the first study in the literature that has evaluated the difference in treatment outcome of combined prefrontal and temporal cortex rTMS according to the number of pulses. MATERIALS AND METHODS Patients Fourteen patients (aged 50.1 T 16.1 yr; 10 male, 4 female) with chronic essential tinnitus longer than 6 months were recruited in the study after giving written informed consents. Tinnitus severity was assessed before treatment using the Tinnitus Handicap Inventory (THI) and tinnitus-related self-rating Visual Analog Scale (VAS) of awareness, loudness, annoyance, and effect on daily life.

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Pretreatment questionnaire was checked at least two times in every subject, and their THI score was higher than 18. All participants had undergone and were dissatisfied with the general tinnitus treatment modalities such as antidepressants, hearing aids, noise generators, and TRT. Normal middle ear status was demonstrated by audiogram and otoscopy. Patients with a history of seizures or a suspected diagnosis of organic brain damage and patients with cardiac pacemakers or other electronic implants were excluded. Patients who had concomitant medication with antipsychotics and serious heart disease or other unstable major medical conditions were also excluded. The personal psychological status that can affect the tinnitus treatment outcome was evaluated by the validated Korean version of Beck’s Depression Inventory (BDI) for depression (27,28), State-Trait Anxiety Inventory (STAI) for anxiety (29), and Pittsburgh Sleep Quality Index (PSQI) for sleep quality (30,31). Patients were prospectively assigned to an rTMS program with 6,000 pulses (Group 1) or 12,000 pulses (Group 2). This study was approved by the institutional review board and was conducted according to the tenets of the Declaration of Helsinki.

rTMS Treatment Left primary AC and left DLPFC were targeted independently of handedness or tinnitus laterality. The patients were seated in a comfortable chair. An individualized head cap was used for each subject to identify and mark the international 10-20 electroencephalographic landmarks. On these caps, a line from T3 over C3 to Cz were individually measured and marked (32). AC and DLPFC were determined using the 10-20 electroencephalographic method proposed by Langguth et al. (33) in 2006. Magnetic stimulation was administered at a frequency of 1 Hz using a Medtronic system (MagPro; Medtronic, Minneapolis, MN, USA) with a Figure-eight coil (MCF-B65, 90-mm outer diameter; Medtronic). The center of the Figure-eight coil was positioned on the individually identified AC and DLPFC target and was held with a mechanical arm. Stimulation intensity was at 110% motor threshold. The resting motor threshold was determined for the right abductor pollicis brevis and defined as the lowest intensity at which at least four of eight consecutive motor evoked potentials were 50 KV in amplitude or higher while the investigated muscle was at rest (34). Audiovisual electromyographic feedback was provided to control for muscle relaxation. Train duration and off-time were 40 and 20 seconds. Six patients were assigned to a 6,000-pulse rTMS treatment program (Group 1) and received 1,000 pulses on the AC and 1,000 pulses on the DLPFC daily for three consecutive days. Eight patients were treated with a 12,000-pulse program (Group 2): 2,000 pulses on the AC and 1,000 pulses on the DLPFC daily for 4 days. For 11 patients, a structural T1-weighted high-resolution magnetic resonance (MR) image was acquired (3-T Magnetom Tim Trio Scanner; Siemens Medical Solutions, Erlangen, Germany). Individual subject’s MR image and Neuronavigation System (Cybermed; In2vision, Seoul, Korea) based on frameless stereotaxy and adapted for magnetic stimulation (35) enabled navigation of the coil on the surface of the skull over the targeted region. Because the primary AC is conventionally referred to as the first traverse gyrus of Heschl, we determined left Heschl’s gyrus within the individual data set according to anatomic landmarks (36) and the position of the center of the coil was marked on the scientific head cap.

Outcomes The effect of rTMS treatment was assessed with a change in THI scores (37) and tinnitus-related self-rating VAS on Otology & Neurotology, Vol. 36, No. 8, 2015

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FIG. 1. Longitudinal Tinnitus Handicap Inventory (THI) scores after rTMS treatment in group 1 (A) and group 2 (B). Thick black lines indicate group mean THI score, and thin gray lines indicate THI scores of each individual subject. In Group 1, none of the subjects experienced tinnitus reduction, and the mean posttreatment THI score was also not different from the pretreatment score. In Group 2, a significant decrease of THI scores was observed at 1 and 2 weeks after treatment compared with pretreatment THI score. *p G 0.05.

awareness, loudness, annoyance, and effect on daily life (38) of tinnitus at 1, 2, 4, 8, and 12 weeks after rTMS treatment. The psychological status of the subjects was also evaluated at 1, 2, and 3 months after treatment. Correlation between the change in THI/VAS scores and BDI/STAI/PSQI scores was assessed to determine whether the improvement in THI was the effect of psychological improvement.

Statistical Analysis Statistical analysis was performed with a nonparametric analysis using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA). Wilcoxon signed-rank test was used when comparing the outcome within each group, and Mann-Whitney U test was used when comparing the difference of the outcome between the two groups. In all analyses, p G 0.05 was considered statistically significant.

RESULTS Table 1 summarizes the patients’ characteristics of the two different rTMS treatment groups. There were no TABLE 1.

significant differences in sex, age, affected ear, duration of tinnitus, threshold of pure-tone audiometry, and pretreatment THI score. All patients in the two groups tolerated rTMS well and completed the study without any adverse or side effects. In Group 1, regardless of the time point, there was no statistically significant change of THI and VAS (Figs. 1A and 2A) after rTMS. On the contrary, a substantial decrease of THI scores was observed in Group 2. Compared with pretreatment baseline score (mean, 52.5 T 21.3), a significant reduction was already observed after 1 week of rTMS treatment (mean, 42.0 T 21.0, p = 0.010), which was even more pronounced after 2 weeks of rTMS application (mean, 37.8 T 16.6; p = 0.020). However, the THI scores started to increase again 4 weeks after treatment. After 4 weeks, there was no statistical difference compared with the baseline THI score (Fig. 1B). When improvement in THI scores was compared between Group 1 and Group 2, Group 2 showed a better outcome. The greatest

Demographics of the two groups

Group 1 (n = 6) Protocol

Group 2 (n = 8)

AC 1,000; DLPFC 1,000

AC 2,000; DLPFC 1,000

Total stimuli

6,000 Pulses 3 Consecutive Days

12,000 Pulses 4 Consecutive Days

p Value

Sex (M:F) Age (yr) Duration of illness (mo) Side (R:L:B) Pre-TMS THI score PTA threshold (3 tone average/4 k/8 k) BDI score STAI score (X-1/X-2) PSQI score

5:1 59.2 (13.4) 94.7 (144.6) 0:3:3 48.3 (19.9) 19.8 (15.3)/36.7 (23.4)/57.5 (23.6) 5.8 (5.6) 39.3 (4.8)/40.5 (6.1) 6.2 (1.5)

5:3 43.3 (15.0) 112.1 (141.6) 1:4:3 54.5 (19.8) 33.8 (31.4)/53.8 (27.1)/60.6 (23.5) 8.9 (5.0) 41.3 (5.2)/43.0 (8.2) 6.4 (3.3)

0.580 0.059 0.491 0.646 0.662 0.662/0.225/0.950 0.297 0.431/0.517 0.852

AC indicates auditory cortex; DLPFC, dorsolateral prefrontal cortex; THI, Tinnitus Handicap Inventory; PTA, pure-tone audiometry; BDI, Beck’s Depression Inventory; STAI, Stat-Trait Anxiety Inventory; PSQI, Pittsburgh Sleep Quality Index; ( ), standard deviation. Otology & Neurotology, Vol. 36, No. 8, 2015

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FIG. 2. Longitudinal Visual Analogue Scale (VAS) scores for tinnitus after rTMS treatment in Group 1 (A) and Group 2 (B). In Group 1, no treatment effect was observed even after rTMS treatment. In Group 2, significant decrease of VAS for tinnitus awareness and loudness was observed at 1-week follow-up. And the reduction of tinnitus loudness VAS score lasted until 4 weeks after treatment compared with the pretreatment VAS scores. VAS for tinnitus effect on daily life decreased significantly at 2 weeks after treatment. Error bar represents standard deviation, *p G 0.05.

difference in the outcome was observed at 2 weeks after rTMS, and it was statistically significant ( p = 0.028). Similarly, in Group 2, there was significant improvement of VAS for awareness ( p = 0.026), loudness of tinnitus ( p = 0.018), and its effect on daily life ( p = 0.041) at the first to second week after rTMS. Most of the treatment effect did not last long (G4 wk), but the VAS for tinnitus loudness showed a sustained decrease until 4 weeks ( p = 0.014) after rTMS and showed a significant decrease even at 12 weeks ( p = 0.047) after rTMS (Fig. 2B). When the BDI, STAI, and PSQI were followed up after the rTMS treatment, there was no significant change in each questionnaire outcome after 3 months in both groups (Table 2). DISCUSSION From this study, we observed a beneficial effect of rTMS on tinnitus suppression related to the total number of stimuli: a significant decrease of tinnitus (represented by THI and VAS) was observed in patients who received 12,000 pulses of rTMS but not in patients who received 6,000 pulses of rTMS. It seems that the total number of rTMS pulses is important in the outcome of tinnitus treatment and that a larger number of rTMS pulses are more beneficial. The good treatment outcome was also demonstrated on the individual subject level. Five (63%) of the eight patients in Group 2 showed a clinically significant reduction (97-point reduction) in THI score (39). On the contrary, in Group 1, no one showed a clinically significant improvement of THI or VAS score. It is also important to note that the treatment effect was clinically significant even after several weeks. In Group 2, VAS for tinnitus loudness showed a significant decrease until 4 weeks and showed a significant decrease even at 12 weeks. The mean THI score showed an improvement of more than 7 points compared with the baseline even at 8 weeks (mean THI improvement: 1 wk, 10.3 points; 2 wk, 16.7 points; 4 wk, 9.2 points; 8 wk, 9.3 points). From these results, it seems that frontal and temporal rTMS may have a beneficial effect on tinnitus treatment that lasts for several weeks when a sufficient number of stimuli are delivered to the patients.

It is not clear why the treatment outcome differed between the two groups. However, it may in part be explained by a dose-response relationship. That is, if rTMS does have a beneficial effect on tinnitus control, the treatment outcome should be better with a larger dose (greater number of pulses). We believe that the treatment outcome was good in Group 2 because the dose was sufficient, but it was bad in Group 1 because the dose did not reach a therapeutic level. Previous publications have also mentioned that multiple consecutive sessions of rTMS with larger numbers of pulses per session produce superior tinnitus suppression compared with single sessions or rTMS with smaller numbers of pulses delivered per session (25). For example, Kleinjung et al. (40), who used a total of 10,000 pulses (five sessions of 2,000 pulses), reported that 79% of patients experienced a reduction of tinnitus. This result was much better than that of earlier reports (response rate, 25%Y58%) that used fewer pulses (30Y200 pulses) per session (5,10,41,42). As for more direct evidence, Plewnia et al. (24) compared the effect of different pulse numbers of rTMS treatments (300, 900, 1,800 pulses) on tinnitus treatment. All patients experienced a reduction of tinnitus loudness, and this reduction was related to the number of stimuli applied. That is, patients who received a larger number of rTMS pulses showed a better treatment outcome. To the best of our knowledge, this is the only study that has directly elucidated a dose-response relationship between rTMS pulse TABLE 2.

Scores of questionnaires for psychological status 3 months after rTMS treatment

Scores BDI score STAI-X1 score STAI-X2 score PSQI score $THI score

Group 1 (n = 6) 3 Months After rTMS

Group 2 (n = 8) 3 Months After rTMS

p Value

6.8 (5.3) 38.8 (6.5) 41.3 (9.5) 5.0 (2.5) 3.8 (23)

6.6 (4.3) 38.4 (4.9) 41.3 (9.5) 5.4 (1.5) j9.5 (9.3)

0.881 0.941 0.304 0.824 0.366

$THI indicates post-rTMS THI score Y pre-rTMS THI score. BDI indicates Beck’s Depression Inventory; STAI, Stat-Trait Anxiety Inventory; PSQI, Pittsburgh Sleep Quality Index; THI, Tinnitus Handicap Inventory; ( ), standard deviation. Otology & Neurotology, Vol. 36, No. 8, 2015

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numbers and tinnitus treatment outcome. But, in the studies mentioned above, the non-AC such as the frontal cortex was not considered. Although not focused on tinnitus, there are also well-designed studies that have examined the doseresponse relationship of rTMS and the treatment outcome of other neurologic disorders. According to rTMS studies on major depression (43) and auditory hallucination (44,45), multiple sessions of rTMS across several days or weeks have demonstrated greater beneficial effects. rTMS studies on motor cortex excitability reported that the number of rTMS stimuli influenced the duration of post-rTMS effects (46,47). It seems that a larger number of rTMS stimuli can facilitate a greater improvement in various disorders including tinnitus. Although additional evidence is needed with more groups (groups with different pulse numbers) to confirm this assumption, our result may also reflect the dose-response relationship. With regard to the VAS of tinnitus, a remarkable reduction was observed for tinnitus loudness at 1, 2, and 4 weeks after treatment. It is also notable that six (75%) of the eight patients showed more than 3 points of decrease in VAS for loudness. A reduction of tinnitus loudness itself is considered to be a difference and superiority of rTMS treatment compared with other tinnitus therapies such as TRT and CBT. This is because TRT and CBT mainly focus on reducing the tinnitus-induced distress and not the tinnitus itself. For example, it has been reported that the numeric VAS on loudness of tinnitus does not change, even after a thorough CBT program (48Y51). In addition, randomized clinical trials on TRT reported that the intensity of tinnitus loudness does not change even in patients with a significant improvement in tinnitus-induced disability (52Y54). Meanwhile, two randomized trials that compared the treatment outcome of rTMS and sham stimulation demonstrated a significant reduction of tinnitus loudness only in the rTMS group (55,56), which is quite similar to our results. Khedr et al. (57) also reported a significant improvement in tinnitus loudness after rTMS, although the effect only lasted for a short time. From our results, it seems that when an adequate number of stimuli are delivered, rTMS is capable of controlling the tinnitus loudness itself as well as the tinnitus-induced distress. Tinnitus severity, duration of illness, and comorbid depression can be related to the treatment outcome of rTMS. Although some authors do not concur (58Y60), many studies have reported a better treatment outcome in patients with a shorter duration of illness (6,42,61). In our study, the duration of illness was similar between the two groups, excluding the possibility of this variable acting as a confounding factor. Pretreatment tinnitus severity represented by the preTMS THI score was also similar between the two groups. Psychological status of the subject may also affect the outcome (2,62). We evaluated our subjects using validated questionnaires for depression, anxiety, and sleep quality. No difference was proven between the two groups before treatment. The same questionnaires were also checked 3 months after treatment. We found no difference between the two groups even after the treatment. Because there was no difference in tinnitus severity, duration of illness, and

psychological status between the two groups, we believe that these already known prognostic factors were controlled in our study. And, consequently, the difference in outcome should probably be caused by the pulse number of rTMS. One of the major problems of rTMS in the treatment of tinnitus is that the term of validity is short. For example, the duration of tinnitus control with rTMS is reported to be within the range of a few days to several weeks (25). We also found a similar tendency: the treatment effect of rTMS started to deteriorate after 4 weeks. If the effect of rTMS can only last for a few weeks, it may be a crucial drawback and the clinical utility of rTMS in treatment of tinnitus may be quite limited. To overcome this problem, some authors have advocated that a booster or maintenance sessions of rTMS might increase treatment efficacy (63,64). For example, Langguth et al. (63) provided 10 booster sessions of rTMS in 12 subjects who showed a good response during the first rTMS trial. These subjects again reported a significant improvement in tinnitus severity after the booster sessions. We think that these booster sessions may be helpful and acceptable for longer-lasting tinnitus reduction, especially for patients who responded favorably to initial rTMS treatment. Another strategy to prolong the term of validity is stimulating more than two areas of the brain. Lehner et al. (21) compared the treatment effect between a single-site stimulation group (left temporal cortex) and a multisite stimulation group (three sites: left dorsolateral prefrontal, left temporoparietal, right temporoparietal cortex). Although the treatment outcome was similar between the two groups until Day 12, only the multisite stimulation group maintained the improvement up to 3 months. Patients who received single-site stimulation returned to baseline level. In our study, we also stimulated two sites (left temporal and left dorsolateral prefrontal cortex) but failed to maintain the treatment effect until 3 months. It is not clear whether adding the right temporoparietal cortex as the third site of stimulation is essential for the long-term effect. But considering that the treatment outcome was better with a larger number of stimulations, it may be that the treatment outcome was better in the multisite stimulation group because the total number of stimulations was greater. Further studies are needed on this issue. It seems that development of an rTMS protocol that can provide a longer duration of tinnitus control as well as a greater reduction of tinnitus may be important. Although the results are interesting, we should be careful with interpreting the treatment outcome of rTMS. Because the placebo effect in tinnitus patients is often a significant problem, our results may also have been affected by a placebo effect. For example, Group 1 visited the clinic for three consecutive days and Group 2 visited the clinic for four consecutive days. Although we do not believe that this factor had a significant effect, the 1-day difference may have played a role as a placebo. That is, longer and exhausted sessions of visits may have caused the subjects in Group 2 to have more confidence in their treatment program. A more essential problem is that rTMS itself may have a placebo effect. Because there was no sham treatment group in this study, we were not able to

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TINNITUS TREATMENT OUTCOME DIFFERENCES rigorously control this factor. However, many randomized controlled trials have already reported a significant treatment outcome of rTMS compared with the sham treatment group (4,6,25,40,59). Based on numerous prior publications, we believe that the good treatment outcome in Group 2 was caused by the treatment effect of rTMS, and that the poor outcome in Group 1 was caused by an insufficient number of TMS stimulations. But we admit that a sham treatment group is always needed to prove the treatment effect of rTMS. CONCLUSION Although rTMS is a potential treatment for chronic tinnitus and many researchers feel positive about the therapeutic effect, several key questions should be answered before coming into wide use: optimal site of stimulation, optimal frequency and intensity of stimulation, and optimal number of stimulations. In this study, we tried to determine whether the treatment outcome was different according to the number of stimulations, especially when stimulating two sites (AC and frontal cortex). A beneficial effect of rTMS on tinnitus suppression was found in the 12,000-pulse treatment group, whereas no effect was found in the 6,000pulse treatment group. Considering that all the other known prognostic factors were similar between the two groups, it may be that tinnitus reduction is dependent on the total number of stimuli applied. In addition, at least 12,000 pulses of rTMS may be recommended to achieve a favorable outcome. REFERENCES 1. George MS, Wassermann EM, Post RM. Transcranial magnetic stimulation: a neuropsychiatric tool for the 21st century. J Neuropsychiatry Clin Neurosci 1996;8:373Y82. 2. Melkerson MN. Special premarket 510(k) notification for NeuroStar TMS Therapy System for major depressive disorder. Food and Drug Administration 2008;12:16. Available at: http://www.accessdata.fda.gov/ cdrh_docs/pdf8/K083538.pdf. Accessed January 10, 2014. 3. Khedr EM, Rothwell JC, El-Atar A. One-year follow up of patients with chronic tinnitus treated with left temporoparietal rTMS. Eur J Neurol 2009;16:404Y8. 4. 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;78:857Y63. 5. Plewnia C, Bartels M, Gerloff C. Transient suppression of tinnitus by transcranial magnetic stimulation. Ann Neurol 2003;53:263Y6. 6. 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;79:212Y5. 7. Chung HK, Tsai CH, Lin YC, et al. Effectiveness of theta-burst repetitive transcranial magnetic stimulation for treating chronic tinnitus. Audiol Neurootol 2012;17:112Y20. 8. Vanneste S, Plazier M, van der Loo E, Ost J, Van de Heyning P, De Ridder D. Burst transcranial magnetic stimulation: which tinnitus characteristics influence the amount of transient tinnitus suppression? Eur J Neurol 2010;17:1141Y7. 9. Chen R, Classen J, Gerloff C, et al. Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 1997;48:1398Y403. 10. Folmer RL, Carroll JR, Rahim A, Shi Y, Hal Martin W. Effects of repetitive transcranial magnetic stimulation (rTMS) on chronic tinnitus. Acta Otolaryngol Suppl 2006;(556):96Y101.

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Difference in Tinnitus Treatment Outcome According to the Pulse Number of Repetitive Transcranial Magnetic Stimulation.

We aimed to compare the treatment result between 6,000 and 12,000 pulses of low-frequency repetitive transcranial magnetic stimulation (rTMS) and to e...
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