The Laryngoscope C 2014 The American Laryngological, V
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Long-Term Effects of Repetitive Transcranial Magnetic Stimulation in Unilateral Tinnitus Hyun J. Kim, MD; Deog Y. Kim, MD, PhD; Hyo I. Kim, MD; Hee S. Oh, BSc; Nam S. Sim, MD; In S. Moon, MD, PhD Objectives/Hypothesis: We investigated the long-term effects of repetitive transcranial magnetic stimulation (rTMS) delivered to the temporoparietal junction and compared contralateral and ipsilateral application in patients with unilateral tinnitus. Study Design: Prospective study. Methods: A total of 61 patients with asymmetric hearing loss and nonpulsatile chronic tinnitus localized to the poorer ear who were refractory to medical treatment were enrolled. Patients were randomly assigned to one of two treatment groups: 1-Hz stimulation applied to the temporoparietal junction either ipsilaterally (n 5 30) or contralaterally (n 5 31) to the symptomatic ear. Changes in the Tinnitus Handicap Inventory (THI) scores and self-rating visual analog scores (VAS) for loudness, awareness, and annoyance were analyzed before and after treatment for 6 months. Improved patients were defined as those with decreases in their THI scores by >10 points and 20%. Results: There were no major complications or worsening of hearing. When analyzing the THI scores and VAS pre-rTMS and 6 months after rTMS, significant decreases were observed in patients overall (P .05). In addition, there was no significant difference in the rate of patients who improved between the ipsilateral (14 of 30) and contralateral (16 of 31) stimulation groups (P 5.800). The ipsilateral group showed a more rapid improvement than the contralateral group. Conclusions: Daily application of 1-Hz rTMS to the temporoparietal area is safe and has long-term beneficial effects. The laterality of stimulation is not the decisive factor. Key Words: Repetitive transcranial magnetic stimulation, tinnitus, contralateral, ipsilateral. Level of Evidence: 1b Laryngoscope, 124:2155–2160, 2014
INTRODUCTION Tinnitus is the perception of sound in the absence of external acoustic stimulation. Various hypotheses have been proposed regarding the generation of tinnitus, but the exact pathophysiology of tinnitus remains unknown. Jastreboff et al. suggested a neurophysiological model, postulating that the limbic and autonomic nervous systems are associated with processing tinnitus neuronal activities in addition to behavioral factors.1,2 If the habituation of brain reflexes is sustained, then subjective tinnitus is generated. That is, tinnitus may result from the activation of neural plasticity in parts of
Additional Supporting Information may be found in the online version of this article. From the Department and Research Institute of Rehabilitation Medicine (D.Y.K., H.I.K.), and Department of Otorhinolaryngology (H.J.K., H.S.O., N.S.S., I.S.M.), Yonsei University College of Medicine, Seoul, South Korea. This study was supported by a grant from the National Research Foundation of Korea (Project No: 2012R1A1A2004323). Editor’s Note: This Manuscript was accepted for publication April 14, 2014. The authors have no other funding, financial relationships, or conflicts of interest to disclose. H.J.K and D.Y.K contributed equally to this work. Send correspondence to In Seok Moon, MD, PhD, Department of Otorhinolaryngology, Yonsei University College of Medicine, 50 Yonseiro, Seodaemun-gu, Seoul 120-752, Korea. E-mail: [email protected] DOI: 10.1002/lary.24722
Laryngoscope 124: September 2014
the central nervous system (CNS) involved in auditory processing. Therefore, tinnitus can potentially be treated by interfering with abnormal activity of the CNS. Based on this hypothesis, neuromodulation has been developed as a treatment for tinnitus. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique of applying magnetic fields to the brain through the intact scalp.3 Repetitive magnetic fields generated by rTMS can reduce neural overactivity in cortical areas and can alleviate tinnitus.4 Specifically, rTMS of the auditory cortex has a positive effect in the treatment of tinnitus5; however, the rTMS protocols used in previous studies were variable, and most results were analyzed in the short-term responses. In addition, there is debate concerning which part of the hemisphere to treat. Previous studies suggested that stimulation contralateral to the side of tinnitus would have a greater effect on symptoms than ipsilateral stimulation.6,7 Conversely, Plewnia et al.8 suggested that rTMS applied to the left temporoparietal cortex was effective irrespective of the laterality of tinnitus. This study was performed to assess the long-term effects of rTMS in patients with unilateral hearing loss with ipsilateral tinnitus when rTMS was applied to the auditory cortex. Furthermore, we compared the outcomes of rTMS between ipsilateral and contralateral application. Kim et al.: rTMS in Unilateral Tinnitus
2155
MATERIALS AND METHODS Patients From March 2012 to February 2013, a total of 761 adults with tinnitus were seen at our clinic. We enrolled the patients who were suffering from tinnitus at least 6 months and they also carried out medical treatment over 2 months in our hospital. The hearing threshold was evaluated based on the average of pure tone audiogram results at 500, 1,000, 2,000, and 4,000 Hz. The inclusion criteria were 1) asymmetric hearing impairment (affected ear >10 dB loss compared to the unaffected ear), 2) subjective tinnitus localized to the poorer ear (Tinnitus Handicap Inventory [THI] > 38, duration > 6 months), and 3) refractory to medication (>2 months). The exclusion criteria were 1) acute onset, 2) pulsatile or clicking tinnitus, 3) bilateral symmetrical hearing, 4) good response to medication, and 5) refusal to participate. Initially, 68 adults (33 males, 35 females) were enrolled in this study. All patients had been medicated with Gingko biloba plus benzodiazepine or G. biloba plus a selective serotonin reuptake inhibitor for at least 2 months and were found to be refractory to medical treatment. To exclude retrocochlear lesion, we checked auditory brainstem response (ABR) latency in all patients. The patients with abnormal findings in ABR latency or who showed no response in ABR latency due to the severe hearing loss all underwent temporal magnetic resonance imaging. Patients were assigned randomly to the ipsilateral (n 5 34) or contralateral (n 5 34) group and treated prospectively after giving informed consent. The ipsilateral and contralateral groups consisted of patients whose tinnitus site (i.e., ear) was on the same or the opposite side as the rTMS stimulation. This study was approved by the institutional review board of Severance Hospital, Yonsei University Health System (4-2012-0361).
Tinnitus Treatment and rTMS Protocol rTMS of the temporoparietal junction was performed for 5 days, with stimulation applied ipsilaterally or contralaterally to the symptomatic ear. A MagPro TMS unit connected to a Medtronic C-B65 figure-of-eight coil was used to deliver the stimulation (Magstim, Whitland, UK). The resting motor threshold (RMT) of the motor cortex was determined for the opposite-side abductor digiti minimi; the RMT was defined as the lowest intensity that evoked motor-evoked potentials of 50 mV in at least five of 10 stimuli. For sham stimulation, the coil was placed in the same location at an angle of 90 to the scalp for 5 minutes. In this way, it generated a clicking sound of stimulation without actually stimulating the auditory cortex. Immediately after sham stimulation, THI was conducted, and we defined responders to sham as those who showed a change of THI score >20% of the initial score. None of the 68 patients enrolled in this study responded to the sham stimulation. rTMS was applied once daily to the temporoparietal junction at an intensity of 90% of the motor threshold measured that day and at a rate of 1 Hz for 600 pulses per session (9 seconds on, 1 seconds off, over 10 minutes). We followed the protocol of the early reports by the Antwerp group (Dirk De Ridder group).9 The group reported that there was close relation between immediate and long-term results. A similar result was reported in a study by Khedr et al.6
The severity of tinnitus was measured using the THI and a visual analog scale (VAS) for loudness, awareness, and annoyance. The THI and VAS were evaluated six times: before sham, right after sham, immediately after the session, 1 month after the session, 3 months after the session, and 6 months after the session (Fig. 1).10,11 Changes in the THI scores were classified as improved when there were decreases in THI scores by 10 points and 20% of initial score, as worsened when there were increases in the THI score by 10 points and 20%, and as unchanged when there were other changes. Favorable improvement was defined as THI scores that decreased by >20 points and 50% of initial score.
Statistical Analysis For statistical analysis, we used SPSS (v20.0; SPSS/IBM, Chicago, IL) and Origin (OriginLab, Northampton, MA) software for Windows. Paired t tests were used to compare the changes in parameters within each individual. The v2 test was applied to compare the nonparametric variables between the ipsilateral and contralateral groups. Two-sample t tests were used to compare parameters between groups. In all analyses, P
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Long-Term Effects of Repetitive Transcranial Magnetic Stimulation in Unilateral Tinnitus Hyun J. Kim, MD; Deog Y. Kim, MD, PhD; Hyo I. Kim, MD; Hee S. Oh, BSc; Nam S. Sim, MD; In S. Moon, MD, PhD Objectives/Hypothesis: We investigated the long-term effects of repetitive transcranial magnetic stimulation (rTMS) delivered to the temporoparietal junction and compared contralateral and ipsilateral application in patients with unilateral tinnitus. Study Design: Prospective study. Methods: A total of 61 patients with asymmetric hearing loss and nonpulsatile chronic tinnitus localized to the poorer ear who were refractory to medical treatment were enrolled. Patients were randomly assigned to one of two treatment groups: 1-Hz stimulation applied to the temporoparietal junction either ipsilaterally (n 5 30) or contralaterally (n 5 31) to the symptomatic ear. Changes in the Tinnitus Handicap Inventory (THI) scores and self-rating visual analog scores (VAS) for loudness, awareness, and annoyance were analyzed before and after treatment for 6 months. Improved patients were defined as those with decreases in their THI scores by >10 points and 20%. Results: There were no major complications or worsening of hearing. When analyzing the THI scores and VAS pre-rTMS and 6 months after rTMS, significant decreases were observed in patients overall (P .05). In addition, there was no significant difference in the rate of patients who improved between the ipsilateral (14 of 30) and contralateral (16 of 31) stimulation groups (P 5.800). The ipsilateral group showed a more rapid improvement than the contralateral group. Conclusions: Daily application of 1-Hz rTMS to the temporoparietal area is safe and has long-term beneficial effects. The laterality of stimulation is not the decisive factor. Key Words: Repetitive transcranial magnetic stimulation, tinnitus, contralateral, ipsilateral. Level of Evidence: 1b Laryngoscope, 124:2155–2160, 2014
INTRODUCTION Tinnitus is the perception of sound in the absence of external acoustic stimulation. Various hypotheses have been proposed regarding the generation of tinnitus, but the exact pathophysiology of tinnitus remains unknown. Jastreboff et al. suggested a neurophysiological model, postulating that the limbic and autonomic nervous systems are associated with processing tinnitus neuronal activities in addition to behavioral factors.1,2 If the habituation of brain reflexes is sustained, then subjective tinnitus is generated. That is, tinnitus may result from the activation of neural plasticity in parts of
Additional Supporting Information may be found in the online version of this article. From the Department and Research Institute of Rehabilitation Medicine (D.Y.K., H.I.K.), and Department of Otorhinolaryngology (H.J.K., H.S.O., N.S.S., I.S.M.), Yonsei University College of Medicine, Seoul, South Korea. This study was supported by a grant from the National Research Foundation of Korea (Project No: 2012R1A1A2004323). Editor’s Note: This Manuscript was accepted for publication April 14, 2014. The authors have no other funding, financial relationships, or conflicts of interest to disclose. H.J.K and D.Y.K contributed equally to this work. Send correspondence to In Seok Moon, MD, PhD, Department of Otorhinolaryngology, Yonsei University College of Medicine, 50 Yonseiro, Seodaemun-gu, Seoul 120-752, Korea. E-mail: [email protected] DOI: 10.1002/lary.24722
Laryngoscope 124: September 2014
the central nervous system (CNS) involved in auditory processing. Therefore, tinnitus can potentially be treated by interfering with abnormal activity of the CNS. Based on this hypothesis, neuromodulation has been developed as a treatment for tinnitus. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive technique of applying magnetic fields to the brain through the intact scalp.3 Repetitive magnetic fields generated by rTMS can reduce neural overactivity in cortical areas and can alleviate tinnitus.4 Specifically, rTMS of the auditory cortex has a positive effect in the treatment of tinnitus5; however, the rTMS protocols used in previous studies were variable, and most results were analyzed in the short-term responses. In addition, there is debate concerning which part of the hemisphere to treat. Previous studies suggested that stimulation contralateral to the side of tinnitus would have a greater effect on symptoms than ipsilateral stimulation.6,7 Conversely, Plewnia et al.8 suggested that rTMS applied to the left temporoparietal cortex was effective irrespective of the laterality of tinnitus. This study was performed to assess the long-term effects of rTMS in patients with unilateral hearing loss with ipsilateral tinnitus when rTMS was applied to the auditory cortex. Furthermore, we compared the outcomes of rTMS between ipsilateral and contralateral application. Kim et al.: rTMS in Unilateral Tinnitus
2155
MATERIALS AND METHODS Patients From March 2012 to February 2013, a total of 761 adults with tinnitus were seen at our clinic. We enrolled the patients who were suffering from tinnitus at least 6 months and they also carried out medical treatment over 2 months in our hospital. The hearing threshold was evaluated based on the average of pure tone audiogram results at 500, 1,000, 2,000, and 4,000 Hz. The inclusion criteria were 1) asymmetric hearing impairment (affected ear >10 dB loss compared to the unaffected ear), 2) subjective tinnitus localized to the poorer ear (Tinnitus Handicap Inventory [THI] > 38, duration > 6 months), and 3) refractory to medication (>2 months). The exclusion criteria were 1) acute onset, 2) pulsatile or clicking tinnitus, 3) bilateral symmetrical hearing, 4) good response to medication, and 5) refusal to participate. Initially, 68 adults (33 males, 35 females) were enrolled in this study. All patients had been medicated with Gingko biloba plus benzodiazepine or G. biloba plus a selective serotonin reuptake inhibitor for at least 2 months and were found to be refractory to medical treatment. To exclude retrocochlear lesion, we checked auditory brainstem response (ABR) latency in all patients. The patients with abnormal findings in ABR latency or who showed no response in ABR latency due to the severe hearing loss all underwent temporal magnetic resonance imaging. Patients were assigned randomly to the ipsilateral (n 5 34) or contralateral (n 5 34) group and treated prospectively after giving informed consent. The ipsilateral and contralateral groups consisted of patients whose tinnitus site (i.e., ear) was on the same or the opposite side as the rTMS stimulation. This study was approved by the institutional review board of Severance Hospital, Yonsei University Health System (4-2012-0361).
Tinnitus Treatment and rTMS Protocol rTMS of the temporoparietal junction was performed for 5 days, with stimulation applied ipsilaterally or contralaterally to the symptomatic ear. A MagPro TMS unit connected to a Medtronic C-B65 figure-of-eight coil was used to deliver the stimulation (Magstim, Whitland, UK). The resting motor threshold (RMT) of the motor cortex was determined for the opposite-side abductor digiti minimi; the RMT was defined as the lowest intensity that evoked motor-evoked potentials of 50 mV in at least five of 10 stimuli. For sham stimulation, the coil was placed in the same location at an angle of 90 to the scalp for 5 minutes. In this way, it generated a clicking sound of stimulation without actually stimulating the auditory cortex. Immediately after sham stimulation, THI was conducted, and we defined responders to sham as those who showed a change of THI score >20% of the initial score. None of the 68 patients enrolled in this study responded to the sham stimulation. rTMS was applied once daily to the temporoparietal junction at an intensity of 90% of the motor threshold measured that day and at a rate of 1 Hz for 600 pulses per session (9 seconds on, 1 seconds off, over 10 minutes). We followed the protocol of the early reports by the Antwerp group (Dirk De Ridder group).9 The group reported that there was close relation between immediate and long-term results. A similar result was reported in a study by Khedr et al.6
The severity of tinnitus was measured using the THI and a visual analog scale (VAS) for loudness, awareness, and annoyance. The THI and VAS were evaluated six times: before sham, right after sham, immediately after the session, 1 month after the session, 3 months after the session, and 6 months after the session (Fig. 1).10,11 Changes in the THI scores were classified as improved when there were decreases in THI scores by 10 points and 20% of initial score, as worsened when there were increases in the THI score by 10 points and 20%, and as unchanged when there were other changes. Favorable improvement was defined as THI scores that decreased by >20 points and 50% of initial score.
Statistical Analysis For statistical analysis, we used SPSS (v20.0; SPSS/IBM, Chicago, IL) and Origin (OriginLab, Northampton, MA) software for Windows. Paired t tests were used to compare the changes in parameters within each individual. The v2 test was applied to compare the nonparametric variables between the ipsilateral and contralateral groups. Two-sample t tests were used to compare parameters between groups. In all analyses, P
