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Transcranial magnetic stimulation (TMS) for treatment of chronic tinnitus: clinical effects
B. Langguth, G. Hajak, T. Kleinjung, A. Cacace & A.R. Møller (Eds.) Progress in Brain Research, Vol. 166 ISSN 0079-6123 Copyright r 2007 Elsevier B.V. All rights reserved
CHAPTER 34
Transcranial magnetic stimulation (TMS) for treatment of chronic tinnitus: clinical effects T. Kleinjung1,, T. Steffens1, A. Londero3 and B. Langguth2 1 Department of Otorhinolaryngology, University of Regensburg, Regensburg, Germany Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany 3 Service ORL et chirurgie cervicofaciale, hoˆpital europe´en Georges-Pompidou, Paris, France
2
Abstract: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method used to induce electrical current in the brain through impulses of strong magnetic fields applied externally. The technique can relieve tinnitus by modulating the excitability of neurons in the auditory cortex to decrease the hyperexcitability that is associated with generating the neural activity that causes some form of tinnitus. This chapter will review clinical studies using rTMS for the treatment of tinnitus. Keywords: tinnitus; transcranial neuronavigation; auditory cortex
magnetic
stimulation;
functional
imaging;
impulses of magnetic field. The lines of magnetic flux are oriented perpendicularly to the plane of the coil (Fig. 1). The electric current that is induced perpendicularly to the magnetic field can depolarize cells in the underlying brain area. Magnetic coils of different shapes are in use. Round coils are relatively powerful. The eightshaped coils generate more focal stimulation with a maximal current at the intersection of the two round parts (Hallett, 2000). Due to the rapid decline of the magnetic field with increasing distance from the coil, effective stimulation is limited to superficial cortical areas. When used for the suppression of tinnitus, a single magnetic impulse does not produce long-lasting effects. Application of multiple impulses, known as rTMS, can have effects that outlast the stimulation. Depending on stimulation parameters, rTMS can cause excitation or inhibition. Low frequency (r1 Hz) rTMS has been repeatedly shown to decrease cortical excitability (Chen et al., 1997; Hoffman and
Transcranial magnetic stimulation In 1985 Barker and colleagues showed that it was possible to depolarize neurons in the brain using external magnetic stimulation (Barker et al., 1985). Transcranial magnetic stimulation (TMS) involves applying strong impulses of magnetic fields with a duration of 100–300 ms and a strength of 1.5–2.0 T. Taking advantage of the fact that magnetic fields pass largely undistorted through the scalp and skull, repetitive TMS (rTMS) induces an electric current in the brain that can cause neuronal depolarization in the cortex of humans (Bohning et al., 2000). TMS is much less painful than the transcranial electrical stimulation (TES). For TMS, a brief (100–300 ms) impulse of a strong electrical current in the wires of a coil generates Corresponding author. Tel.: +49 9419449505; Fax: +49 941 944 9512; E-mail: [email protected] DOI: 10.1016/S0079-6123(07)66034-8
neuroplasticity;
359
360
Fig. 1. The principle of TMS with symbolized spread of magnetic fields perpendicular to the coil windings (Adapted with permission from Jaako Malmivuo and Robert Plonsey: Bioelectromagnetism — Principles and Applications of Bioelectric and Biomagnetic Fields, Oxford University Press, New York, 1995). (See Color Plate 34.1 in color plate section.)
Cavus, 2002), while high-frequency (5–20 Hz) rTMS increases the excitability of cortical neurons (Pascual-Leone et al., 1994). This is similar to the effect of direct electrical stimulation as demonstrated in animal studies (Post and Keck, 2001; Hoffman and Cavus, 2002). It was assumed that the effect of low frequency rTMS might be similar to long-term depression (LTD), which diminish the efficiency of intercellular connections, whereas high frequency rTMS might generate long-term potentiation (LTP) (Wang et al., 1996). In addition, rTMS can block or inhibit specific functions for brief periods after the stimulation, thus creating a similar effect as a transient functional lesion in the immediate post-stimulation period (Walsh and Rushworth, 1999). The effects of rTMS can outlast the time of stimulation, and the technique is used in the therapy of patients with different kinds of cortical dysfunction (Hallett, 2000).
Rationale for the use of rTMS in treatment of tinnitus There is increasing evidence that expression of neural plasticity is involved in tinnitus (Møller, 2001, 2003) (see Chapter 3). In particular, many
forms of chronic tinnitus are auditory phantom perceptions (Jastreboff, 1990) that might be a result of maladaptive attempts at cortical reorganization due to distorted sensory input (Møller, 2000). Re-organization may occur at several levels of the ascending auditory pathways and re-direction of auditory information (Chapter 3) may be involved in generating the abnormal neural activity that causes tinnitus and other abnormalities that often accompany severe tinnitus such as hyperacusis (Chapters 1 and 15), depression and phonophobia (Chapter 20). Signs of re-organization of the auditory cerebral cortex have been shown in magnetoencepholographic (MEG) studies. Some such studies have showed indications of a shift in the tonotopic map of the auditory cortex contralateral to the side to which the tinnitus is referred (Mu¨hlnickel et al., 1998). The results of positron emission tomography (PET) have shown signs of an abnormal asymmetry in the auditory cortices of some individuals with tinnitus indicating higher levels of spontaneous activity on the left side, independent on the side to which the tinnitus is referred (Arnold et al., 1996; Kleinjung et al., 2005; Langguth et al., 2006c). Other studies revealed changes in the middle temporal and temporoparietal regions as well as abnormal
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activation of frontal and limbic areas (Lockwood et al., 1998; Giraud et al., 1999; Mirz et al., 2000; Johnsrude et al., 2002). Since rTMS has the ability to modulate cortical activity focally, it seems likely to assume that application of rTMS to cortical auditory areas can alleviate tinnitus. Promising results have been obtained by the use of rTMS in the treatment of other disorders which have been associated with abnormal cortical activity such as auditory hallucinations (Hoffman et al., 2003, 2005; Langguth et al., 2006d), writer’s cramp (Siebner et al., 1999) and some obsessive compulsive disorders (Mantovani et al., 2006). It has been shown that trains of high-frequency rTMS (10–20 Hz) can induce an immediate, shortlasting interruption of tinnitus perception, whereas repeated stimulations with low-frequency (1 Hz) rTMS on several consecutive days can have a lasting beneficial effect on tinnitus and thus represent a potential therapeutic method. The designs and results of recent studies regarding the effect of rTMS on tinnitus are summarized in Table 1 (for review see Langguth et al., 2006b; Londero et al., 2006b; Pridmore et al., 2006). High frequency rTMS The hypothesis that the temporoparietal cortex plays a major role in the pathophysiology of some forms of tinnitus is supported by the results of studies using high frequency rTMS. In a study where high-frequency rTMS (10 Hz) was applied to eight scalp and four control positions in 14 individuals with chronic tinnitus (2 left-sided, 12 bilateral), a significant transient reduction of tinnitus was only observed when stimulation was administered to the left temporoparietal cortex (Plewnia et al., 2003) and suppression of the tinnitus occurred in 57% of the participants. In a larger series of 114 individuals with unilateral tinnitus, De Ridder et al. (2005) applied rTMS at frequencies between 1 and 20 Hz over the auditory cortex contralateral to the site of the tinnitus. Twenty-eight percent of the participants reported improvement (20–79% reduction in
subjective tinnitus perception) and 25% reported suppression (80–100% reduction in subjective tinnitus perception). The amount of tinnitus suppression was correlated positively with stimulation frequency and negatively with tinnitus duration, indicating the potential of TMS as a diagnostic tool for differentiating different forms of chronic tinnitus. These findings were confirmed in two other studies, Fregni et al. (2006) and Folmer et al. (2006) showing suppression of tinnitus in 42% and 40% of the participants. In addition, one of the studies (Fregni et al., 2006) found that the participants in their study who had significant reduction after rTMS also showed good response to anodal transcranial electrical current stimulation (dTCS). Low frequency rTMS Based on the success of 1 Hz rTMS in treating other conditions which appeared to be associated with increased cortical activity, low frequency rTMS has been proposed as a potential treatment for patients with disabling tinnitus (Eichhammer et al., 2003; Langguth et al., 2003). In these studies PET imaging and a neuronavigational system were used to focus the magnetic field on the site of maximum activation of the auditory cortex. Stimulation with 2000 magnetic impulses per day at an intensity of 110% of the motor threshold (MT) was used in three individuals with chronic tinnitus (2 left-sided, 1 bilateral) on five consecutive days in a sham-controlled cross-over design (Fig. 2). Active and sham treatments were separated by one week. Two patients reported improvement of the tinnitus by an average of 10.5 points on the tinnitus questionnaire (Goebel and Hiller, 1994), three days after active stimulation but not after sham treatment. Treatment success sustained for the following week. Patient 3 had moderate improvement during both sham and active TMS. As the first results were encouraging, the same authors (Kleinjung et al., 2005) conducted a sham-controlled TMS study on 14 patients using the identical study design. After five days of rTMS, a highly significant improvement of the tinnitus score was found whereas
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Table 1. Clinical effects of high- and low-frequency rTMS in tinnitus patientsa Authors
Number of patients, tinnitus laterality
Cortical target
(a) High-frequency rTMS in tinnitus patients Plewnia et al. 14 (12 bilateral, 2 Various scalp (2003) left-sided) positions according to 10–20 EEG system Fregni et al. 7 (bilateral) Left (2006) temporoparietal and mesial parietal areas, according to 10–20 EEG system Folmer et al. 15 (8 right-sided, 7 Left and right (2006) left-sided temporal cortex, according to 10–20 EEG system
Stimulation frequency, intensity
Sham control
Number and duration of trains
Results
10 Hz, 120% MTb
Control positions
1 train of 3 s (30 p.)b
8 responders for left temporal/temporoparietal stimulation
10 Hz, 120% MT
Sham coil
1 train of 3 s (30 p.)
3 responders for active stimulation of left temporoparietal target
10 Hz, 100% MT
Sham coil
5 trains of 3 s (150 p.) during 5 min
6 responders for active stimulation (5 left temporal cortex, 1 right temporal cortex), 2 responders for sham TMS 28 good and 32 partial suppression to active rTMS, 38 responders to sham rTMS; highest amount of tinnitus suppression for tinnitus duration up to 3 years at 20 Hz, in tinnitus for more than 3 years only partial suppression 1 responder for nonspecific stimulation site
De Ridder et al. (2005)
114 (106 unilateral, 8 bilateral)
Auditory cortex contralateral to tinnitus site
1–20 Hz, 90% MT
Control positions, coil perpendicular to the skull
1 train of 10–66 s (200 p.)
Londero et al. (2006a)
13 (10 left-sided, 3 right-sided)
Various positions (target areas determined by fMRI, as well as adjacent nonspecific cortical areas)
10 Hz, 120% MT
Control positions
1 train of 3 s (30 p.)
(b) Low-frequency rTMS in tinnitus patientsa Kleinjung et al. 14 (2 bilateral, 6 (2005) bilateral leftpredominant, 6 bilateral right predominant)
Londero et al. (2006a)
13 (10 left-sided, 3 right-sided)
Plewnia et al. (2007a)
9 (8 bilateral, 1 right-sided)
Langguth et al. (2006a)
28 (13 bilateral, 9 left-sided, 6 rightsided)
Plewnia et al. (2007b)
6 (all bilateral)
Kleinjung et al. (2007)
45 (30 bilateral, 8 left-sided, 7 rightsided)
a
Area of maximum tinnitus related PET activation (12 left and 2 right auditory cortex), neuronavigational system Auditory cortex contralateral to tinnitus: area of maximal fMRI activation Area of maximum tinnitus related PET activation, neuronavigational system
Left primary auditory cortex according to 10–20 EEG system Area of maximum tinnitus-related PET activation, neuronavigational system Left primary auditory cortex, neuronavigational system
1 Hz, 110% MTb
Sham coil
5 trains of 33 min (2000 p.)b on 5 following days
8 responders for active rTMS, 5 non-responders, 1 worsened patient, clinical improvement remained stable over a 6 months follow-up
1 Hz, 120% MT
(Occipital) control position
1 train of 20 min (1200 p.)
1 Hz, 120% MT
Non-specific (occipital) control position
3 trains of 5, 15, 30 min (300, 900, 1800 p.) with intertrain intervals of 30 min
1 Hz, 110% MT
None
1 Hz, 120% MT
Non-specific (occipital) control position
10 trains of 33 min (2000 p.) on 10 subsequent working days 20 trains of 30 min (1800 p.) on 20 subsequent working days
5 responders for the auditory target stimulation (effects remained from 2 to 10 days), 1 responder for the control position 6 responders for active rTMS with reduced tinnitus perception up to 30 min. Increasing amount of rTMS pulses causes more pronounced suppression of tinnitus, long tinnitus duration is correlated with less effect Significant change in tinnitus score until end of follow-up (13 weeks)
1 Hz, 110% MT
None
10 trains of 33 min (2000 p.) on 10 subsequent working days
5 responders for active rTMS, 2 weeks after treatment tinnitus perception returned to baseline 18 responders, they were characterized by shorter tinnitus duration and less hearing impairment
Case series of less than five patients were excluded from the table, but they are cited in the text. MT: motor threshold, p.: pulses.
b
363
364
Fig. 2. Laboratory setting: rTMS application in a tinnitus patient. The neuronavigational system (1) is used to determine the optimal position of the stimulation coil (2) in relation to the patient’s skull. (See Color Plate 34.2 in color plate section.)
the sham treatment did not show any significant changes. At 6 months after treatment, eight patients reported a sustained reduction in tinnitus perception reflected by an average reduction of the tinnitus score by 12.4 points in these eight patients. However, there was a high interindividual variability of the treatment effect, which led the authors into a new study that focussed on possible predictors for treatment response (Kleinjung et al., 2007). The main finding was a significant relationship between tinnitus duration and benefit from treatment. In accordance to other studies (De Ridder et al., 2005, 2006; Plewnia et al., 2007a), shorter tinnitus duration was related to a better treatment outcome. Normal hearing has been identified as a second predictor for favorable treatment outcome. Another study (Langguth et al., 2007a) investigated whether neuroimaging guided coil localization is a necessary condition for treatment success using low frequency rTMS in tinnitus patients. An easily applicable coil positioning method based
on the international 10–20 EEG system has been developed to target the left auditory cortex. The use of this coil positioning method improved the outcome of the rTMS, achieving significant reduction of tinnitus severity after 10 sessions of 1 Hz rTMS. Interestingly a case study, which investigated systematically the optimal coil position for tinnitus reduction over the temporal region, resulted in a very similar position, but on the right side (Fierro et al., 2006). Several other studies using low frequency rTMS in tinnitus patients offered new approaches in the assessment of tinnitus-related activity. Two studies by Plewnia et al. (2007a, b) investigated tinnitus patients, which responded to an intravenous bolus of lidocaine. By using [15O]H2O PET before and after lidocaine injection they identified changes in neuronal activity in the left middle and inferior temporal (BA 37), in the right temporoparietal cortex (BA 39) and in the posterior cingulum. Then single sessions of 5, 15 and 30 min low frequency rTMS were performed in a
365
sham-controlled design with the coil localized over the brain areas where lidocaine exerted maximal effects. Tinnitus reduction occurred in six out of eight subjects and lasted up to 30 min. There was a high variability of treatment results with better effects after longer duration of the stimulation, and in patients with shorter tinnitus duration. In a second study the same authors (Plewnia et al., 2007b) extended the effects of single sessions of 1 Hz rTMS into a therapeutic application by using a sham-controlled cross-over design with 2 2 weeks of rTMS applied over the area of maximum lidocaine-related activity change as determined by [15O]H2O PET. They reported moderate, but significant effects after active stimulation with high interindividual variability. However, 2 weeks after the last session treatment effects were no longer detectable. Another recent study (Londero et al., 2006a) compared high- and low-frequency rTMS in 13 patients. The target for stimulation was determined by functional magnetic resonance imaging (fMRI). Auditory stimulation with sounds similar to the individual subjective tinnitus sensation resulted in activation of the auditory cortex contralateral to the perceived tinnitus. Single short highfrequency rTMS trains over this area resulted only in one patient in any reliable tinnitus suppression. On the other hand after one long single train of low-frequency rTMS, the majority of investigated patients reported a reduction of their tinnitus. The duration of effects was highly variable, lasting up to 10 days. Further support for beneficial therapeutic effects of low frequency rTMS comes from a recent case study (Richter et al., 2006). 1 Hz rTMS was applied on five consecutive days (1800 pulses/ day) to a patient with a 30-year history of bilateral tinnitus. The coil was navigated to the area of increased cortical activation as identified by fluordeoxyglucose positron emission tomography (FDG PET)-CT (right primary auditory cortex). The patient reported beneficial changes in tinnitus perception persisting up to 4 weeks, and there was a statistically significant improvement in objective measures of attention and vigilance. Interestingly a PET study performed two days after rTMS treatment did not demonstrate any relevant changes as
compared to the baseline scan. The authors suggest that the persistent changes of neural activity after rTMS treatment might represent a predictor for the return of tinnitus perception.
Conclusion The results of an increasing number of published results of studies using rTMS indicate that treatment of tinnitus with this method is promising for patients with certain forms of tinnitus. However further clinical and neurobiological research is needed before rTMS can be considered to be a practical treatment option for routine use. Replication of the published results must be done in multicenter trials with many patients and longer follow-up periods in order to estimate the efficacy of rTMS for treatment of tinnitus. Further research is needed to define subgroups of patients that benefit most from rTMS and to optimize stimulation protocols.
Abbreviations FDG PET fMRI LTD LTP MEG MT PET TES TMS rTMS
fluordeoxyglucose positron emission tomography functional magnetic resonance imaging long-term depression long-term potentiation magnetoencephalography motor threshold positron emission tomography transcranial electrical stimulation transcranial magnetic stimulation repetitive transcranial magnetic stimulation
References Arnold, W., Bartenstein, P., Oestreicher, E., Romer, W. and Schwaiger, M. (1996) Focal metabolic activation in the predominant left auditory cortex in patients suffering from tinnitus: a PET study with [18F] deoxyglucose. ORL J. Otorhinolaryngol. Relat. Spec., 58: 195–199.
366 Barker, A.T., Jalinous, R. and Freeston, I.L. (1985) Non-invasive stimulation of the human motor cortex. Lancet, 1(8437): 1106–1107. Bohning, D.E., Shastri, A., McGavin, L., McConnell, K.A., Nahas, Z., Lorberbaum, J.P., Roberts, D.R. and George, M.S. (2000) Motor cortex brain activity induced by 1-Hz transcranial magnetic stimulation is similar in location and level to that for volitional movement. Invest. Radiol., 35: 676–683. Chen, R., Classen, J., Gerloff, C., Celnik, P., Wassermann, E.M., Hallett, M. and Cohen, L.G. (1997) Depression of motorcortex excitability by low-frequency transcranial magnetic stimulation. Neurology, 48: 1398–1403. De Ridder, D., De Mulder, G., Verstraeten, E., Van der Kelen, K., Sunaert, S., Smits, M., Kovacs, S., Verlooy, J., Van de Heyning, P. and Møller, A. (2006) Primary and secondary auditory cortex stimulation for intractable tinnitus. ORL J. Otorhinolaryngol. Relat. Spec., 68: 48–54. De Ridder, D., Verstraeten, E., Van der Kelen, K., De Mulder, G., Sunaert, S., Verlooy, J., Van de Heyning, P. and Møller, A. (2005) Transcranial magnetic stimulation for tinnitus: influence of tinnitus duration on stimulation parameter choice and maximal tinnitus suppression. Otol. Neurotol., 26: 616–619. Eichhammer, P., Langguth, B., Marienhagen, J., Kleinjung, T. and Hajak, G. (2003) Neuronavigated repetitive transcranial magnetic stimulation in patients with tinnitus: a short case series. Biol. Psychiatry, 54: 862–865. Fierro, M., Bobadilla, H., Cordoba-R, R., Vanegas, C. and Olarte, A. (2006) Repeated transcranial magnetic stimulation in a patient with bilateral chronic tinnitus. Rev. Neurol., 43: 758–759. Folmer, R.L., Carroll, J.R., Rahim, A., Shi, Y. and Martin, W.H. (2006) Effects of repetitive transcranial magnetic stimulation (rTMS) on chronic tinnitus. Acta Otolaryngol., 126: 96–101. Fregni, F., Marondes, R., Boggio, P.S., Marcolin, M.A., Rigonatti, S.P., Sanchez, T.G., Nitsche, N.A. and PascualLeone, A. (2006) Transient tinnitus suppression induced by repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Eur. J. Neurol., 13: 996–1001. Giraud, A.L., Chery-Croze, S., Fischer, G., Fischer, C., Vighetto, A., Gregoire, M.C., Lavenne, F. and Collet, L. (1999) A selective imaging of tinnitus. Neuroreport, 10: 1–5. Goebel, G. and Hiller, W. (1994) Tinnitus-Fragebogen (TF). HNO, 42: 166–172. Hallett, M. (2000) Transcranial magnetic stimulation and the human brain. Nature, 406: 147–150. Hoffman, R.E. and Cavus, I. (2002) Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders. Am. J. Psychiatry, 159: 1093–1102. Hoffman, R.E., Gueorguieva, R., Hawkins, K., Varanko, M., Boutros, N.N., Wu, Y.T., Carroll, K. and Krystal, J.H. (2005) Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators in a fifty patient sample. Biol. Psychiatry, 58: 97–104.
Hoffman, R.E., Hawkins, K.A., Gueorguieva, R., Boutros, N.N., Rachid, F., Carroll, K. and Krystal, J.H. (2003) Transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory hallucinations. Arch. Gen. Psychiatry, 60: 49–56. Jastreboff, P.J. (1990) Auditory phantom perception (tinnitus): mechanisms of generation and perception. Neurosci. Res., 8: 221–254. Johnsrude, I.S., Giraud, A.L. and Frackowiak, R.S.J. (2002) Functional imaging of the auditory system: the use of positron emission tomography. Audiol. Neurootol., 7: 251–276. Kleinjung, T., Eichhammer, P., Langguth, B., Jacob, P., Marienhagen, J., Hajak, G., Wolf, S.R. and Strutz, J. (2005) Long-term effects of repetitive transcranial magnetic stimulation (rTMS) in patients with chronic tinnitus. Otol. Head Neck Surg., 132: 566–569. Kleinjung, T., Steffens, T., Sand, P.G., Murthum, T., Hajak, G., Strutz, J., Langguth, B. and Eichhammer, P. (2007) Which tinnitus patients benefit from transcranial magnetic stimulation? Otol. Head Neck Surg. in press. Langguth, B., Eichhammer, P., Kreutzer, A., Maenner, P., Marienhagen, J., Kleinjung, T., Sand, P. and Hajak, G. (2006c) The impact of auditory cortex activity on characterizing and treating patients with chronic tinnitus: first results from a PET study. Acta Otolaryngol., 126: 84–88. Langguth, B., Eichhammer, P., Wiegand, R., Marienhagen, J., Maenner, P., Jacob, P. and Hajak, G. (2003) Neuronavigated rTMS in a patient with chronic tinnitus. Effects of 4 weeks treatment. Neuroreport, 14: 977–980. Langguth, B., Eichhammer, P., Zowe, M., Marienhagen, J., Spiessl, H. and Hajak, G. (2006d) Neuronavigated transcranial magnetic stimulation and auditory hallucinations in a schizophrenic patient: monitoring of neurobiological effects. Schizophr. Res., 84: 185–186. Langguth, B., Hajak, G., Kleinjung, T., Pridmore, S., Sand, P. and Eichhammer, P. (2006b) Repetitive transcranial magnetic stimulation and chronic tinnitus. Acta Otolaryngol., 126: 102–105. Langguth, B., Zowe, M., Landgrebe, M., Sand, P., Kleinjung, T., Binder, H., Hajak, G. and Eichhammer, P. (2006a) Transcranial magnetic stimulation for the treatment of tinnitus: a new coil positioning method and first results. Brain Topogr., 18: 241–247. Lockwood, A.H., Salvi, R.J., Coad, M.L., Towsley, M.L., Wack, D.S. and Murphy, B.W. (1998) the functional neuroanatomy of tinnitus: evidence for limbic system links and neural plasticity. Neurology, 50: 114–120. Londero, A., Langguth, B., De Riccer, D., Bonfils, P. and Lefaucheur, J.-P. (2006b) Repetitive transcranial magnetic stimulation (rTMS): a new therapeutic approach in subjective tinnitus? Neurophysiol. Clin., 26: 145–155. Londero, A., Lefaucheur, J.-P., Malvinaud, D., Brugie`res, P., Peignard, P., Nguyen, J.P., Avan, P. and Bonfils, P. (2006a) Magnetic stimulation of the auditory cortex for disabling tinnitus: preliminary results. Presse Med., 35: 200–206. Mantovani, A., Lisanby, S., Fulvio, P., Ulivelli, M., Castrogiovanni, P. and Rossi, S. (2006) Repetitive transcranial
367 magnetic stimulation in the treatment of obsessivecompulsive disorder (OCD) and Tourette’s syndrome. Int. J. Neuropsychopharmacol., 9: 95–100. Mirz, F., Pedersen, B., Ishizu, K. and Pedersen, C.B. (2000) Cortical networks subserving the perception of tinnitus — a PET study. Acta Otolaryngol. Suppl., 543: 241–243. Møller, A.R. (2000) Similarities between severe tinnitus and chronic pain. J. Am. Acad. Audiol., 11: 115–124. Møller, A.R. (2001) Symptoms and signs caused by neural plasticity. Neurol. Res., 23: 565–572. Møller, A.R. (2003) Pathophysiology of tinnitus. Otolaryngol. Clin. N. Am., 36: 249–266. Mu¨hlnickel, W., Elbert, T., Taub, E. and Flor, H. (1998) Reorganization of auditory cortex in tinnitus. Proc. Natl. Acad. Sci. U.S.A., 95: 10340–10343. Pascual-Leone, A., Valls-Solle, J., Wassermann, E.M. and Hallett, M. (1994) Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain, 117: 847–858. Plewnia, C., Bartels, M. and Gerloff, C. (2003) Suppressing tinnitus by repetitive transcranial magnetic stimulation to the temporoparietal cortex. Ann. Neurol., 253: 263–266. Plewnia, C., Reimold, M., Najib, A., Brehm, B., Reischl, G., Plontke, S. and Gerloff, C. (2007a) Dose-dependent attenuation of auditory phantom perception (tinnitus) by PET-guided repetitive transcranial magnetic stimulation. Hum. Brain Mapp., 28: 238–246.
Plewnia, C., Reimold, M., Najib, A., Reischl, G., Plontke, S.K. and Gerloff, C. (2007b) Moderate therapeutic efficacy of PET-navigated repetitive transcranial magnetic stimulation against chronic tinnitus, controlled pilot study. J. Neurol. Neurosurg. Psychiatry, 78: 152–156. Post, A. and Keck, M.E. (2001) Transcranial magnetic stimulation as a therapeutic tool in psychiatry: what do we know about the neurobiological mechanisms? J. Psychiatr. Res., 35: 193–215. Pridmore, S., Kleinjung, T., Langguth, B. and Eichhammer, P. (2006) Transcranial magnetic stimulation: potential treatment for tinnitus? Psychiatry Clin. Neurosci., 60: 133–138. Richter, G.T., Mennemeier, M., Bartel, T., Chelette, K.C., Kimbrell, T., Triggs, W. and Dornhoffer, J.L. (2006) Repetitive transcranial magnetic stimulation for tinnitus: a case study. Laryngoscope, 116: 1867–1872. Siebner, H., Tormos, J., Ceballos-Baumann, A., Auer, C., Catala, M.D., Conrad, B. and Pascual-Leone, A. (1999) Low-frequency repetitive transcranial magnetic stimulation of the motor cortex in writer’s cramp. Neurology, 52: 529–537. Walsh, V. and Rushworth, M. (1999) A primer of magnetic stimulation as a tool for neuropsychology. Neuropsychologia, 37: 125–135. Wang, H., Wang, X. and Scheich, H. (1996) LTD and LTP induced by transcranial magnetic stimulation in auditory cortex. Neuroreport, 112: 521–525.
Plate 13.1. Number of PubMed hits as a function of year for the search term ‘‘tinnitus’’ as well as a variety of other sensory conditions. Even though tinnitus is much more common in the general population than either ‘‘glaucoma’’ or ‘‘cataracts’’, the level of research produced on tinnitus is substantially less. Also surprising is the relatively flat research productivity on ‘‘deafness’’. (For B/W version, see page 148 in the volume.)
Plate 34.1. The principle of TMS with symbolized spread of magnetic fields perpendicular to the coil windings (Adapted with permission from Jaako Malmivuo and Robert Plonsey: Bioelectromagnetism — Principles and Applications of Bioelectric and Biomagnetic Fields, Oxford University Press, New York, 1995). (For B/W version, see page 360 in the volume.)
Plate 34.2. Laboratory setting: rTMS application in a tinnitus patient. The neuronavigational system (1) is used to determine the optimal position of the stimulation coil (2) in relation to the patient’s skull. (For B/W version, see page 364 in the volume.)
Plate 37.1. Representation of the pathways involved in somatic tinnitus modulation. We show the possible place where the transelectrical nerve stimulation could act and reduce tinnitus intensity. The effect of TENS in the somatic tinnitus could restore the dorsal cochlear nucleus (DCN) inhibition through the electrical stimulation of the somatic pathway. (For B/W version, see page 390 in the volume.)
CHAPTER 34
Transcranial magnetic stimulation (TMS) for treatment of chronic tinnitus: clinical effects T. Kleinjung1,, T. Steffens1, A. Londero3 and B. Langguth2 1 Department of Otorhinolaryngology, University of Regensburg, Regensburg, Germany Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany 3 Service ORL et chirurgie cervicofaciale, hoˆpital europe´en Georges-Pompidou, Paris, France
2
Abstract: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method used to induce electrical current in the brain through impulses of strong magnetic fields applied externally. The technique can relieve tinnitus by modulating the excitability of neurons in the auditory cortex to decrease the hyperexcitability that is associated with generating the neural activity that causes some form of tinnitus. This chapter will review clinical studies using rTMS for the treatment of tinnitus. Keywords: tinnitus; transcranial neuronavigation; auditory cortex
magnetic
stimulation;
functional
imaging;
impulses of magnetic field. The lines of magnetic flux are oriented perpendicularly to the plane of the coil (Fig. 1). The electric current that is induced perpendicularly to the magnetic field can depolarize cells in the underlying brain area. Magnetic coils of different shapes are in use. Round coils are relatively powerful. The eightshaped coils generate more focal stimulation with a maximal current at the intersection of the two round parts (Hallett, 2000). Due to the rapid decline of the magnetic field with increasing distance from the coil, effective stimulation is limited to superficial cortical areas. When used for the suppression of tinnitus, a single magnetic impulse does not produce long-lasting effects. Application of multiple impulses, known as rTMS, can have effects that outlast the stimulation. Depending on stimulation parameters, rTMS can cause excitation or inhibition. Low frequency (r1 Hz) rTMS has been repeatedly shown to decrease cortical excitability (Chen et al., 1997; Hoffman and
Transcranial magnetic stimulation In 1985 Barker and colleagues showed that it was possible to depolarize neurons in the brain using external magnetic stimulation (Barker et al., 1985). Transcranial magnetic stimulation (TMS) involves applying strong impulses of magnetic fields with a duration of 100–300 ms and a strength of 1.5–2.0 T. Taking advantage of the fact that magnetic fields pass largely undistorted through the scalp and skull, repetitive TMS (rTMS) induces an electric current in the brain that can cause neuronal depolarization in the cortex of humans (Bohning et al., 2000). TMS is much less painful than the transcranial electrical stimulation (TES). For TMS, a brief (100–300 ms) impulse of a strong electrical current in the wires of a coil generates Corresponding author. Tel.: +49 9419449505; Fax: +49 941 944 9512; E-mail: [email protected] DOI: 10.1016/S0079-6123(07)66034-8
neuroplasticity;
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Fig. 1. The principle of TMS with symbolized spread of magnetic fields perpendicular to the coil windings (Adapted with permission from Jaako Malmivuo and Robert Plonsey: Bioelectromagnetism — Principles and Applications of Bioelectric and Biomagnetic Fields, Oxford University Press, New York, 1995). (See Color Plate 34.1 in color plate section.)
Cavus, 2002), while high-frequency (5–20 Hz) rTMS increases the excitability of cortical neurons (Pascual-Leone et al., 1994). This is similar to the effect of direct electrical stimulation as demonstrated in animal studies (Post and Keck, 2001; Hoffman and Cavus, 2002). It was assumed that the effect of low frequency rTMS might be similar to long-term depression (LTD), which diminish the efficiency of intercellular connections, whereas high frequency rTMS might generate long-term potentiation (LTP) (Wang et al., 1996). In addition, rTMS can block or inhibit specific functions for brief periods after the stimulation, thus creating a similar effect as a transient functional lesion in the immediate post-stimulation period (Walsh and Rushworth, 1999). The effects of rTMS can outlast the time of stimulation, and the technique is used in the therapy of patients with different kinds of cortical dysfunction (Hallett, 2000).
Rationale for the use of rTMS in treatment of tinnitus There is increasing evidence that expression of neural plasticity is involved in tinnitus (Møller, 2001, 2003) (see Chapter 3). In particular, many
forms of chronic tinnitus are auditory phantom perceptions (Jastreboff, 1990) that might be a result of maladaptive attempts at cortical reorganization due to distorted sensory input (Møller, 2000). Re-organization may occur at several levels of the ascending auditory pathways and re-direction of auditory information (Chapter 3) may be involved in generating the abnormal neural activity that causes tinnitus and other abnormalities that often accompany severe tinnitus such as hyperacusis (Chapters 1 and 15), depression and phonophobia (Chapter 20). Signs of re-organization of the auditory cerebral cortex have been shown in magnetoencepholographic (MEG) studies. Some such studies have showed indications of a shift in the tonotopic map of the auditory cortex contralateral to the side to which the tinnitus is referred (Mu¨hlnickel et al., 1998). The results of positron emission tomography (PET) have shown signs of an abnormal asymmetry in the auditory cortices of some individuals with tinnitus indicating higher levels of spontaneous activity on the left side, independent on the side to which the tinnitus is referred (Arnold et al., 1996; Kleinjung et al., 2005; Langguth et al., 2006c). Other studies revealed changes in the middle temporal and temporoparietal regions as well as abnormal
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activation of frontal and limbic areas (Lockwood et al., 1998; Giraud et al., 1999; Mirz et al., 2000; Johnsrude et al., 2002). Since rTMS has the ability to modulate cortical activity focally, it seems likely to assume that application of rTMS to cortical auditory areas can alleviate tinnitus. Promising results have been obtained by the use of rTMS in the treatment of other disorders which have been associated with abnormal cortical activity such as auditory hallucinations (Hoffman et al., 2003, 2005; Langguth et al., 2006d), writer’s cramp (Siebner et al., 1999) and some obsessive compulsive disorders (Mantovani et al., 2006). It has been shown that trains of high-frequency rTMS (10–20 Hz) can induce an immediate, shortlasting interruption of tinnitus perception, whereas repeated stimulations with low-frequency (1 Hz) rTMS on several consecutive days can have a lasting beneficial effect on tinnitus and thus represent a potential therapeutic method. The designs and results of recent studies regarding the effect of rTMS on tinnitus are summarized in Table 1 (for review see Langguth et al., 2006b; Londero et al., 2006b; Pridmore et al., 2006). High frequency rTMS The hypothesis that the temporoparietal cortex plays a major role in the pathophysiology of some forms of tinnitus is supported by the results of studies using high frequency rTMS. In a study where high-frequency rTMS (10 Hz) was applied to eight scalp and four control positions in 14 individuals with chronic tinnitus (2 left-sided, 12 bilateral), a significant transient reduction of tinnitus was only observed when stimulation was administered to the left temporoparietal cortex (Plewnia et al., 2003) and suppression of the tinnitus occurred in 57% of the participants. In a larger series of 114 individuals with unilateral tinnitus, De Ridder et al. (2005) applied rTMS at frequencies between 1 and 20 Hz over the auditory cortex contralateral to the site of the tinnitus. Twenty-eight percent of the participants reported improvement (20–79% reduction in
subjective tinnitus perception) and 25% reported suppression (80–100% reduction in subjective tinnitus perception). The amount of tinnitus suppression was correlated positively with stimulation frequency and negatively with tinnitus duration, indicating the potential of TMS as a diagnostic tool for differentiating different forms of chronic tinnitus. These findings were confirmed in two other studies, Fregni et al. (2006) and Folmer et al. (2006) showing suppression of tinnitus in 42% and 40% of the participants. In addition, one of the studies (Fregni et al., 2006) found that the participants in their study who had significant reduction after rTMS also showed good response to anodal transcranial electrical current stimulation (dTCS). Low frequency rTMS Based on the success of 1 Hz rTMS in treating other conditions which appeared to be associated with increased cortical activity, low frequency rTMS has been proposed as a potential treatment for patients with disabling tinnitus (Eichhammer et al., 2003; Langguth et al., 2003). In these studies PET imaging and a neuronavigational system were used to focus the magnetic field on the site of maximum activation of the auditory cortex. Stimulation with 2000 magnetic impulses per day at an intensity of 110% of the motor threshold (MT) was used in three individuals with chronic tinnitus (2 left-sided, 1 bilateral) on five consecutive days in a sham-controlled cross-over design (Fig. 2). Active and sham treatments were separated by one week. Two patients reported improvement of the tinnitus by an average of 10.5 points on the tinnitus questionnaire (Goebel and Hiller, 1994), three days after active stimulation but not after sham treatment. Treatment success sustained for the following week. Patient 3 had moderate improvement during both sham and active TMS. As the first results were encouraging, the same authors (Kleinjung et al., 2005) conducted a sham-controlled TMS study on 14 patients using the identical study design. After five days of rTMS, a highly significant improvement of the tinnitus score was found whereas
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Table 1. Clinical effects of high- and low-frequency rTMS in tinnitus patientsa Authors
Number of patients, tinnitus laterality
Cortical target
(a) High-frequency rTMS in tinnitus patients Plewnia et al. 14 (12 bilateral, 2 Various scalp (2003) left-sided) positions according to 10–20 EEG system Fregni et al. 7 (bilateral) Left (2006) temporoparietal and mesial parietal areas, according to 10–20 EEG system Folmer et al. 15 (8 right-sided, 7 Left and right (2006) left-sided temporal cortex, according to 10–20 EEG system
Stimulation frequency, intensity
Sham control
Number and duration of trains
Results
10 Hz, 120% MTb
Control positions
1 train of 3 s (30 p.)b
8 responders for left temporal/temporoparietal stimulation
10 Hz, 120% MT
Sham coil
1 train of 3 s (30 p.)
3 responders for active stimulation of left temporoparietal target
10 Hz, 100% MT
Sham coil
5 trains of 3 s (150 p.) during 5 min
6 responders for active stimulation (5 left temporal cortex, 1 right temporal cortex), 2 responders for sham TMS 28 good and 32 partial suppression to active rTMS, 38 responders to sham rTMS; highest amount of tinnitus suppression for tinnitus duration up to 3 years at 20 Hz, in tinnitus for more than 3 years only partial suppression 1 responder for nonspecific stimulation site
De Ridder et al. (2005)
114 (106 unilateral, 8 bilateral)
Auditory cortex contralateral to tinnitus site
1–20 Hz, 90% MT
Control positions, coil perpendicular to the skull
1 train of 10–66 s (200 p.)
Londero et al. (2006a)
13 (10 left-sided, 3 right-sided)
Various positions (target areas determined by fMRI, as well as adjacent nonspecific cortical areas)
10 Hz, 120% MT
Control positions
1 train of 3 s (30 p.)
(b) Low-frequency rTMS in tinnitus patientsa Kleinjung et al. 14 (2 bilateral, 6 (2005) bilateral leftpredominant, 6 bilateral right predominant)
Londero et al. (2006a)
13 (10 left-sided, 3 right-sided)
Plewnia et al. (2007a)
9 (8 bilateral, 1 right-sided)
Langguth et al. (2006a)
28 (13 bilateral, 9 left-sided, 6 rightsided)
Plewnia et al. (2007b)
6 (all bilateral)
Kleinjung et al. (2007)
45 (30 bilateral, 8 left-sided, 7 rightsided)
a
Area of maximum tinnitus related PET activation (12 left and 2 right auditory cortex), neuronavigational system Auditory cortex contralateral to tinnitus: area of maximal fMRI activation Area of maximum tinnitus related PET activation, neuronavigational system
Left primary auditory cortex according to 10–20 EEG system Area of maximum tinnitus-related PET activation, neuronavigational system Left primary auditory cortex, neuronavigational system
1 Hz, 110% MTb
Sham coil
5 trains of 33 min (2000 p.)b on 5 following days
8 responders for active rTMS, 5 non-responders, 1 worsened patient, clinical improvement remained stable over a 6 months follow-up
1 Hz, 120% MT
(Occipital) control position
1 train of 20 min (1200 p.)
1 Hz, 120% MT
Non-specific (occipital) control position
3 trains of 5, 15, 30 min (300, 900, 1800 p.) with intertrain intervals of 30 min
1 Hz, 110% MT
None
1 Hz, 120% MT
Non-specific (occipital) control position
10 trains of 33 min (2000 p.) on 10 subsequent working days 20 trains of 30 min (1800 p.) on 20 subsequent working days
5 responders for the auditory target stimulation (effects remained from 2 to 10 days), 1 responder for the control position 6 responders for active rTMS with reduced tinnitus perception up to 30 min. Increasing amount of rTMS pulses causes more pronounced suppression of tinnitus, long tinnitus duration is correlated with less effect Significant change in tinnitus score until end of follow-up (13 weeks)
1 Hz, 110% MT
None
10 trains of 33 min (2000 p.) on 10 subsequent working days
5 responders for active rTMS, 2 weeks after treatment tinnitus perception returned to baseline 18 responders, they were characterized by shorter tinnitus duration and less hearing impairment
Case series of less than five patients were excluded from the table, but they are cited in the text. MT: motor threshold, p.: pulses.
b
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364
Fig. 2. Laboratory setting: rTMS application in a tinnitus patient. The neuronavigational system (1) is used to determine the optimal position of the stimulation coil (2) in relation to the patient’s skull. (See Color Plate 34.2 in color plate section.)
the sham treatment did not show any significant changes. At 6 months after treatment, eight patients reported a sustained reduction in tinnitus perception reflected by an average reduction of the tinnitus score by 12.4 points in these eight patients. However, there was a high interindividual variability of the treatment effect, which led the authors into a new study that focussed on possible predictors for treatment response (Kleinjung et al., 2007). The main finding was a significant relationship between tinnitus duration and benefit from treatment. In accordance to other studies (De Ridder et al., 2005, 2006; Plewnia et al., 2007a), shorter tinnitus duration was related to a better treatment outcome. Normal hearing has been identified as a second predictor for favorable treatment outcome. Another study (Langguth et al., 2007a) investigated whether neuroimaging guided coil localization is a necessary condition for treatment success using low frequency rTMS in tinnitus patients. An easily applicable coil positioning method based
on the international 10–20 EEG system has been developed to target the left auditory cortex. The use of this coil positioning method improved the outcome of the rTMS, achieving significant reduction of tinnitus severity after 10 sessions of 1 Hz rTMS. Interestingly a case study, which investigated systematically the optimal coil position for tinnitus reduction over the temporal region, resulted in a very similar position, but on the right side (Fierro et al., 2006). Several other studies using low frequency rTMS in tinnitus patients offered new approaches in the assessment of tinnitus-related activity. Two studies by Plewnia et al. (2007a, b) investigated tinnitus patients, which responded to an intravenous bolus of lidocaine. By using [15O]H2O PET before and after lidocaine injection they identified changes in neuronal activity in the left middle and inferior temporal (BA 37), in the right temporoparietal cortex (BA 39) and in the posterior cingulum. Then single sessions of 5, 15 and 30 min low frequency rTMS were performed in a
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sham-controlled design with the coil localized over the brain areas where lidocaine exerted maximal effects. Tinnitus reduction occurred in six out of eight subjects and lasted up to 30 min. There was a high variability of treatment results with better effects after longer duration of the stimulation, and in patients with shorter tinnitus duration. In a second study the same authors (Plewnia et al., 2007b) extended the effects of single sessions of 1 Hz rTMS into a therapeutic application by using a sham-controlled cross-over design with 2 2 weeks of rTMS applied over the area of maximum lidocaine-related activity change as determined by [15O]H2O PET. They reported moderate, but significant effects after active stimulation with high interindividual variability. However, 2 weeks after the last session treatment effects were no longer detectable. Another recent study (Londero et al., 2006a) compared high- and low-frequency rTMS in 13 patients. The target for stimulation was determined by functional magnetic resonance imaging (fMRI). Auditory stimulation with sounds similar to the individual subjective tinnitus sensation resulted in activation of the auditory cortex contralateral to the perceived tinnitus. Single short highfrequency rTMS trains over this area resulted only in one patient in any reliable tinnitus suppression. On the other hand after one long single train of low-frequency rTMS, the majority of investigated patients reported a reduction of their tinnitus. The duration of effects was highly variable, lasting up to 10 days. Further support for beneficial therapeutic effects of low frequency rTMS comes from a recent case study (Richter et al., 2006). 1 Hz rTMS was applied on five consecutive days (1800 pulses/ day) to a patient with a 30-year history of bilateral tinnitus. The coil was navigated to the area of increased cortical activation as identified by fluordeoxyglucose positron emission tomography (FDG PET)-CT (right primary auditory cortex). The patient reported beneficial changes in tinnitus perception persisting up to 4 weeks, and there was a statistically significant improvement in objective measures of attention and vigilance. Interestingly a PET study performed two days after rTMS treatment did not demonstrate any relevant changes as
compared to the baseline scan. The authors suggest that the persistent changes of neural activity after rTMS treatment might represent a predictor for the return of tinnitus perception.
Conclusion The results of an increasing number of published results of studies using rTMS indicate that treatment of tinnitus with this method is promising for patients with certain forms of tinnitus. However further clinical and neurobiological research is needed before rTMS can be considered to be a practical treatment option for routine use. Replication of the published results must be done in multicenter trials with many patients and longer follow-up periods in order to estimate the efficacy of rTMS for treatment of tinnitus. Further research is needed to define subgroups of patients that benefit most from rTMS and to optimize stimulation protocols.
Abbreviations FDG PET fMRI LTD LTP MEG MT PET TES TMS rTMS
fluordeoxyglucose positron emission tomography functional magnetic resonance imaging long-term depression long-term potentiation magnetoencephalography motor threshold positron emission tomography transcranial electrical stimulation transcranial magnetic stimulation repetitive transcranial magnetic stimulation
References Arnold, W., Bartenstein, P., Oestreicher, E., Romer, W. and Schwaiger, M. (1996) Focal metabolic activation in the predominant left auditory cortex in patients suffering from tinnitus: a PET study with [18F] deoxyglucose. ORL J. Otorhinolaryngol. Relat. Spec., 58: 195–199.
366 Barker, A.T., Jalinous, R. and Freeston, I.L. (1985) Non-invasive stimulation of the human motor cortex. Lancet, 1(8437): 1106–1107. Bohning, D.E., Shastri, A., McGavin, L., McConnell, K.A., Nahas, Z., Lorberbaum, J.P., Roberts, D.R. and George, M.S. (2000) Motor cortex brain activity induced by 1-Hz transcranial magnetic stimulation is similar in location and level to that for volitional movement. Invest. Radiol., 35: 676–683. Chen, R., Classen, J., Gerloff, C., Celnik, P., Wassermann, E.M., Hallett, M. and Cohen, L.G. (1997) Depression of motorcortex excitability by low-frequency transcranial magnetic stimulation. Neurology, 48: 1398–1403. De Ridder, D., De Mulder, G., Verstraeten, E., Van der Kelen, K., Sunaert, S., Smits, M., Kovacs, S., Verlooy, J., Van de Heyning, P. and Møller, A. (2006) Primary and secondary auditory cortex stimulation for intractable tinnitus. ORL J. Otorhinolaryngol. Relat. Spec., 68: 48–54. De Ridder, D., Verstraeten, E., Van der Kelen, K., De Mulder, G., Sunaert, S., Verlooy, J., Van de Heyning, P. and Møller, A. (2005) Transcranial magnetic stimulation for tinnitus: influence of tinnitus duration on stimulation parameter choice and maximal tinnitus suppression. Otol. Neurotol., 26: 616–619. Eichhammer, P., Langguth, B., Marienhagen, J., Kleinjung, T. and Hajak, G. (2003) Neuronavigated repetitive transcranial magnetic stimulation in patients with tinnitus: a short case series. Biol. Psychiatry, 54: 862–865. Fierro, M., Bobadilla, H., Cordoba-R, R., Vanegas, C. and Olarte, A. (2006) Repeated transcranial magnetic stimulation in a patient with bilateral chronic tinnitus. Rev. Neurol., 43: 758–759. Folmer, R.L., Carroll, J.R., Rahim, A., Shi, Y. and Martin, W.H. (2006) Effects of repetitive transcranial magnetic stimulation (rTMS) on chronic tinnitus. Acta Otolaryngol., 126: 96–101. Fregni, F., Marondes, R., Boggio, P.S., Marcolin, M.A., Rigonatti, S.P., Sanchez, T.G., Nitsche, N.A. and PascualLeone, A. (2006) Transient tinnitus suppression induced by repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Eur. J. Neurol., 13: 996–1001. Giraud, A.L., Chery-Croze, S., Fischer, G., Fischer, C., Vighetto, A., Gregoire, M.C., Lavenne, F. and Collet, L. (1999) A selective imaging of tinnitus. Neuroreport, 10: 1–5. Goebel, G. and Hiller, W. (1994) Tinnitus-Fragebogen (TF). HNO, 42: 166–172. Hallett, M. (2000) Transcranial magnetic stimulation and the human brain. Nature, 406: 147–150. Hoffman, R.E. and Cavus, I. (2002) Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders. Am. J. Psychiatry, 159: 1093–1102. Hoffman, R.E., Gueorguieva, R., Hawkins, K., Varanko, M., Boutros, N.N., Wu, Y.T., Carroll, K. and Krystal, J.H. (2005) Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators in a fifty patient sample. Biol. Psychiatry, 58: 97–104.
Hoffman, R.E., Hawkins, K.A., Gueorguieva, R., Boutros, N.N., Rachid, F., Carroll, K. and Krystal, J.H. (2003) Transcranial magnetic stimulation of left temporoparietal cortex and medication-resistant auditory hallucinations. Arch. Gen. Psychiatry, 60: 49–56. Jastreboff, P.J. (1990) Auditory phantom perception (tinnitus): mechanisms of generation and perception. Neurosci. Res., 8: 221–254. Johnsrude, I.S., Giraud, A.L. and Frackowiak, R.S.J. (2002) Functional imaging of the auditory system: the use of positron emission tomography. Audiol. Neurootol., 7: 251–276. Kleinjung, T., Eichhammer, P., Langguth, B., Jacob, P., Marienhagen, J., Hajak, G., Wolf, S.R. and Strutz, J. (2005) Long-term effects of repetitive transcranial magnetic stimulation (rTMS) in patients with chronic tinnitus. Otol. Head Neck Surg., 132: 566–569. Kleinjung, T., Steffens, T., Sand, P.G., Murthum, T., Hajak, G., Strutz, J., Langguth, B. and Eichhammer, P. (2007) Which tinnitus patients benefit from transcranial magnetic stimulation? Otol. Head Neck Surg. in press. Langguth, B., Eichhammer, P., Kreutzer, A., Maenner, P., Marienhagen, J., Kleinjung, T., Sand, P. and Hajak, G. (2006c) The impact of auditory cortex activity on characterizing and treating patients with chronic tinnitus: first results from a PET study. Acta Otolaryngol., 126: 84–88. Langguth, B., Eichhammer, P., Wiegand, R., Marienhagen, J., Maenner, P., Jacob, P. and Hajak, G. (2003) Neuronavigated rTMS in a patient with chronic tinnitus. Effects of 4 weeks treatment. Neuroreport, 14: 977–980. Langguth, B., Eichhammer, P., Zowe, M., Marienhagen, J., Spiessl, H. and Hajak, G. (2006d) Neuronavigated transcranial magnetic stimulation and auditory hallucinations in a schizophrenic patient: monitoring of neurobiological effects. Schizophr. Res., 84: 185–186. Langguth, B., Hajak, G., Kleinjung, T., Pridmore, S., Sand, P. and Eichhammer, P. (2006b) Repetitive transcranial magnetic stimulation and chronic tinnitus. Acta Otolaryngol., 126: 102–105. Langguth, B., Zowe, M., Landgrebe, M., Sand, P., Kleinjung, T., Binder, H., Hajak, G. and Eichhammer, P. (2006a) Transcranial magnetic stimulation for the treatment of tinnitus: a new coil positioning method and first results. Brain Topogr., 18: 241–247. Lockwood, A.H., Salvi, R.J., Coad, M.L., Towsley, M.L., Wack, D.S. and Murphy, B.W. (1998) the functional neuroanatomy of tinnitus: evidence for limbic system links and neural plasticity. Neurology, 50: 114–120. Londero, A., Langguth, B., De Riccer, D., Bonfils, P. and Lefaucheur, J.-P. (2006b) Repetitive transcranial magnetic stimulation (rTMS): a new therapeutic approach in subjective tinnitus? Neurophysiol. Clin., 26: 145–155. Londero, A., Lefaucheur, J.-P., Malvinaud, D., Brugie`res, P., Peignard, P., Nguyen, J.P., Avan, P. and Bonfils, P. (2006a) Magnetic stimulation of the auditory cortex for disabling tinnitus: preliminary results. Presse Med., 35: 200–206. Mantovani, A., Lisanby, S., Fulvio, P., Ulivelli, M., Castrogiovanni, P. and Rossi, S. (2006) Repetitive transcranial
367 magnetic stimulation in the treatment of obsessivecompulsive disorder (OCD) and Tourette’s syndrome. Int. J. Neuropsychopharmacol., 9: 95–100. Mirz, F., Pedersen, B., Ishizu, K. and Pedersen, C.B. (2000) Cortical networks subserving the perception of tinnitus — a PET study. Acta Otolaryngol. Suppl., 543: 241–243. Møller, A.R. (2000) Similarities between severe tinnitus and chronic pain. J. Am. Acad. Audiol., 11: 115–124. Møller, A.R. (2001) Symptoms and signs caused by neural plasticity. Neurol. Res., 23: 565–572. Møller, A.R. (2003) Pathophysiology of tinnitus. Otolaryngol. Clin. N. Am., 36: 249–266. Mu¨hlnickel, W., Elbert, T., Taub, E. and Flor, H. (1998) Reorganization of auditory cortex in tinnitus. Proc. Natl. Acad. Sci. U.S.A., 95: 10340–10343. Pascual-Leone, A., Valls-Solle, J., Wassermann, E.M. and Hallett, M. (1994) Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain, 117: 847–858. Plewnia, C., Bartels, M. and Gerloff, C. (2003) Suppressing tinnitus by repetitive transcranial magnetic stimulation to the temporoparietal cortex. Ann. Neurol., 253: 263–266. Plewnia, C., Reimold, M., Najib, A., Brehm, B., Reischl, G., Plontke, S. and Gerloff, C. (2007a) Dose-dependent attenuation of auditory phantom perception (tinnitus) by PET-guided repetitive transcranial magnetic stimulation. Hum. Brain Mapp., 28: 238–246.
Plewnia, C., Reimold, M., Najib, A., Reischl, G., Plontke, S.K. and Gerloff, C. (2007b) Moderate therapeutic efficacy of PET-navigated repetitive transcranial magnetic stimulation against chronic tinnitus, controlled pilot study. J. Neurol. Neurosurg. Psychiatry, 78: 152–156. Post, A. and Keck, M.E. (2001) Transcranial magnetic stimulation as a therapeutic tool in psychiatry: what do we know about the neurobiological mechanisms? J. Psychiatr. Res., 35: 193–215. Pridmore, S., Kleinjung, T., Langguth, B. and Eichhammer, P. (2006) Transcranial magnetic stimulation: potential treatment for tinnitus? Psychiatry Clin. Neurosci., 60: 133–138. Richter, G.T., Mennemeier, M., Bartel, T., Chelette, K.C., Kimbrell, T., Triggs, W. and Dornhoffer, J.L. (2006) Repetitive transcranial magnetic stimulation for tinnitus: a case study. Laryngoscope, 116: 1867–1872. Siebner, H., Tormos, J., Ceballos-Baumann, A., Auer, C., Catala, M.D., Conrad, B. and Pascual-Leone, A. (1999) Low-frequency repetitive transcranial magnetic stimulation of the motor cortex in writer’s cramp. Neurology, 52: 529–537. Walsh, V. and Rushworth, M. (1999) A primer of magnetic stimulation as a tool for neuropsychology. Neuropsychologia, 37: 125–135. Wang, H., Wang, X. and Scheich, H. (1996) LTD and LTP induced by transcranial magnetic stimulation in auditory cortex. Neuroreport, 112: 521–525.
Plate 13.1. Number of PubMed hits as a function of year for the search term ‘‘tinnitus’’ as well as a variety of other sensory conditions. Even though tinnitus is much more common in the general population than either ‘‘glaucoma’’ or ‘‘cataracts’’, the level of research produced on tinnitus is substantially less. Also surprising is the relatively flat research productivity on ‘‘deafness’’. (For B/W version, see page 148 in the volume.)
Plate 34.1. The principle of TMS with symbolized spread of magnetic fields perpendicular to the coil windings (Adapted with permission from Jaako Malmivuo and Robert Plonsey: Bioelectromagnetism — Principles and Applications of Bioelectric and Biomagnetic Fields, Oxford University Press, New York, 1995). (For B/W version, see page 360 in the volume.)
Plate 34.2. Laboratory setting: rTMS application in a tinnitus patient. The neuronavigational system (1) is used to determine the optimal position of the stimulation coil (2) in relation to the patient’s skull. (For B/W version, see page 364 in the volume.)
Plate 37.1. Representation of the pathways involved in somatic tinnitus modulation. We show the possible place where the transelectrical nerve stimulation could act and reduce tinnitus intensity. The effect of TENS in the somatic tinnitus could restore the dorsal cochlear nucleus (DCN) inhibition through the electrical stimulation of the somatic pathway. (For B/W version, see page 390 in the volume.)