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A comparison study of repetitive transcranial magnetic stimulation for tinnitus treatment in an Asian population
Clinical Neurology and Neurosurgery 119 (2014) 96–99
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
A comparison study of repetitive transcranial magnetic stimulation for tinnitus treatment in an Asian population Y.L. Lo a,∗ , P.W.T. Cheong b , M. Wong c , S. Fook-Chong d , H.W. Yuen e , Y.M. Chan c a
Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Outram Road, Singapore 169608, Singapore Department of Neurology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore Department of Otolaryngorhinology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore d Department of Clinical Research, Singapore General Hospital, Outram Road, Singapore 169608, Singapore e Department of Otolaryngorhinology, Changi General Hospital, Singapore, Singapore b c
a r t i c l e
i n f o
Article history: Received 19 June 2013 Received in revised form 7 January 2014 Accepted 11 January 2014 Available online 25 January 2014 Keywords: Tinnitus Transcranial magnetic stimulation Trial Treatment
a b s t r a c t Background: Tinnitus, a subjective auditory perception of sounds or noise not triggered by external auditory stimuli, carries considerable morbidity. To date, pharmacological, physical or behavioral therapy is the mainstay of management. Methods: We compared repetitive transcranial magnetic stimulation (rTMS) of 1000 or 2000 stimulations/day at 1 Hz and 110% of the motor threshold for 5 consecutive days over the left auditory cortex. Ratings based on the Tinnitus Handicap Inventory (THI) rating scale were completed weekly for 4 weeks. None of the patients had significant hearing impairment. Results: All 28 patients (age range 21–72; 18 men) tolerated rTMS well and no adverse effects were observed. Analysis of variance (ANOVA) showed significant decrease in THI scores over the entire time period (F (1, 26) = 11.33, p = 0.002). At every weekly time point of evaluation, ANOVA with repeated measures demonstrated significantly lower THI score compared to baseline (p < 0.02 for all). RTMS treatment had resulted in tinnitus reduction in the range of 15–25% over the 4 week period. Separately, ANOVA also demonstrated significantly reducing THI for both the 1000 pulse (F (1, 14) = 4.8, p = 0.04) and 2000 pulse (F (1, 14) = 6.56, p = 0.02) rTMS treatment arms. Comparison of THI ratings between the 2 treatment arms did not result in significant difference (F (1, 26) = 1.48, p = 0.24). Conclusions: The present study has revalidated the efficacy and safety of rTMS for improving tinnitus up to 4 weeks post-treatment in Asians. However, there was no significant difference with THI evaluation between the 1000 pulse and 2000 pulse treatment arms. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Tinnitus, a subjective auditory perception of sounds or noise not triggered by external auditory stimuli, may adversely affect quality of life in 1–3% of the general population [1]. To date, pharmacological, physical or behavioral therapy is the mainstay of management. Animal data [2], and in vivo human brain imaging studies, suggest that tinnitus could be associated with maladaptive plastic brain reorganization at multiple brain levels following an initial cochlear dysfunction. Functional brain imaging changes include hyperactivity of primary auditory cortex (AC) and the secondary or associative cortex [3].
∗ Corresponding author. Tel.: +65 63265003; fax: +65 62203321. E-mail addresses: [email protected], [email protected] (Y.L. Lo). 0303-8467/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2014.01.012
More direct evidence for the role played by the AC in the perception/ of tinnitus comes from repetitive transcranial magnetic stimulation (rTMS), a technique that transiently modulates targeted areas engaged in processing of specific cortical functions. Most studies have employed rTMS to alleviate tinnitus at 1800–2000 pulses a day over a 1 or 2 week period [4,5]. In some cases, a single course of rTMS can result in improvement for up to 6 months [6], in tandem with SPECT imaging demonstrating reduced metabolism in the inferior left temporal lobe despite stimulation applied to the superior temporal cortex. In contrast, earlier studies utilizing only 200 pulses have also been effective in alleviating tinnitus for a very short duration [7], suggesting that shorter duration of rTMS may be investigated for this purpose. To this end, our previous experience point to a positive effect of short duration rTMS using 1000 pulses a day over 5 days using the Tinnitus Handicap Inventory (THI) evaluation [8]. Although well tolerated and convenient, this short duration rTMS protocol may prove inadequate for
Y.L. Lo et al. / Clinical Neurology and Neurosurgery 119 (2014) 96–99
97
Table 1 Summary of rTMS and tinnitus data. Patient
Pulses
Baseline THI
1 week THI
2 week THI
3 week THI
4 week THI
Intensity (dB)
Frequency (Hz)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 2000 2000 2000 2000 2000 2000 2000 2000 2000 2000 2000 2000 2000 2000
44 31 3 21 24 2 34 88 44 8 8 68 80 26 62 24 42 84 8 48 42 70 36 62 96 52 24 12
20 24 3 21 24 2 34 40 44 8 8 68 80 26 62 24 44 84 4 48 26 46 34 62 28 52 10 12
22 24 3 21 24 2 40 40 44 2 8 68 80 26 62 24 40 84 4 8 32 46 34 62 46 52 6 12
33 25 1 21 24 2 18 40 44 0 8 68 80 26 62 24 46 82 4 48 42 40 34 62 48 50 6 10
1 25 1 21 24 2 18 40 44 0 8 68 80 26 62 24 34 84 4 18 42 40 34 50 38 52 6 10
25 55 NM NM 70 NM 65 50/55 NM 50 50/75 NM NM NM 70/75 70/60 65 NM NM 15/10 NM NM NM 80/95 NM 95 NM NM
125 4000
8000 8000 8000/1000 6000 8000/8000
4000/4000 8000/6000 8000
12,000/12,000
8000/8000 8000
THI: tinnitus handicap inventory; NM: not matched; The first intensity and frequency refers to the right side.
modulating maladaptive plastic changes at the cortical level, and suggest the need for delivery of more stimuli. Here, we perform a comparative trial of rTMS with 1000 or 2000 pulses a day over 5 days for tinnitus treatment. 2. Methods With local ethics committee approval, we recruited 28 tinnitus patients in a prospective fashion, who gave written consent to participate in the study. The trial was registered with clinicaltrials.gov, with informed consent obtained from all subjects before participation. Patients were randomized into the 1000 or 2000 pulse treatment arms, consisting of 14 patients in each arm. Patients were randomized over a 2 year period with the main investigators (YMC, YLL) blinded to the treatment arm of each one enrolled. A detailed history was obtained, clinical examination performed and audiogram recorded. Audiometry and otoscopy were performed at enrolment. Tinnitus and acoustic evaluations were then collected by collaborators not directly involved with rTMS application. All patients had chronic tinnitus (>6 months duration) and no significant hearing impairment, defined as within 25 dB of the speech range. Repetitive TMS consisted of 1000 or 2000 stimulations/day at 1 Hz and 110% of the motor threshold for 5 consecutive days over the left AC. Using the International EEG system as anatomical reference for rTMS stimulation, surface marking of the stimulation point was located over the left scalp between T3 and midpoint of line joining C3/T5, with the coil handle directed backwards. Stimulation was delivered with a Medtronic (Medtronic Corporation, New York, USA) MagPro TMS unit connected to a Medtronic C-B60 figure-of-8 shaped coil. This coil positioning was similar to that in our previous study [5,8]. Upon recruitment, patients answered a baseline tinnitus rating questionnaire prior to treatment. All patients underwent 1 week
treatment consisting of 5 rTMS sessions, after which tinnitus rating was performed weekly for 4 weeks. The total study period was 5 weeks for each patient. Ratings based on the commonly used Tinnitus Handicap Inventory (THI) rating scale consisting of a 25 point questionnaire were completed weekly [9]. 3. Results All patients included had chronic tinnitus of >6 months duration. For the 1000 pulses group, 2 of the 14 patients had bilateral tinnitus between 50 and 75 dB, and were matched to 1000 Hz. Five other patients had unilateral tinnitus between 25 and 70 dB matched to 125 and 8000 Hz. The remaining patients were unmatchable. For the 2000 pulse group, 4 of the 14 patients had bilateral tinnitus between 15 and 95 dB and matched to 4000 and 12,000 Hz. Two others had tinnitus from 65 and 95 dB, both matched to 8000 Hz. The remaining patients were unmatchable. All 28 patients (age range 21–72; 18 men) tolerated rTMS well and no adverse effects were observed. There was no significant difference in age between the 2 treatment arms (Student’s t-test, p = 0.27). No significant differences were noted for the baseline THI of both groups (Mann–Whitney U test, p = 0.18). Overall, analysis of variance (ANOVA) showed significant decrease in THI scores over the entire time period (F (1, 26) = 11.33, p = 0.002). At every weekly time point of evaluation, ANOVA with repeated measures demonstrated significantly lower THI score compared to baseline (p < 0.02 for all). Separately, ANOVA also demonstrated significantly reducing THI for both the 1000 pulse (F (1, 14) = 4.8, p = 0.04) and 2000 pulse (F (1, 14) = 6.56, p = 0.02) rTMS treatment arms. Comparison of THI ratings between the 2 treatment arms, however, did not reach statistical significance (F (1, 26) = 1.48, p = 0.24). In terms of responders, the 1000 pulse arm resulted in an average of 64.3% THI reduction at 4 weeks, compared with 39.3% in the 2000 pulse arm. However, the difference was not statistically
98
Y.L. Lo et al. / Clinical Neurology and Neurosurgery 119 (2014) 96–99
80
1000 pulses
2000 pulses
70 60
THI
50 40 30 20 10 0
T0
T1
T2
T3
T4
T0
T1
T2
T3
T4
Fig. 1. Graphical illustration of reduction of mean THI scores from baseline (T0) to 4 weeks after rTMS treatment (T4). Error bars denote 1 standard deviation from the mean.
significant between the 2 arms, again suggesting equal efficacy of the two rTMS regimens. Bonferroni adjustment was done to maintain the type I error at 0.05 by testing the comparison of “THI” at each time point versus baseline at p significance level of 0.01 (=0.05/5). For data pooled over both rTMS arms, the p-values for each of the pairwise comparison of THI at time points 1, 2, 3 and 4 versus baseline were 0.024, 0.009, 0.012, and 0.003. Using Bonferroni correction significance testing at p < 0.01, we conclude that there is a significant drop from baseline value as from time 2 onwards. Test for linear trend in THI also confirmed an overall linear drop in both arms (p = 0.002). We did not find any correlation between laterality, intensity, pitch and matching with rTMS outcomes. There were no significant differences between the 2 treatment groups for both tinnitus intensity and frequency (t-test, p = 0.3 for both). Table 1 summarizes rTMS and tinnitus data. Fig. 1 summarizes our results in graphical format. 4. Discussion The current study is part of a local pilot trial to look at tolerability and safety as well, riding on our previous study [8] and Western literature showing efficacy. We also add that all patients have failed standard therapy, including counselling and use of masking devices. Lack of a placebo arm can be viewed as a limitation. However, the responder effect sizes in both treatment arms are beyond the 35% threshold accorded to the likelihood of a placebo effect [10]. This study was not extended to 3 months as it was primarily intended as a comparison of number of pulses delivered, and the likelihood of showing a difference between the 2 arms in terms of safety and efficacy would be extremely minute beyond the current time window. Plewnia et al. [11] had investigated use of rTMS in 9 patients with chronic tinnitus at 1 Hz for 5 min (300 pulses), 15 min (1500 pulses) and 30 min (3000 pulses in a single session), with PET to assess regional cerebral blood flow. It was determined that tinnitus reduction lasted up to 30 min, dependent upon the number of stimuli given. These data were consistent with our findings, whereby use of up to 2000 pulses a day over 5 days is efficacious up to 4 weeks. While our previous study has shown effects of rTMS on tinnitus reduction up to 4 weeks post treatment, it remains to be seen in future trials if similar regimens can be efficacious beyond this period. In the previous first study of rTMS in the treatment of tinnitus in an Asian population, we have shown that it is safe, well tolerated
and efficacious up to 4 weeks after the procedure [8], and corroborate European studies whereby implementing rTMS treatment can positively affect perception of tinnitus using the THI scale. To investigate if greater number of pulses resulted in a better clinical outcome, the present study has revalidated the efficacy of rTMS for improving tinnitus using 1000 pulses a day over 5 days. However, there was no significant difference with THI evaluation between the 1000 pulse and 2000 pulse treatment arms. The primary mechanism of rTMS here appears to be modulation of maladaptive cortical plasticity and tandem changes in hemodynamic of the auditory areas [12]. Lack of difference in efficacy demonstrated in this study suggests that net increase in rTMS pulses delivered may not be the crucial factor for better clinical outcome in the Asian setting. Although the exact reasons remain uncertain, it may be related to fundamental physiological differences between Asians and Western patients. It is therefore justifiable to explore other rTMS parameters in future clinical trials. This may comprise variation in frequency, intensity, pulse characteristics and coil positioning [13], all of which may be instrumental in modulating cortical excitability and plasticity [14]. Other treatment strategies, including transcranial direct current stimulation [15] and combination with pharmacological agents will also be of interest in the Asian setting. Theodoroff et al. [16] had critically reviewed that the heterogeneity of studies and small subject numbers render it not possible to perform a meta-analysis on the efficacy of rTMS treatment of tinnitus. Some investigators report the immediate short-term effect of rTMS, while others suggest a more lasting action. Phasic and burst simulations protocols were also considered. Recently, Lehner et al. [17] compared 1000–2000 pulse rTMS over the prefrontal or temporo-parietal areas with historical controls of 2000 pulse rTMS over the left temporal region in a multisite study distinct from ours. Cima et al. [18], in a randomized trial comparing usual (n = 247) and stepped specialized care (n = 245), have shown that the latter, consisting cognitive behavioural and retraining therapy, was more efficacious in managing tinnitus as evidenced by quality of life and tinnitus specific measurements. In the light of inherent heterogeneity of patients, subjective nature of perception and absence of widely accepted standards for outcome measurement, studies of tinnitus intervention are challenging to execute [19]. It may be relevant that future treatment of tinnitus leans towards an escalating care approach, whereby cognitive behavioural therapy as an initial method before more technical interventional such as rTMS be utilized. To this end, successful management of tinnitus necessitates a multidisciplinary approach. To date, our study, to the best of our knowledge, remains as the only to address the effect total rTMS pulses in managing tinnitus primarily. This can point the direction to future larger trials with newer stimulation protocols, powered to demonstrate significant effect in distinct patient groups. References [1] Coles RR. Epidemiology of tinnitus: (1) prevalence. J Laryngol Otol Suppl 1984;9:7–15. [2] Jackson P. A comparison of the effects of eighth nerve section with lidocaine on tinnitus. J Laryngol Otol 1985;99:663–6. [3] Arnold W, Bartenstein P, Oestreicher E, Römer W, Schwaiger M. Focal metabolic activation in the predominant left auditory cortex in patients suffering from tinnitus: 1 PET study with [18F] deoxyglucose. ORL J Otorhinolaryngol Relat Spec 1996;58:95–199. [4] Plewnia C, Reimold M, Najib A, Reischl G, Plontke SK, Gerloff C. Moderate therapeutic efficacy of positron emission tomography-navigated repetitive transcranial magnetic stimulation for chronic tinnitus: a randomized, controlled pilot study. J Neurol Neurosurg Psychiatry 2007;78:152–6. [5] Langguth B, Zowe M, Landgrebe M, Sand P, Kleinjung T, Binder H, et al. Transcranial magnetic stimulation for treatment of tinnitus: a new coil positioning method and first results. Brain Topogr 2006;18:241–7. [6] Marcondes RA, Sanchez TG, Kii MA, Ono CR, Buchpiguel CA, Langguth B, et al. Repetitive transcranial magnetic stimulation improves tinnitus in normal
Y.L. Lo et al. / Clinical Neurology and Neurosurgery 119 (2014) 96–99
[7]
[8]
[9] [10] [11]
[12]
hearing patients: a double-blind controlled, clinical and neuroimaging outcome study. Eur J Neurol 2010;17:28–44. De Ridder D, Verstraeten E, Van der Kelen K, De Mulder G, Sunaert S, Verlooy J, et al. Transcranial magnetic stimulation for tinnitus: influence of tinnitus duration on stimulation parameter choice and maximal tinnitus suppression. Otol Neurotol 2005;26:616–9. Ting SKS, Chan YM, Cheong PWT, Wong M, Fook-Chong S, Lo YL. Short duration repetitive transcranial magnetic stimulation for tinnitus treatment: a prospective Asian study. Clin Neurol Neurosurg 2011;113:556–8. Newman CW, Jacobson GP, Spitzer JB. Development of the tinnitus handicap inventory. Arch Otolaryngol Head Neck Surg 1996;122(2):143–8. Beecher HK. The powerful placebo. JAMA 1995;159:1602–6. Plewnia C, Reimold M, Najib A, Brehm B, Reischl G, Plontke SK, et al. Dose-dependent attenuation of auditory phantom perceptions (tinnitus) by PET-guided repetitive transcranial magnetic stimulation. Human Brain Mapp 2007;28:238–46. Smith JA, Mennemeier M, Bartel T, Chelette KC, Kimbrell T, Triggs W, et al. Repetitive transcranial magnetic stimulation for tinnitus: a pilot study. Laryngoscope 2007;117:529–34.
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[13] Langguth B, Kleinjung T, Landgrebe M, de Ridder D, Hajak G. RTMS for the treatment of tinnitus: the role of neuronavigation for coil positioning. Neurophysiol Clin 2010;40:45–58. [14] Kleinjung T, Eichammer P, Langguth B, Jacob P, Marienhagen J, Hajak G, et al. Long term effects of repetitive trabscranial magnetic stimulation (rTMS) in patients with chronic tinnitus. Otolaryngol Head Neck Surg 2005;132:566–9. [15] Garin P, Gilain C, Van damme JP, de Fays K, Jamart J, Ossemann M, et al. Short and long-lasting tinnitus relief induced by transcranial direct current stimulation. J Neurol 2011;258:1940–8. [16] Theodoroff SM, Folmer RL. Repetitive transcranial magnetic stimulation as a treatment for chronic tinnitus: a critical review. Oto Neurotol 2013;34: 199–208. [17] Lehner A, Schecklmann M, Poeppl TB, Kreuzer PM, Vielsmeier V, Rupprecht R, et al. Multisite rTMS for the treatment of chronic tinnitus: stimulation of the cortical tinnitus network: a pilot study. Brain Topogr 2013;26:501–10. [18] Cima RF, Maes IH, Joore MA, Scheyen DJ, Refaie A, Anteunis LJ, et al. Specialised treatment based on cognitive behavioural therapy versus usual care for tinnitus: a randomised controlled trial. Lancet 2012;379:1951–9. [19] Langguth B. Tinnitus: the end of therapeutic nihilism. Lancet 2012;379:1926–8.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
A comparison study of repetitive transcranial magnetic stimulation for tinnitus treatment in an Asian population Y.L. Lo a,∗ , P.W.T. Cheong b , M. Wong c , S. Fook-Chong d , H.W. Yuen e , Y.M. Chan c a
Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Outram Road, Singapore 169608, Singapore Department of Neurology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore Department of Otolaryngorhinology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore d Department of Clinical Research, Singapore General Hospital, Outram Road, Singapore 169608, Singapore e Department of Otolaryngorhinology, Changi General Hospital, Singapore, Singapore b c
a r t i c l e
i n f o
Article history: Received 19 June 2013 Received in revised form 7 January 2014 Accepted 11 January 2014 Available online 25 January 2014 Keywords: Tinnitus Transcranial magnetic stimulation Trial Treatment
a b s t r a c t Background: Tinnitus, a subjective auditory perception of sounds or noise not triggered by external auditory stimuli, carries considerable morbidity. To date, pharmacological, physical or behavioral therapy is the mainstay of management. Methods: We compared repetitive transcranial magnetic stimulation (rTMS) of 1000 or 2000 stimulations/day at 1 Hz and 110% of the motor threshold for 5 consecutive days over the left auditory cortex. Ratings based on the Tinnitus Handicap Inventory (THI) rating scale were completed weekly for 4 weeks. None of the patients had significant hearing impairment. Results: All 28 patients (age range 21–72; 18 men) tolerated rTMS well and no adverse effects were observed. Analysis of variance (ANOVA) showed significant decrease in THI scores over the entire time period (F (1, 26) = 11.33, p = 0.002). At every weekly time point of evaluation, ANOVA with repeated measures demonstrated significantly lower THI score compared to baseline (p < 0.02 for all). RTMS treatment had resulted in tinnitus reduction in the range of 15–25% over the 4 week period. Separately, ANOVA also demonstrated significantly reducing THI for both the 1000 pulse (F (1, 14) = 4.8, p = 0.04) and 2000 pulse (F (1, 14) = 6.56, p = 0.02) rTMS treatment arms. Comparison of THI ratings between the 2 treatment arms did not result in significant difference (F (1, 26) = 1.48, p = 0.24). Conclusions: The present study has revalidated the efficacy and safety of rTMS for improving tinnitus up to 4 weeks post-treatment in Asians. However, there was no significant difference with THI evaluation between the 1000 pulse and 2000 pulse treatment arms. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Tinnitus, a subjective auditory perception of sounds or noise not triggered by external auditory stimuli, may adversely affect quality of life in 1–3% of the general population [1]. To date, pharmacological, physical or behavioral therapy is the mainstay of management. Animal data [2], and in vivo human brain imaging studies, suggest that tinnitus could be associated with maladaptive plastic brain reorganization at multiple brain levels following an initial cochlear dysfunction. Functional brain imaging changes include hyperactivity of primary auditory cortex (AC) and the secondary or associative cortex [3].
∗ Corresponding author. Tel.: +65 63265003; fax: +65 62203321. E-mail addresses: [email protected], [email protected] (Y.L. Lo). 0303-8467/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.clineuro.2014.01.012
More direct evidence for the role played by the AC in the perception/ of tinnitus comes from repetitive transcranial magnetic stimulation (rTMS), a technique that transiently modulates targeted areas engaged in processing of specific cortical functions. Most studies have employed rTMS to alleviate tinnitus at 1800–2000 pulses a day over a 1 or 2 week period [4,5]. In some cases, a single course of rTMS can result in improvement for up to 6 months [6], in tandem with SPECT imaging demonstrating reduced metabolism in the inferior left temporal lobe despite stimulation applied to the superior temporal cortex. In contrast, earlier studies utilizing only 200 pulses have also been effective in alleviating tinnitus for a very short duration [7], suggesting that shorter duration of rTMS may be investigated for this purpose. To this end, our previous experience point to a positive effect of short duration rTMS using 1000 pulses a day over 5 days using the Tinnitus Handicap Inventory (THI) evaluation [8]. Although well tolerated and convenient, this short duration rTMS protocol may prove inadequate for
Y.L. Lo et al. / Clinical Neurology and Neurosurgery 119 (2014) 96–99
97
Table 1 Summary of rTMS and tinnitus data. Patient
Pulses
Baseline THI
1 week THI
2 week THI
3 week THI
4 week THI
Intensity (dB)
Frequency (Hz)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 1000 2000 2000 2000 2000 2000 2000 2000 2000 2000 2000 2000 2000 2000 2000
44 31 3 21 24 2 34 88 44 8 8 68 80 26 62 24 42 84 8 48 42 70 36 62 96 52 24 12
20 24 3 21 24 2 34 40 44 8 8 68 80 26 62 24 44 84 4 48 26 46 34 62 28 52 10 12
22 24 3 21 24 2 40 40 44 2 8 68 80 26 62 24 40 84 4 8 32 46 34 62 46 52 6 12
33 25 1 21 24 2 18 40 44 0 8 68 80 26 62 24 46 82 4 48 42 40 34 62 48 50 6 10
1 25 1 21 24 2 18 40 44 0 8 68 80 26 62 24 34 84 4 18 42 40 34 50 38 52 6 10
25 55 NM NM 70 NM 65 50/55 NM 50 50/75 NM NM NM 70/75 70/60 65 NM NM 15/10 NM NM NM 80/95 NM 95 NM NM
125 4000
8000 8000 8000/1000 6000 8000/8000
4000/4000 8000/6000 8000
12,000/12,000
8000/8000 8000
THI: tinnitus handicap inventory; NM: not matched; The first intensity and frequency refers to the right side.
modulating maladaptive plastic changes at the cortical level, and suggest the need for delivery of more stimuli. Here, we perform a comparative trial of rTMS with 1000 or 2000 pulses a day over 5 days for tinnitus treatment. 2. Methods With local ethics committee approval, we recruited 28 tinnitus patients in a prospective fashion, who gave written consent to participate in the study. The trial was registered with clinicaltrials.gov, with informed consent obtained from all subjects before participation. Patients were randomized into the 1000 or 2000 pulse treatment arms, consisting of 14 patients in each arm. Patients were randomized over a 2 year period with the main investigators (YMC, YLL) blinded to the treatment arm of each one enrolled. A detailed history was obtained, clinical examination performed and audiogram recorded. Audiometry and otoscopy were performed at enrolment. Tinnitus and acoustic evaluations were then collected by collaborators not directly involved with rTMS application. All patients had chronic tinnitus (>6 months duration) and no significant hearing impairment, defined as within 25 dB of the speech range. Repetitive TMS consisted of 1000 or 2000 stimulations/day at 1 Hz and 110% of the motor threshold for 5 consecutive days over the left AC. Using the International EEG system as anatomical reference for rTMS stimulation, surface marking of the stimulation point was located over the left scalp between T3 and midpoint of line joining C3/T5, with the coil handle directed backwards. Stimulation was delivered with a Medtronic (Medtronic Corporation, New York, USA) MagPro TMS unit connected to a Medtronic C-B60 figure-of-8 shaped coil. This coil positioning was similar to that in our previous study [5,8]. Upon recruitment, patients answered a baseline tinnitus rating questionnaire prior to treatment. All patients underwent 1 week
treatment consisting of 5 rTMS sessions, after which tinnitus rating was performed weekly for 4 weeks. The total study period was 5 weeks for each patient. Ratings based on the commonly used Tinnitus Handicap Inventory (THI) rating scale consisting of a 25 point questionnaire were completed weekly [9]. 3. Results All patients included had chronic tinnitus of >6 months duration. For the 1000 pulses group, 2 of the 14 patients had bilateral tinnitus between 50 and 75 dB, and were matched to 1000 Hz. Five other patients had unilateral tinnitus between 25 and 70 dB matched to 125 and 8000 Hz. The remaining patients were unmatchable. For the 2000 pulse group, 4 of the 14 patients had bilateral tinnitus between 15 and 95 dB and matched to 4000 and 12,000 Hz. Two others had tinnitus from 65 and 95 dB, both matched to 8000 Hz. The remaining patients were unmatchable. All 28 patients (age range 21–72; 18 men) tolerated rTMS well and no adverse effects were observed. There was no significant difference in age between the 2 treatment arms (Student’s t-test, p = 0.27). No significant differences were noted for the baseline THI of both groups (Mann–Whitney U test, p = 0.18). Overall, analysis of variance (ANOVA) showed significant decrease in THI scores over the entire time period (F (1, 26) = 11.33, p = 0.002). At every weekly time point of evaluation, ANOVA with repeated measures demonstrated significantly lower THI score compared to baseline (p < 0.02 for all). Separately, ANOVA also demonstrated significantly reducing THI for both the 1000 pulse (F (1, 14) = 4.8, p = 0.04) and 2000 pulse (F (1, 14) = 6.56, p = 0.02) rTMS treatment arms. Comparison of THI ratings between the 2 treatment arms, however, did not reach statistical significance (F (1, 26) = 1.48, p = 0.24). In terms of responders, the 1000 pulse arm resulted in an average of 64.3% THI reduction at 4 weeks, compared with 39.3% in the 2000 pulse arm. However, the difference was not statistically
98
Y.L. Lo et al. / Clinical Neurology and Neurosurgery 119 (2014) 96–99
80
1000 pulses
2000 pulses
70 60
THI
50 40 30 20 10 0
T0
T1
T2
T3
T4
T0
T1
T2
T3
T4
Fig. 1. Graphical illustration of reduction of mean THI scores from baseline (T0) to 4 weeks after rTMS treatment (T4). Error bars denote 1 standard deviation from the mean.
significant between the 2 arms, again suggesting equal efficacy of the two rTMS regimens. Bonferroni adjustment was done to maintain the type I error at 0.05 by testing the comparison of “THI” at each time point versus baseline at p significance level of 0.01 (=0.05/5). For data pooled over both rTMS arms, the p-values for each of the pairwise comparison of THI at time points 1, 2, 3 and 4 versus baseline were 0.024, 0.009, 0.012, and 0.003. Using Bonferroni correction significance testing at p < 0.01, we conclude that there is a significant drop from baseline value as from time 2 onwards. Test for linear trend in THI also confirmed an overall linear drop in both arms (p = 0.002). We did not find any correlation between laterality, intensity, pitch and matching with rTMS outcomes. There were no significant differences between the 2 treatment groups for both tinnitus intensity and frequency (t-test, p = 0.3 for both). Table 1 summarizes rTMS and tinnitus data. Fig. 1 summarizes our results in graphical format. 4. Discussion The current study is part of a local pilot trial to look at tolerability and safety as well, riding on our previous study [8] and Western literature showing efficacy. We also add that all patients have failed standard therapy, including counselling and use of masking devices. Lack of a placebo arm can be viewed as a limitation. However, the responder effect sizes in both treatment arms are beyond the 35% threshold accorded to the likelihood of a placebo effect [10]. This study was not extended to 3 months as it was primarily intended as a comparison of number of pulses delivered, and the likelihood of showing a difference between the 2 arms in terms of safety and efficacy would be extremely minute beyond the current time window. Plewnia et al. [11] had investigated use of rTMS in 9 patients with chronic tinnitus at 1 Hz for 5 min (300 pulses), 15 min (1500 pulses) and 30 min (3000 pulses in a single session), with PET to assess regional cerebral blood flow. It was determined that tinnitus reduction lasted up to 30 min, dependent upon the number of stimuli given. These data were consistent with our findings, whereby use of up to 2000 pulses a day over 5 days is efficacious up to 4 weeks. While our previous study has shown effects of rTMS on tinnitus reduction up to 4 weeks post treatment, it remains to be seen in future trials if similar regimens can be efficacious beyond this period. In the previous first study of rTMS in the treatment of tinnitus in an Asian population, we have shown that it is safe, well tolerated
and efficacious up to 4 weeks after the procedure [8], and corroborate European studies whereby implementing rTMS treatment can positively affect perception of tinnitus using the THI scale. To investigate if greater number of pulses resulted in a better clinical outcome, the present study has revalidated the efficacy of rTMS for improving tinnitus using 1000 pulses a day over 5 days. However, there was no significant difference with THI evaluation between the 1000 pulse and 2000 pulse treatment arms. The primary mechanism of rTMS here appears to be modulation of maladaptive cortical plasticity and tandem changes in hemodynamic of the auditory areas [12]. Lack of difference in efficacy demonstrated in this study suggests that net increase in rTMS pulses delivered may not be the crucial factor for better clinical outcome in the Asian setting. Although the exact reasons remain uncertain, it may be related to fundamental physiological differences between Asians and Western patients. It is therefore justifiable to explore other rTMS parameters in future clinical trials. This may comprise variation in frequency, intensity, pulse characteristics and coil positioning [13], all of which may be instrumental in modulating cortical excitability and plasticity [14]. Other treatment strategies, including transcranial direct current stimulation [15] and combination with pharmacological agents will also be of interest in the Asian setting. Theodoroff et al. [16] had critically reviewed that the heterogeneity of studies and small subject numbers render it not possible to perform a meta-analysis on the efficacy of rTMS treatment of tinnitus. Some investigators report the immediate short-term effect of rTMS, while others suggest a more lasting action. Phasic and burst simulations protocols were also considered. Recently, Lehner et al. [17] compared 1000–2000 pulse rTMS over the prefrontal or temporo-parietal areas with historical controls of 2000 pulse rTMS over the left temporal region in a multisite study distinct from ours. Cima et al. [18], in a randomized trial comparing usual (n = 247) and stepped specialized care (n = 245), have shown that the latter, consisting cognitive behavioural and retraining therapy, was more efficacious in managing tinnitus as evidenced by quality of life and tinnitus specific measurements. In the light of inherent heterogeneity of patients, subjective nature of perception and absence of widely accepted standards for outcome measurement, studies of tinnitus intervention are challenging to execute [19]. It may be relevant that future treatment of tinnitus leans towards an escalating care approach, whereby cognitive behavioural therapy as an initial method before more technical interventional such as rTMS be utilized. To this end, successful management of tinnitus necessitates a multidisciplinary approach. To date, our study, to the best of our knowledge, remains as the only to address the effect total rTMS pulses in managing tinnitus primarily. This can point the direction to future larger trials with newer stimulation protocols, powered to demonstrate significant effect in distinct patient groups. References [1] Coles RR. Epidemiology of tinnitus: (1) prevalence. J Laryngol Otol Suppl 1984;9:7–15. [2] Jackson P. A comparison of the effects of eighth nerve section with lidocaine on tinnitus. J Laryngol Otol 1985;99:663–6. [3] Arnold W, Bartenstein P, Oestreicher E, Römer W, Schwaiger M. Focal metabolic activation in the predominant left auditory cortex in patients suffering from tinnitus: 1 PET study with [18F] deoxyglucose. ORL J Otorhinolaryngol Relat Spec 1996;58:95–199. [4] Plewnia C, Reimold M, Najib A, Reischl G, Plontke SK, Gerloff C. Moderate therapeutic efficacy of positron emission tomography-navigated repetitive transcranial magnetic stimulation for chronic tinnitus: a randomized, controlled pilot study. J Neurol Neurosurg Psychiatry 2007;78:152–6. [5] Langguth B, Zowe M, Landgrebe M, Sand P, Kleinjung T, Binder H, et al. Transcranial magnetic stimulation for treatment of tinnitus: a new coil positioning method and first results. Brain Topogr 2006;18:241–7. [6] Marcondes RA, Sanchez TG, Kii MA, Ono CR, Buchpiguel CA, Langguth B, et al. Repetitive transcranial magnetic stimulation improves tinnitus in normal
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