Brain Stimulation (2008) 1, 192–205 www.brainstimjrnl.com Controversy: Does repetitive transcranial magnetic stimulation/ transcranial direct current stimulation show efficacy in treating tinnitus patients? Berthold Langguth, MDa, Dirk de Ridder, MD, PhDb, John L. Dornhoffer, MDc, Peter Eichhammer, MDa, Robert L. Folmer, PhDd, Elmar Frank, MDa, Felipe Fregni, MD, PhDe, Christian Gerloff, MDf, Eman Khedr, MDg, Tobias Kleinjung, MDh, Michael Landgrebe, MDa, Scott Lee, MDi, Jean-Pascal Lefaucheur, MDj, Alain Londero, MDk, Renata Marcondes, MDl, Aage R. Moller, PhDm, Alvaro Pascual-Leone, MDe, Christian Plewnia, MDn, Simone Rossi, MDo, Tanit Sanchez, MDl, Philipp Sand, MDa, Winfried Schlee, Dipl Pyschp, Thomas Steffens, PhDg, Paul van de Heyning, MD, PhDq, Goeran Hajak, MDa aDepartments of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany bBRAI2N & Department of Neurosurgery, University of Antwerp, Antwerp, Belgium cDepartment of Otolaryngology, University of Arkansas for Medical Sciences, Little Rock, Arkansas dNational Center for Rehabilitative Auditory Research, VA Medical Center, Portland, Oregon eBerenson-Allen Center for Noninvasive Brain Stimulation, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts fDepartment of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg-Eppendorf, Germany gDepartment of Neurology, Faculty of Medicine, Assiut University, Assiut, Egypt hDepartment of Otorhinolaryngology, University of Regensburg, Regensburg, Germany iDivision of Otolaryngology, Head and Neck Surgery, Albany Medical College, Albany, New York jDepartment of Physiology, Henri-Mondor Hospital, Creteil, France kEuropean Hospital G. Pompidou, Depatment of ORL and CCF, Paris, France lDepartment of Otolaryngology and Psychiatry, Clinics Hospital, University of Sao Paulo, Sao Paulo, Brazil mSchool of Behavioral and Brain Science, University of Texas at Dallas, Dallas, Texas nDepartment of Psychiatry and Psychotherapy, University Hospital Tuebingen, Tuebingen, Germany oDepartment of Neuroscience, Neurology Section, University of Siena, Italy pDepartment of Psychology, University of Konstanz, Konstanz, Germany qBRAI2N & Department of ENT and Head and Neck Surgery, University of Antwerp, Belgium Address reprint requests to: Dr. Berthold Langguth, Department of Psychiatry, University of Regensburg, Universitaetsstraße 84, 93053 Regensburg, Germany. E-mail address: [email protected] Submitted April 30, 2008; revised May 29, 2008. Accepted for publication June 6, 2008. 1935-861X/08/$ -see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.brs.2008.06.003 Consensus tinnitus 193 Background Tinnitus affects 10% of the population, its pathophysiology remains incompletely understood, and treatment is elusive. Functional imaging has demonstrated a relationship between the intensity of tinnitus and the degree of reorganization in the auditory cortex. Experimental studies have further shown that tinnitus is associated with synchronized hyperactivity in the auditory cortex. Therefore, targeted modulation of auditory cortex has been proposed as a new therapeutic approach for chronic tinnitus. Methods Repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are noninvasive methods that can modulate cortical activity. These techniques have been applied in different ways in patients with chronic tinnitus. Single sessions of high-frequency rTMS over the temporal cortex have been successful in reducing the intensity of tinnitus during the time of stimulation and could be predictive for treatment outcome of chronic epidural stimulation using implanted electrodes. Results Another approach that uses rTMS as a treatment for tinnitus is application of low-frequency rTMS in repeated sessions, to induce a lasting change of neuronal activity in the auditory cortex beyond the duration of stimulation. Beneficial effects of this treatment have been consistently demonstrated in several small controlled studies. However, results are characterized by high interindividual variability and only a moderate decrease of the tinnitus. The role of patient-related (for example, hearing loss, tinnitus duration, age) and stimulation-related (for example, stimulation site, stimulation protocols) factors still remains to be elucidated. Conclusions Even in this early stage of investigation, there is a convincing body of evidence that rTMS represents a promising tool for pathophysiological assessment and therapeutic management of tinnitus. Further development of this technique will depend on a more detailed understanding of the neurobiological effects mediating the benefit of TMS on tinnitus perception. Moreover clinical studies with larger sample sizes and longer follow-up periods are needed. Ó 2008 Elsevier Inc. All rights reserved. Keywords tinnitus; transcranial magnetic stimulation; transcranial direct current stimulation; func- tional imaging; neuronavigation; neuroplasticity; auditory cortex; neuromodulation With a prevalence of 10% in the adult population, neuroscientific community that dysfunctional neuroplastic tinnitus is a very common symptom. Approximately 1% of processes in the brain are involved.5-11 In particular, phe- the population is severely affected by tinnitus with major nomenologic analogies with deafferentiation or phantom negative impacts on quality of life.1 Severe tinnitus is fre- limb pain suggest that chronic tinnitus as an auditory phan- quently associated with depression, anxiety and insomnia2,3 tom perception might be the correlate of maladaptive at- and is very difficult to treat.4 The most frequently used tempts of the brain at reorganization because of distorted therapies consist of auditory stimulation and cognitive sensory input.12 Early support for this concept came from behavioral treatment aiming at improving habituation and a magnetoencephalography study (MEG) showing reorga- coping strategies. However, more causally oriented thera- nization of the auditory cortex with a shift in the tonotopic peutic strategies are lacking and need to be developed to map of the auditory cortex contralaterally to the tinnitus.13 relieve auditory perception disturbances. Recent functional imaging studies demonstrated that tinni- tus is associated with neuroplastic alterations in the central Rationale for the application of repetitive auditory system and associated areas. Positron emission transcranial magnetic stimulation (rTMS) tomography (PET) investigations showed asymmetry in the auditory cortices of tinnitus patients with higher levels and transcranial direct current stimulation of spontaneous neuronal activity on the left side, irrespec- (tDCS) in tinnitus tive of tinnitus laterality.14-16 Other imaging studies re- vealed additional changes in the middle temporal and Even if the pathophysiology of tinnitus remains incom- temporoparietal regions as well as activation in frontal pletely understood, there is a growing consensus in the and limbic areas.17-20 194 B. Langguth et al Electrophysiologic studies in animal models of tinnitus summarized in Tables 1 and 2. Single sessions of rTMS have shown an increase of firing rate and neuronal synchrony have been performed to transiently disrupt tinnitus percep- in both the lemniscal and extralemniscal systems.21-23 tion (Table 1). In these types of studies mainly trains of Electroencephalography (EEG) and MEG studies in high-frequency rTMS (10-20 Hz) have been administered humans have demonstrated that tinnitus is associated with to induce an immediate, short-lasting interruption of tinni- reduced alpha and increased gamma activity in the contra- tus perception. The second approach consists of repeated lateral auditory cortex.24,25 This appears to fit with earlier sessions of rTMS on consecutive days (Table 2). These studies about auditory perception in which it was shown types of studies mainly use low-frequency (1 Hz) rTMS that gamma band activity in the auditory cortex correlates and aim at inducing a lasting modulation of tinnitus-related with the conscious perception of auditory signals.26 Very neural activity as a potential therapeutic application (Table recent MEG data indicate that the amount of tinnitus- 2). Other differences in study design consist in the methods related emotional distress correlates with the degree of syn- for target detection, coil localization, and the control chronicity between temporal and frontal areas25 and that condition. the tinnitus-related cortical network changes over time with a more widespread distribution and less relevance of Studies using single sessions of tDCS and rTMS auditory areas in longer tinnitus duration.27 The model of thalamocortical dysrhythmia, which has Plewnia et al41 investigated 14 chronic tinnitus patients to been elaborated by Llinas et al,28 could provide an explana- find out whether focal stimulation of different cortical areas tion for the abovementioned findings in tinnitus patients. Ac- can transiently suppress tinnitus. High-frequency rTMS cording to this model thalamic deafferentiation from auditory (10 Hz) was applied to 12 different positions over the scalp. input, which is associated with hearing loss, may produce A significant reduction of tinnitus was observed when stim- slow theta-frequency oscillations in thalamocortical ensem- ulation was administered to the left temporoparietal cortex. bles caused by changes in firing pattern of thalamic relay This result suggests that the secondary