Comment on “neuronavigated repetitive transcranial magnetic stimulation in patients with tinnitus: a short case series”: Reply

CORRESPONDENCE Comment on “Neuronavigated Repetitive Transcranial Magnetic Stimulation in Patients with Tinnitus: A Short Case Series” To the Editor: Eichhammer et al (2003) report on the attenuation of tinnitus by navigated repetitive transcranial magnetic stimulation (rTMS) in three patients. They found a reduction of tinnitus intensity in two of three patients after repeated sessions of low-frequency rTMS (1 Hz) to the left temporoparietal cortex. Because evidence is accumulating that maladaptive neuroplasticity in secondary (and primary) auditory cortex is a critical pathophysiologic element in some types of tinnitus (Lockwood et al 1998; Mu¨hlnickel et al 1998; Plewnia et al 2003), the reduction of hyperexcitability in those regions by low-frequency rTMS (Chen et al 1997) could represent a promising new tool for future clinical studies on tinnitus treatment. Together with a previous case report on one of these patients (Eichhammer et al 2003; Langguth et al 2003), this is the first documentation that lowfrequency rTMS can induce a lasting reduction of tinnitus. We believe that the therapeutic application of brain stimulation methods to tinnitus patients is a highly innovative and promising field. This is the reason that we feel obliged to add a couple of comments to the report by Eichhammer and colleagues. First, for physical reasons, TMS is a tool appropriate for the stimulation of superficial cortical regions rather than deeper brain structures (Epstein et al 1990). Therefore, we cannot follow one of the main conclusions of the authors, that their data indicate the participation of the primary auditory cortex (PAC) in tinnitus sensation. Although, in view of previous data (e.g., Mu¨hlnickel et al 1998) this is a rather likely concept, PAC is located in the medial portion of the first transverse temporal gyrus of Heschl, buried deep within the Sylvian fissure (Morosan et al 2001). Hence, with the rather low intensity of 110% of the motor threshold, a modulation of PAC activity is rather unlikely if not impossible. Owing to the decay of the magnetic field with distance from the coil, deeper targets like PAC might be reached with much higher stimulation intensities. It is much more likely that rTMS with the parameters described by Eichhammer and colleagues affects superficial cortical areas (Brodmann’s areas 42, 22, and 21). This would be in keeping with the results of a recent rTMS study that indicated a critical role of excess activation in higher-order auditory cortex for tinnitus perception (Plewnia et al 2003). Second, placebo control in innovative rTMS treatment studies is difficult. Tinnitus perception is subject to a strong placebo effect (Lockwood et al 2002). Therefore, an effective control condition is critical. In our experience, the amount of discomfort evoked by both noise and aversive muscle and nerve activation varies with the site of stimulation. Owing to coactivation of the facial and trigeminal nerve fibers, temporal stimulation sites as used in the study by Eichhammer et al (2003) are associated with marked unpleasant sensations, such as itches and uncomfortable muscle jerks. The placebo coils currently available are not suited to overcome this potential bias because they do not produce equivalent sensations (Lisanby et al 2001). In previous studies on the effects of rTMS on behavioral parameters (including tinnitus perception), this problem has been addressed by mapping multiple scalp positions, including aversive, noncortical areas, with rTMS (Cohen et al 1997; Gerloff et al 1998; Plewnia et al. 2003). The data from Eichhammer and colleagues are lacking critical 0006-3223/04/$30.00

controls, and the interpretation with respect to the role of the PAC must be questioned. Nevertheless, the results are stimulating and emphasize the need of controlled treatment trials with larger numbers of patients with tinnitus. Christian Plewnia Thomas Kammer Christian Gerloff Cortical Physiology Research Group Department of General Neurology Hertie Institute for Clinical Brain Research Eberhard-Karls University Medical School Hoppe-Seyler-Str. 3 72076 Tu¨bingen, Germany Chen R, Classen J, Gerloff C, Celnik P, Wassermann EM, Hallett M, Cohen LG (1997): Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 48:1398 –1403. Cohen LG, Celnik P, Pascual-Leone A, Corwell B, Falz L, Dambrosia J, et al (1997): Functional relevance of cross-modal plasticity in blind humans. Nature 389:180 –183. Eichhammer P, Langguth B, Marienhagen J, Kleinjung T, Hajak G (2003): Neuronavigated repetitive transcranial magnetic stimulation in patients with tinnitus: A short case series. Biol Psychiatry 54:862–865. Epstein CM, Schwartzberg DG, Davey KR, Sudderth DB (1990): Localizing the site of magnetic brain stimulation in humans. Neurology 40:666 –670. Gerloff C, Corwell B, Chen R, Hallett M, Cohen LG (1998): The role of the human motor cortex in the control of complex and simple finger movement sequences. Brain 121:1695–1709. Langguth B, Eichhammer P, Wiegand R, Marienhegen J, Maenner P, Jacob P, Hajak G (2003): Neuronavigated rTMS in a patient with chronic tinnitus. Effects of 4 weeks treatment. Neuroreport 23:977–980. Lisanby SH, Gutman D, Luber B, Schroeder C, Sackeim HA (2001): Sham TMS: Intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials. Biol Psychiatry 49:460 –463. Lockwood AH, Salvi RJ, Coad ML, Towsley ML, Wack DS, Murphy BW (1998): The functional neuroanatomy of tinnitus: Evidence for limbic system links and neural plasticity. Neurology 50:114 –120. Lockwood AH, Salvi RJ, Burkard RF (2002): Tinnitus. N Engl J Med 347:904 – 910. Morosan P, Rademacher J, Schleicher A, Amunts K, Schormann T, Zilles K (2001): Human primary auditory cortex: Cytoarchitectonic subdivisions and mapping into a spatial reference system. Neuroimage 13:684 –701. Mu¨hlnickel W, Elbert T, Taub E, Flor H (1998): Reorganization of auditory cortex in tinnitus. Proc Natl Acad Sci U S A 95:10340 –10343. Plewnia C, Bartels M, Gerloff C (2003): Transient suppression of tinnitus by transcranial magnetic stimulation. Ann Neurol 53:263–266.

doi:10.1016/j.biopsych.2004.03.014

Reply We want to thank Dr. Plewnia and colleagues for their critical comments, which offer the opportunity to point to the importance of interpreting rTMS effects in light of current neurobiological findings, including neurophysiologic and functional imaging data (Moller 2003; Siebner et al 2003). First, we assume participation of the primary auditory cortex (PAC) in mediating therapeutic effects of low-frequency rTMS on the basis of our functional imaging data obtained in patients with chronic tinnitus. [18F]deoxyglucose positron emission tomography (PET) gives rise to the conclusion that primarily patients with chronic tinnitus and markedly elevated activity of the PAC benefit from low-frequency rTMS (Eichhammer et al 2003). This hypothesis is supported by a variety of findings. The PAC is a critical component of a complex cortical network involved in the perception of tinnitus (Moller 2003; Mu¨hlnickel et al 1998). Improvement of tinnitus complaints are accompanied by a BIOL PSYCHIATRY 2004;55:1117–1118 © 2004 Society of Biological Psychiatry

1118 BIOL PSYCHIATRY 2004;55:1117–1118 decrease in metabolic activity of the PAC as measured by PET (Arnold et al 1996), and low-frequency rTMS seems to induce neurobiological processes that selectively reduce abnormal cortical hyperexcitability both locally and in functionally linked cortical areas (Hoffman and Cavus 2002). A correct interpretation of rTMS effects on chronic tinnitus has to integrate these data considering sustained changes of synaptic activity after lowfrequency TMS in subcortical brain regions (Siebner et al 2003). Therefore, we can not agree with Plewnia and colleagues’ attributing clinical effects of low-frequency rTMS solely to local cortical stimulation. In this context, transient suppression of tinnitus, as shown by these authors, might be based on a range of neurobiological effects in cortical and subcortical areas and not simply indicate a critical role of higher-order auditory cortex for tinnitus perception (Plewnia et al 2003). Nevertheless, we agree with these authors that TMS effects at the site of stimulation might contribute to the clinical results. Moreover, we believe that a variety of data point to a direct stimulation of the PAC by rTMS. Regarding the structural and functional architecture of the auditory cortex (Read et al 2002), the distance from the PAC to the TMS coil is comparable to that from the center of the hand knob to the lateral surface of the brain (approximately 2.5 cm; Yousry et al 1997), a cortical area that can be efficiently stimulated with TMS. Additionally, trains of rTMS pulses, as used in our therapeutic TMS study, are more effective than single pulses, owing to a temporal summation of stimulus effects (Gerloff et al 1997). With regard to the placebo stimulation in TMS treatment studies, we agree with Plewnia and colleagues that an optimal blinding option is currently not available, a problem that is also known in pharmaceutical studies (Stahl 2000). In agreement with Siebner et al (2003), we believe that the choice of an adequate placebo condition should be guided by pathophysiologic considerations and should not be based solely on the goal of maximizing unpleasant sensations. As has been pointed out by Plewnia and colleagues, aversive TMS stimulation of the mastoid (insertion of sternocleidomastoideus muscle) as a placebo condition in a sham-controlled tinnitus study could induce greater discomfort than any stimulation of other scalp positions (Plewnia et al 2003). However, stimulation of the skin in this region is known to efficiently relieve tinnitus (Engelberg and Bauer 1985; Moller 2003), thus changing the most unpleasant placebo condition to a possible effective verum stimulation for chronic tinnitus. Considering different placebo conditions for TMS treatment studies together with the complex pathophysiology of chronic tinnitus (Moller 2003), we decided to use a specially designed sham coil to exclude substantial cortical stimulation, as has been demonstrated by alternative placebo TMS methods (Lisanby et al 2001). For a better understanding of low-frequency rTMS in the treatment of chronic tinnitus, we further aimed to document neurobiological processes induced by this method. Using TMS as

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Correspondence a mapping method, Langguth et al (2003) demonstrated longlasting changes of cortical excitability associated with improvement of tinnitus beyond the immediate phase of rTMS treatment. On the basis of these findings, we believe that our study can help in the development of rTMS at 1 Hz as a “therapeutic tool in treating tinnitus perception,” as has been suggested by Plewnia et al (2003). Peter Eichhammer Berthold Langguth Go¨ran Hajak Department of Psychiatry and Psychotherapy University of Regensburg Universitaetsstrasse 84 Regensburg 93053, Germany Arnold W, Bartenstein P, Oestreicher E, Romer W, 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. Eichhammer P, Langguth B, Marienhagen J, Kleinjung T, Hajak G (2003): Neuronavigated repetitive transcranial magnetic stimulation in patients with tinnitus: A short case series. Biol Psychiatry 54:862–865. Engelberg M, Bauer W (1985): Transcutaneous electrical stimulation for tinnitus. Laryngoscope 95:1167–1173. Gerloff C, Corwell B, Chen R, Hallett M, Cohen LG (1997): Stimulation over the human supplementary motor area interferes with the organization of future elements in complex motor sequences. Brain 120:1587–1602. Hoffman RE, Cavus I (2002): Slow transcranial magnetic stimulation, longterm depotentiation, and brain hyperexcitability disorders. Am J Psychiatry 159:1093–1102. Langguth B, Eichhammer P, Wiegand R, Marienhegen J, Maenner P, Jacob P, Hajak G (2003): Neuronavigated rTMS in a patient with chronic tinnitus. Effects of 4 weeks treatment. Neuroreport 14:977–980. Lisanby SH, Gutman D, Luber B, Schroeder C, Sackeim HA (2001): Sham TMS: Intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials. Biol Psychiatry 49:460 –463. Moller AR (2003): Pathophysiology of tinnitus. Otolaryngol Clin North Am 36:249 –266, v–vi. Mu¨hlnickel W, Elbert T, Taub E, Flor H (1998): Reorganization of auditory cortex in tinnitus. Proc Natl Acad Sci U S A 95:10340 –10343. Plewnia C, Bartels M, Gerloff C (2003): Transient suppression of tinnitus by transcranial magnetic stimulation. Ann Neurol 53:263–266. Read HL, Winer JA, Schreiner CE (2002): Functional architecture of auditory cortex. Curr Opin Neurobiol 12:433–440. Siebner HR, Filipovic SR, Rowe JB, Cordivari C, Gerschlager W, Rothwell JC, et al (2003): Patients with focal arm dystonia have increased sensitivity to slow-frequency repetitive TMS of the dorsal premotor cortex. Brain 126:2710 –2725. Stahl SM (2000): Essential Psychopharmacology: Cambridge, United Kingdom: Cambridge University Press. Yousry TA, Schmid UD, Alkadhi H, Schmidt D, Peraud A, Buettner A, Winkler P (1997): Localization of the motor hand area to a knob on the precentral gyrus. A new landmark. Brain 120:141–157.

doi:10.1016/j.biopsych.2004.03.015