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Isabel Lorenz, Nadia Müller, Winfried Schlee, Berthold Langguth and Nathan WeiszTinnitusAuditory Evoked Activity in Patients With Chronic Short-Term Effects of Single Repetitive TMS Sessions on

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Short-Term Effects of Single Repetitive TMS Sessions on Auditory EvokedActivity in Patients With Chronic Tinnitus

Isabel Lorenz,1 Nadia Müller,1 Winfried Schlee,1 Berthold Langguth,3 and Nathan Weisz1,2

1Department of Psychology and 2Zukunftskolleg, University of Konstanz, Konstanz; and 3Department of Psychiatry, Universityof Regensburg, Regensburg, Germany

Submitted 21 April 2010; accepted in final form 23 June 2010

Lorenz I, Müller N, Schlee W, Langguth B, Weisz N. Short-termeffects of single repetitive TMS sessions on auditory evoked activityin patients with chronic tinnitus. J Neurophysiol 104: 1497–1505,2010. First published June 30, 2010; doi:10.1152/jn.00370.2010.Subjective tinnitus is the perception of a sound without any externalsource. Repetitive transcranial magnetic stimulation (rTMS) has beenexamined as a treatment tool for chronic tinnitus for several yearstrying to target hyperactivity/abnormal synchronization within theauditory cortex putatively underlying the auditory phantom percept.However, its exact impact on auditory cortical activity remains largelyunknown. This study’s objective was to systematically examinechanges in auditory responses (N1, auditory steady-state response[aSSR]) measured by means of magnetoencephalography after singlesessions of stimulation with different TMS paradigms. Subjects withchronic tinnitus (n � 10) underwent five sessions of rTMS in whichthey received one of five different stimulation protocols (1 Hz,individual alpha frequency, continuous theta burst stimulation[cTBS], intermittent theta burst stimulation [iTBS], and sham) inrandomized order using a single-blind study design. Cortical steady-state responses to 40 Hz amplitude-modulated tones were measuredbefore and after each magnetic stimulation protocol. The resultsdemonstrate a reduction of the cortical response to the auditorysteady-state stimulus after magnetic stimulation, whereas the N1response was slightly enhanced or remained unchanged. Furthermore,reduction of the aSSR was driven by effects of iTBS, cTBS, and 1 Hzstimulation. Correspondingly, behavioral measures demonstrated thegreatest reduction of tinnitus loudness after the respective rTMSprotocols. The current study offers an interesting insight into theeffects of rTMS on auditory cortical activity. The results of the studyare discussed in the context of current limitations of TMS for thetreatment of chronic tinnitus.

I N T R O D U C T I O N

Tinnitus, the subjective perception of a sound in the absenceof any physical sound source, is characterized by simpleacoustical features, for instance, a pure tone or a narrow-bandnoise. Up to 15% of the general population experiences such aphantom sound (Eggermont and Roberts 2004). In most casestinnitus is associated with hearing loss induced by noise expo-sure or the aging process, as has been demonstrated in animalmodels of hearing loss (Rajan and Irvine 1998; Salvi et al.2000). It is widely assumed that deprivation of afferent inputcaused by hearing damage leads to reduced inhibition in centralauditory structures, which results in hyperexcitability of cir-cumscribed regions of the central auditory system. This isreflected in an increase in the spontaneous firing rate (SFR) incortical and subcortical auditory structures (Eggermont and

Roberts 2004; Kaltenbach 2006). Furthermore, rapid increasesin synchronized firing in the deprived frequency regions afternoise trauma (Norena and Eggermont 2003) and enhancedburst firing in inferior colliculus, primary, and secondary au-ditory cortex after salicylate or quinine injection (substancesknown to trigger tinnitus) have been demonstrated in animalstudies (e.g., Chen and Jastreboff 1995; Kenmochi and Egger-mont 1997; Norena and Eggermont 2003). This aberrant neu-ronal activity within the auditory pathways may have sufficientpostsynaptic impact to be interpreted as a sound at higherauditory processing stages.

The direct measurement of neuronal spiking in humans ispossible only by the use of invasive methods. For the assess-ment of altered neuronal activity in the human central auditorysystem evoked potentials have been examined, which areelicited by a large population of synchronously active neurons.An interesting technique in this context is the so-called audi-tory steady-state response (aSSR), an evoked oscillatory re-sponse driven by the modulation frequency of a given stimulus(Regan 1982). In tinnitus an increase of the aSSR amplitude(Diesch et al. 2004; Wienbruch et al. 2006) and a flattenedtonotopic gradient have been reported (Wienbruch et al. 2006)compared with normal hearing controls. Since the aSSR has itsmain generators in the primary auditory cortex (A1) (Bidet-Caulet et al. 2007; Galambos et al. 1981; Liegeois-Chauvelet al. 1994), the results imply an enhanced excitability ofneuronal cell assemblies in primary auditory areas of tinnitussufferers, which may stem from reduced inhibition leading toan increased ongoing synchronization. In a recent treatmentstudy Okamoto and colleagues (2010) demonstrated a reduc-tion of the perceived tinnitus loudness after individualizedauditory stimulation accompanied by reduced aSSR ampli-tudes. Transient auditory evoked potentials, the most dominantone being the N1, originating mainly from secondary auditory(A2) and association cortices (Liegeois-Chauvel et al. 1994),have also been previously investigated in tinnitus subjects.However, results from these studies have been inconsistent. Anearly study found a reduction in event-related potential ampli-tudes (N1, P2, and P3) in the tinnitus group compared withhearing loss and age-matched controls (Attias et al. 1993).More recent studies have reported increased N1 either forsounds with frequencies at the audiometric edge (Dietrich et al.2001) or at lower (nondeprived) frequencies (Weisz et al.2005). One single study using magnetic source imaging re-ported abnormal tonotopic organization in tinnitus patientswith a linear correlation between the deviation of the N1generator of the tinnitus frequency and the subjective tinnitusstrength (Muhlnickel et al. 1998).

Address for reprint requests and other correspondence: I. Lorenz, University ofKonstanz, Department of Psychology, Clinical and Neuropsychology, P.O. Box5560, D25, 78457 Konstanz, Germany (E-mail: isabel.lorenz@uni-konstanz.de).

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Thus there is an increasing amount of evidence from bothanimal and human studies that tinnitus is related to enhancedexcitability of auditory cortical regions (Dong et al. 2010; Sunet al. 2009), putatively leading to spurious spontaneous syn-chronization (Weisz et al. 2007a). Despite the current knowl-edge about its pathophysiological mechanisms, tinnitus treat-ment is still elusive. Transcranial magnetic stimulation (TMS),a minimally invasive method for depolarizing cortical neuronsbased on the principle of electromagnetic induction (Barkeret al. 1985), has recently gained popularity not only as aresearch tool but also as a possible treatment for chronictinnitus. The rhythmic application of series of single stimuli isreferred to as repetitive TMS (rTMS), a method that has beendemonstrated to induce long-term potentiation (LTP) or de-pression (LTD)-like changes of cortical excitability, whichoutlast the stimulation period (Siebner and Rothwell 2003).Based on its ability to focally modulate cortical excitabilityrTMS has been investigated as a therapeutic tool in disorderscharacterized by functionally altered cortico–subcortical net-works, such as depression, schizophrenia, stroke, or tinnitus(Ridding and Rothwell 2007). Aftereffects of rTMS depend ona complex interplay of various factors, including stimulationfrequency, number of pulses, and stimulation intensity, but alsothe history of synaptic activity of the stimulated brain region(Ridding and Rothwell 2007).

Based on the finding that 1 Hz rTMS in general reducescortical excitability (Chen et al. 1997), 1 Hz rTMS over thetemporo- or temporoparietal cortex has been studied exten-sively, during recent years, as a treatment tool for chronictinnitus. Even if it has overall demonstrated statistically sig-nificant reductions of tinnitus, the effect sizes are only moder-ate (�20% symptom reduction) and interindividual variabilityis high (for an overview see Kleinjung et al. 2007a; Londeroet al. 2006). Thus, despite being conceptually an ideal tool fortackling tinnitus, the clinical impact of the currently usedstimulation protocols is limited. Recently, theta burst stimula-tion (TBS) has been introduced as a new stimulation paradigm.Single sessions of TBS, consisting of bursts of three pulses ofTMS at 50 Hz repeated at theta frequency (5 Hz), have beendemonstrated to induce more pronounced and longer-lastingeffects on motor cortex excitability compared with tonic stim-ulation with rTMS (Huang and Rothwell 2004). However, theeffects of various rTMS protocols on cortical excitatory andinhibitory networks have been investigated mainly in the motorsystem where a direct behavioral impact can be recorded bymeans of electromyography. It is uncertain whether this knowl-edge can be directly transferred to other cortical areas such asthe auditory cortex (Franca et al. 2006; Sparing et al. 2005;Speer et al. 2003).

Surprisingly, the influence of rTMS on auditory responses intinnitus patients has not yet been investigated, although anenhancement of the aSSR has been demonstrated in chronictinnitus patients compared with controls. Our current knowl-edge of the influence of rTMS on auditory cortex activity canbe indirectly inferred from rTMS studies only in nonauditorymodalities, particularly the motor system. Learning more aboutthe impact of rTMS on auditory cortical activity is necessary tounderstand how this technique may alleviate tinnitus symp-toms, how to further improve its efficacy, and about currentlimitations of this method. Thus the primary goal of the presentstudy was an advancement of our understanding of the short-

term influence of different rTMS protocols on the hyperactivitywithin the auditory cortex in tinnitus patients and thus onshort-term changes of tinnitus loudness. Furthermore, the fre-quency selectivity of the rTMS effects will be investigated.However, we do not aim at replicating clinical improvementsrelated to rTMS, which would require larger sample sizes.

Based on the current notion relating tinnitus to hyperexcit-ability in auditory cortical regions we hypothesize that en-hanced auditory cortical activity (reflected in the aSSR and theN1) is reduced after rTMS.

M E T H O D S

Subjects

Ten patients with chronic tinnitus participated in the study (7 males,3 females). The mean age was 49.8 yr (21–70 yr); the mean tinnitusduration was 1.8 yr (0.5–3 yr). Five patients reported unilateraltinnitus (4 left-sided tinnitus, 1 right-sided tinnitus); 5 patients expe-rienced bilateral tinnitus. Mean tinnitus severity according to theGerman version of the Tinnitus Questionnaire (Goebel and Hiller1998) was relatively low (mean: 29.9; range: 8–59). Patients wererecruited via advertisements in the local newspaper and flyers at theUniversity of Konstanz. None of them had any prior experience withrTMS. All patients were investigated thoroughly regarding a previouspersonal or family history of epileptic seizures. Patients with relevantneurological or psychiatric comorbidity (assessed using the MiniInternational Neuropsychiatric Interview; Sheehan et al. 1998), thosewith contraindications for TMS (e.g., epilepsy, cardiac pacemaker,pregnancy, neurodegenerative diseases), and patients taking anticon-vulsant or tranquilizer medication were excluded from the study.Since rTMS in chronic tinnitus has been demonstrated to be morepromising with short tinnitus duration (De Ridder et al. 2005; Klein-jung et al. 2007b) we included only patients with maximum tinnitusduration of 4 yr. All participants were informed about the content ofthe study prior to participation and signed a written informed consent.The study conformed to the Declaration of Helsinki and was approvedby the Ethics Committee of the University of Konstanz. (See Supple-mental Table S1 for data pertaining to patients in this study.)1

Measurement of tinnitus loudness

Before the first and after the second magnetoencephalography(MEG) measurements (see Fig. 1) patients had to rate their tinnitus ona visual analogue scale (VAS) assessing the current loudness on ascale ranging from 0 (minimal) to 10 (maximal) (How loud is yourtinnitus?).

MEG procedure and data acquisition

During the MEG measurement, the participants were stimulatedwith three 40-Hz amplitude-modulated (AM) tones (250, 1,000, and4,000 Hz) appearing in randomized order and presented monoaurallyto the ear affected by the tinnitus (right-sided in the case of bilateraltinnitus). In the following the AM tones will be referred to as“low-frequency tone” (250 Hz), “middle-frequency tone” (1,000 Hz),and “high-frequency tone” (4,000 Hz). The auditory stimulationprocedure consisted of 210 stimuli (i.e., 70 stimuli per frequency),each stimulus lasting 800 ms (75 ms rise/fall time). The interstimulusinterval varied randomly from 2,800 to 3,100 ms. Data were recordedwith a 148-channel whole-head magnetometer system (MAGNES2500 WH, 4D Neuroimaging, San Diego, CA), installed in a magnet-ically shielded room (Vakuumschmelze, Hanau, Germany). The headposition within the MEG helmet had to be assessed and thus positions

1 The online version of this article contains supplemental data.

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of five index points and individual head shapes were sampled using adigitizer. Participants lay in a supine position and were requested tokeep their eyes open during the measurement and to focus on a fixedpoint on the ceiling. To ensure that all stimuli were perceived at thesame subjective loudness level, each stimulus was individuallymatched to the loudness of a reference tone (1 kHz, 50 dB SL) foreach patient. The auditory stimuli were conducted to the patient’s earvia a flexible tubing sound delivery system. The whole procedure,including sending markers to the data acquisition system, was imple-mented in Psyscope X B53 for Mac OS X (http://psy.ck.sissa.it).

MEG measurements were conducted before and after rTMS; theinterval between the end of stimulation and the start of the secondMEG measurement did not exceed 3 min. Since we measured restingstate brain activity for 5 min first (reported in a companion paper), themeasurement of evoked data was started about 8 min after the end ofrTMS.

rTMS stimulation

Five rTMS sessions were applied with a minimum interval of 1 wkbetween sessions using a randomized, single-blind, sham-controlleddesign. Biphasic magnetic pulses were administered with a figure-of-eight coil (coil winding diameter: 2 � 75 mm; Magnetic CoilTransducer C-B60, Medtronic, Skovlunde, Denmark) connected to aMagPro X100 TMS stimulator (Medtronic). Patients were seated in acomfortable chair. The coil was placed over left Heschl’s gyrus bymoving 2.5 cm upward from T3 on the line between T3 and Cz andthen 1.5 cm in the posterior direction perpendicularly to the lineT3–Cz (in the case of right-ear or bilateral tinnitus), analogously overright Heschl’s gyrus (in the case of left-ear tinnitus). This procedurehas been proven to position the TMS coil reliably over the auditorycortex (Langguth et al. 2006). The handle of the coil was pointingupward. During stimulation the coil was held by a mechanical arm.

The following stimulation protocols were applied in randomizedorder: 1 Hz rTMS (one train with 1,000 pulses), individual alphafrequency rTMS (IAF; 20 trains with 50 pulses and 25-s intertraininterval, frequency ranging between 8 and 12 Hz), intermittent thetaburst stimulation (iTBS; 10 trains of 10 bursts at a frequency of 5 Hzwith an 8-s intertrain interval and bursts consisting of three pulses at50 Hz), continuous theta burst stimulation (cTBS; bursts at a fre-quency of 5 Hz with bursts consisting of three pulses at 50 Hz), andsham stimulation [45° coil angulation (one wing), applying the IAFprotocol]. The patients were blind to the TMS condition.

The intensity of stimulation was expressed as a percentage of themaximum output of the stimulator (0–100%) and was adjusted ac-cording to the resting motor threshold (RMT), a common procedure inrTMS studies (Pridmore et al. 1998). The RMT, measured by deliv-ering single pulses at the optimal place over the motor cortex toproduce visible hand muscle contractions, was defined as the loweststimulation intensity for producing a visible hand muscle contractionin at least five of ten trials. For 1 Hz, IAF, and sham stimulation anintensity of 110% RMT was applied, whereas an intensity of 80%RMT was used for iTBS and cTBS (according to Huang et al. 2005).Earplugs were provided to the patients to prevent hearing damage dueto the loud clicking sound of the TMS. For an overview of the studyoutline see Fig. 1.

Data analysis

Continuous data were epoched (�2,000 to 2,000 ms relative tosound onset) and downsampled to 300 Hz. Epochs containing artifactssuch as eyeblinks were excluded via visual inspection. Since theexperimental procedure required the participant to leave the MEG(within one experimental session, as well as between sessions), allcomparisons were performed in source space using the “lcmv” beam-former (Van Veen et al. 1997). A multisphere model was fitted to theheadshape collected in the first measurement, yielding a grid ofdipoles with a 10-mm resolution. This ensured that the same grid wasused across all measurements for a single subject; the lead field foreach grid point was calculated for each measurement separately,however. Time windows representing the early transient response(oversimplified called the N1 period here due to the dominance of theN1m; 0–300 ms) and the steady-state field (SSF; 400–700 ms) weredefined by inspection of the grand average of the sensor-level activityacross all participants. Furthermore, we determined a prestimulusbaseline period of equal length (�300 to 0 ms). The general sourceanalysis strategy for one measurement was to first calculate spatialfilters for each grid point via the lcmv beamformer, by using acommon time period that encompassed baseline and activation peri-ods. To optimize spatial filters for the relevant activity, epochs werelow-pass filtered (20 Hz) for the N1 and band-pass filtered (30–50 Hz)for the SSF prior to calculation of the sensor-level covariance. Afterderiving the common spatial filter, dipole moments were estimated forthe aforementioned activation and baseline periods and relativechanges of brain activity were calculated: (activation � baseline)/baseline. These measures of evoked brain activity were then interpo-lated onto individually collected magnetic resonance images andsubsequently spatially normalized to the Montreal Neurological Insti-tute brain using SPM2 (www.fil.ion.ucl.ac.uk/spm/software/spm2).

We defined two regions of interest (ROIs) for data analysis: theauditory cortices ipsilateral and contralateral to the TMS stimulationside (Fig. 2). Therefore source activity (as described earlier) wasaveraged across all pre-MEG measurements for each subject. Subse-quently, source activations were averaged across all participants ofeach stimulation side separately. The whole procedure was applied forthe N1 and the aSSR, respectively. A cluster of voxels with highactivation was defined in each hemisphere by applying a threshold(85% of the maximum). The masks derived from the N1 and the aSSRwere combined for both hemispheres, resulting in two auditory ROIs.Thereafter, the activity from the respective ROIs was extracted and

FIG. 1. Outline of experimental sessions. Tinnitus loudness was assessedfollowed by a magnetoencephalographic (MEG) measurement of auditorycortical activity while patients were stimulated with 3 different amplitude-modulated tones (70 stimuli in each condition), each lasting 800 ms. Subse-quently, one of 5 repetitive transcranial magnetic stimulation (rTMS) protocols(including a sham stimulation) were applied in a randomized order. After TMSthe MEG procedure and the tinnitus loudness measurement were repeated.

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averaged across all voxels of interest, leading to one single value, eachipsi- and contralateral to the TMS stimulation side for each patient.This procedure was applied for each stimulation parameter, for eachof the three AM tones, for each measurement time, and for N1 andaSSR, respectively, resulting in 60 values per patient—thus 600values overall.

All aspects of analysis of the MEG data were performed using theFieldtrip toolbox (http://fieldtrip.fcdonders.nl) in Matlab 7.6.0 (TheMathWorks, Natick, MA).

Statistical analyses

Statistical analyses were performed using R version 2.6.0 for MacOS X (www.r-project.org). Normalized power was computed bymeans of a (post � pre)/pre (relative to rTMS intervention) ratio tominimize variance resulting from strong interindividual variability.Bilateral auditory evoked responses were not clearly identifiable in allsubjects. This may be attributed to the use of monaural rather thanbinaural auditory stimulation. Data sets without a clear N1 or aSSRwere treated as outliers and removed from the data. Outliers weredefined according to the boxplot criterion as a data point falling morethan 1.5 times the interquartile range above the third quartile or belowthe first quartile (Hoaglin 1986). With the remaining values a linearmixed-effect models statistic (LME) was computed, which is anappropriate method for representing data from repeated measures onthe same statistical units and is furthermore particularly suitablefor analyses with missing values due to removal of outliers(Pinheiro 2000). The following variables were entered as fixedeffects: stimulation protocol, auditory response, tone frequency,and region of interest. Subjects were defined as random effects.LME analysis was performed using the nlme library of R (Pinheiro2000). If significant results were detected in the “omnibus” lmestatistic, post hoc planned contrasts (paired t-test) were computed.Since auditory cortical activity underlies natural changes we com-pared auditory activity after active rTMS protocols to auditoryactivity at baseline, but also to auditory activity after sham stim-ulation (as a control variable). The significance level was set to0.05 in all analyses.

R E S U L T S

None of the patients reported relevant side effects of rTMS,apart from transient mild discomfort due to cutaneous sensa-tions and muscle contractions. One patient reported periods ofcomplete absence of tinnitus lasting for several minutes after 1Hz stimulation. Three patients reported a very loud tinnitusafter IAF stimulation lasting for several hours up to a few days.None of the other stimulation parameters was associated withspontaneously reported increase of tinnitus loudness.

Effects of rTMS on auditory cortical activity

The results of an “omnibus” lme statistic demonstrate asignificant main effect for the factor auditory response (N1 oraSSR) (mean N1 � 0.077, mean aSSR � �0.256, F � 16.159,P � 0.0001). Since the N1 and the aSSR display an oppositereaction pattern after rTMS we divided the data according tothe auditory response for further analyses.

A significant stimulation � ROI interaction for the auditorysteady-state response (F � 3.310, P � 0.011) was found. Posthoc analyses for each stimulation parameter ipsi- and contralat-eral were performed (see Supplemental Table S2). Intermittenttheta burst stimulation led to a significant reduction of theaSSR compared not only with baseline (t � �3.813, P �0.0005) but also with sham (t � �3.525, P � 0.0005) in thestimulated auditory cortex (ipsilateral to rTMS). Furthermore,1 Hz rTMS resulted in a significant reduction of the aSSRipsilateral to rTMS compared with sham (t � �1.687, P �0.049) and a trend was revealed for the aSSR after cTBSipsilateral to rTMS compared with sham (t � �1.533, P �0.064) (Fig. 3). The aSSR contralateral to the stimulation sidewas reduced significantly compared with baseline after shamstimulation (t � �2.997, P � 0.003) (Fig. 3).

Furthermore, a trend was revealed for a stimulation �frequency interaction regarding the N1 (F � 1.972, P � 0.051)(Fig. 4). Post hoc analyses revealed a significant enhancement

FIG. 2. Regions of interest of right and left auditory cortices, respectively, computed by averaging auditory cortical activity across all pre-MEG measurements.A threshold with 85% of the maximum was defined and values below this threshold were set to 0, whereas values above the threshold were set to 1.

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of the N1 for the low-frequency tone after IAF stimulation (t �2.402, P � 0.014) as well as after sham (t � 2.12, P � 0.024)compared with baseline. Compared with sham as a controlvariable we found a significantly reduced N1 after iTBS (t ��1.696, P � 0.049) as well as after cTBS (t � �1.82, P �0.038). Regarding the middle-frequency tone a trend wasrevealed for a reduction of the N1 after sham (t � �1.444, P �0.083) compared with baseline. For the high-frequency tone asignificant reduction of the N1 was found after sham (t ��2.564, P � 0.010), as well as a significant enhancement ofthe N1 after iTBS (t � 1.872, P � 0.041) compared withbaseline. Compared with sham we found a significantly greaterN1 not only after iTBS (t � 3.136, P � 0.002) but also aftercTBS (t � 2.062, P � 0.024). A trend was revealed for a

greater N1 after 1 Hz stimulation (t � 1.508, P � 0.070)compared with sham (see Supplemental Table S3).

No significant interaction effects were revealed for the aSSRregarding the different tone frequencies.

Effects of rTMS on tinnitus loudness

Regarding the behavioral data (measurement of tinnitus loud-ness: visual analogue scale [VAS]), an lme model revealed asignificant effect for the factor stimulation (F � 3.665, P �0.013). Post hoc tests demonstrated a significant reduction oftinnitus loudness after cTBS (t � �3.312, P � 0.005) comparedwith baseline (compared with sham: t � �1.496, P � 0.080) aswell as after 1 Hz stimulation (t � �2.008, P � 0.037) comparedwith baseline (compared with sham: t � �1.750, P � 0.048).Trends were revealed for a reduction of tinnitus loudness afteriTBS (t � �1.583, P � 0.073) compared with baseline (com-pared with sham: t � �1.325, P � 0.100) and for an enhance-ment of tinnitus loudness after IAF stimulation (t � 1.609, P �0.071) compared with baseline [compared with sham: t � 1.301,P � 0.108 (Fig. 5)].

Moreover, linear relationships between the behavioral dataand the aSSR were computed. We detected a positive correla-tion between the aSSR in the stimulated auditory cortex (ipsi-lateral to rTMS) and tinnitus loudness after rTMS [r � 0.475,P � 0.0006 (Fig. 6)].

D I S C U S S I O N

The current study examined the short-term influence ofdifferent rTMS stimulation protocols on auditory cortical ac-tivity (aSSR, N1) in chronic tinnitus patients measured bymeans of MEG. In general, we found a significant reduction ofthe aSSR after rTMS. The results demonstrate that significantchanges after active stimulation occur mainly in the directlystimulated auditory cortex ipsilateral to the coil placement.

FIG. 5. Comparison between tinnitus loudness (visual analogue scale[VAS]) measured after rTMS protocols compared with baseline and withsham. Tinnitus loudness was significantly reduced after 1 Hz stimulation andcTBS, compared with baseline, a trend was revealed for the reduction oftinnitus loudness after intermittent theta burst stimulation (iTBS). Comparedwith sham tinnitus loudness was reduced significantly after 1 Hz stimulationand trends were revealed for cTBS and iTBS. Asterisks demonstrate signifi-cance (**P � 0.01, *P � 0.05, �P � 0.1); bars represent SEs.

FIG. 3. Comparison between the effects of different stimulation protocolson the auditory steady-state response (aSSR) regarding different stimulationsides (ipsilateral vs. contralateral) (shaded bars represent sham control). Inter-mittent theta burst stimulation is the only active stimulation parameter signif-icantly reducing the aSSR in the stimulated auditory cortex (ipsilateral torTMS) compared not only with baseline but also with sham. However,compared with sham, 1 Hz also significantly reduced the aSSR. For continuoustheta burst stimulation (cTBS) a trend was revealed. Asterisks demonstratesignificance (***P � 0.001, **P � 0.01, *P � 0.05, �P � 0.1); bars representSEs.

FIG. 4. Comparison between the effects of different stimulation protocolson the N1 regarding different tone frequencies (250, 1,000, 4,000 Hz) (shadedbars represent sham control). Asterisks demonstrate significance (**P � 0.01,*P � 0.05, �P � 0.1); bars represent SEs.

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Intermittent theta burst stimulation and 1 Hz stimulation hadthe greatest effects on the aSSR compared with sham stimula-tion; however, for cTBS a trend was also revealed. The effectsof rTMS on the N1 regarding the different tone frequenciesdemonstrated quite a complex pattern: sham stimulation en-hanced the N1 for the low-frequency tone and concurrentlyreduced the N1 for both the middle-frequency and the high-frequency tones. This pattern greatly differed from the activestimulation protocols in which only IAF stimulation enhancedthe N1 for the low-frequency tone and iTBS enhanced the N1for the high-frequency tone.

Regarding the behavioral results, 1 Hz stimulation and cTBSresulted in a significant reduction of tinnitus loudness; a trendwas revealed for iTBS. This corresponds nicely to the aSSRdata, exhibiting a reduction of the aSSR precisely after thesestimulation protocols. Thus our data are in line with a recenttreatment study demonstrating a reduction of the perceivedtinnitus loudness after individualized auditory stimulation ac-companied by reduced aSSR amplitudes (Okamoto et al.2010).

Stronger effect of rTMS on the auditorysteady-state response

Our results demonstrate a greater influence of the activestimulation protocols on the aSSR compared with the N1. Thisphenomenon suggests that effects of rTMS occur preferentiallyin A1, which is supposed to play an important role for thegeneration of the aSSR (Bidet-Caulet et al. 2007; Galambos etal. 1981; Liegeois-Chauvel et al. 1994) and only to a lesserextent in A2. The coil was localized directly above the earaccording to the international 10/20 system, a position that wasvalidated before by means of neuronavigation to mainly targetthe A1 (Langguth et al. 2006). Thus our results indirectlyconfirm this coil positioning method. For the first time neuro-physiological data are provided for the debate about the exactcortical region in which rTMS exerts clinical effects in tinnitus

patients (Langguth et al. 2010). It has been argued that A1 isdifficult to reach by TMS, since it is located far from the brainsurface in the Sylvian fissure in the lateromedial direction.Furthermore, patients with low-frequency tinnitus (corticalactivation is expected to be more superficially located) did notrespond better to rTMS than did those with high-frequencytinnitus (Frank et al. 2010). Our results also did not demon-strate any frequency-specific effects regarding the aSSR. Thuseven if our data suggest that the rTMS effects occur predom-inantly in A1, this may not be a direct stimulation effect butrather transynaptically mediated via more superficial corticalareas, either by corticocortical connections or by cortico-thalamo-cortical transmission.

Intermittent theta burst stimulation turned out to be theparameter leading to the greatest reduction of the aSSR, al-though iTBS has been demonstrated to induce excitatory ef-fects on the motor cortex (Huang et al. 2005). Thus our resultsunderscore that specific rTMS protocols may have differenteffects on various cortical areas (Poreisz et al. 2008; Speeret al. 2001). Furthermore, it has to be considered that rTMSeffects were investigated in tinnitus patients who differ fromhealthy controls presumably by increased auditory cortex ac-tivity. Since the excitability state of the stimulated area hasbeen repeatedly shown to have an important impact on rTMSeffects (Lang et al. 2004; Potter-Nerger et al. 2009; Siebner andRothwell 2003; Siebner et al. 2004) the reduction of aSSR afteriTBS may reflect iTBS-induced homeostatic plasticity. Thehomeostatic plasticity rule predicts that the greater the ongoingactivity, the less effective are processes leading to LTP,whereas processes leading to LTD are enhanced (Bienenstocket al. 1982). Our results of strongly reduced auditory excitabil-ity after iTBS are also in line with recent animal data demon-strating a significant increase of the inhibitory transmitter�-aminobutyric acid in the rat cortex acutely (within 30–45min) after stimulation with iTBS (Trippe et al. 2009). How-ever, due to the pioneering aspect of our work these assump-tions are merely speculative and would have to be validated bymeans of examining a healthy control group.

Regarding the N1 we found different results. In general thereis a slight enhancement of the N1 after rTMS. After both shamand IAF rTMS the N1 for the low-frequency tone was signif-icantly enhanced, whereas the N1 for the middle- and high-frequency tones was reduced after sham. In contrast, after theburst protocols (cTBS, iTBS) a converse pattern was observed.At this stage it is unclear why such a distinct frequency-specificpattern was observed both for sham and for IAF stimulation.Since the same stimulation protocol was applied for sham andIAF rTMS, both produced acoustic artifacts (due to the click-ing sound of the TMS machine) in the individual alpha fre-quency. Furthermore, the effects on the N1 were not lateralityspecific; thus it is tempting to speculate that the observedchanges of the N1 after these protocols are a mere consequenceof the rhythmic sound stimulation at the individual alphafrequency. Massive sound stimulation at the individual alphafrequency may be capable of inducing alpha entrainment and,as a consequence, inhibitory effects (Mathewson et al. 2009;Sauseng et al. 2009). This explanation is further supported bythe fact that the N1 is assumed to be generated in secondaryauditory areas (Liegeois-Chauvel et al. 1994), which have notbeen directly magnetically stimulated in the current study, butwhich were activated by the TMS-related sound stimulation. If

FIG. 6. Positive correlation between the aSSR ipsilateral and tinnitus loud-ness after rTMS (r � 0.475, P � 0.0006). Colored points represent thedifferent stimulation protocols (red � cTBS; blue � iTBS; green � 1 Hz;yellow � IAF; black � sham) and dashed colored lines demonstrate therespective individual correlations for cTBS (red), iTBS (blue), and 1 Hzstimulation (green).

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sham and IAF stimulation have a specific frequency effect onthe N1 due to acoustic artifacts in the alpha frequency, itremains unclear whether the effects of the burst protocols onthe N1 are also a mere consequence of the acoustic stimulationor whether they result from the magnetic effects on cortico-cortical connections to A2. Disregarding the exact mechanismsat this point, the sham findings for the N1 raise awareness thatneurophysiological effects may not be induced directly only bymagnetic stimulation, which necessitates further research.

Spatial resolution of rTMS regarding differenttone frequencies

The influence of rTMS on auditory cortical activity regard-ing the three different tone frequencies (i.e., the fine-tuningwithin the auditory cortex) clearly demonstrates diverse re-sults. As mentioned earlier, the converse pattern is moststrongly pronounced for the N1 after sham stimulation, sug-gesting primarily that the specific sound stimulation of theTMS at the alpha frequency is responsible for the frequency-specific effects on the N1. In contrast, the lme model did notreveal any significant interaction effects regarding the aSSR forthe different tone frequencies. Thus our results demonstrate animpact of rTMS on auditory cortex excitability, although this israther nonfrequency specific. In tinnitus patients, assuming thatthe entire auditory cortex does not exhibit hyperactivity/syn-chrony, but only circumscribed parts affected by deprivation(Weisz et al. 2007a), calls for more precise targeting ofneuronal assemblies along the tonotopic map. The pivotalquestion is whether an improvement of the spatial resolution ofTMS regarding the auditory cortex would lead to greatertreatment effects (e.g., Silvanto and Pascual-Leone 2008; Sil-vanto et al. 2007).

Limitations

The sample size of the current study was small because ofthe time-consuming measurements (2.5 h per session, 5 ses-sions per person). Nevertheless, due to the numerous MEGmeasurements (100 recordings) providing the data, the statis-tical power should be sufficient and the data reliable. In anyevent, our study should be regarded as a precursor in thisresearch field and thus conclusions from the current results forthe general tinnitus population are limited and require furtherresearch, with greater sample sizes and nontinnitus controls(regarding protocols that exhibited the greatest neurophysio-logical effects, for instance, iTBS).

An important aspect regarding transcranial magnetic stimu-lation of the auditory cortex is the concomitant massive (non-intentional) sound stimulation of auditory cortical areas due tothe loud clicking sound of the TMS machine when the pulse isgenerated. By tilting the coil for sham stimulation the magneticfield produced by the TMS is greatly reduced; thus a depolar-ization of neurons is impossible. However, auditory stimula-tion by the clicking sound of the TMS still exists. The IAFprotocol was applied for sham stimulation, which turned out tobe the loudest stimulation paradigm (about 93 dB, subtracting30 dB attenuation by means of earplugs). During active rTMSdepolarization caused by the magnetic pulse and depolarizationrelated to the processing of the clicking sound may interact andcontribute to synaptic plasticity due to associative learning

mechanisms (Stefan et al. 2000). This learning process ismissing in the case of sham stimulation since there is noinduced current. Yet, at least for the visual modality, it hasbeen demonstrated that by entrainment of the visual cortex via10-Hz stimulus presentation, functional inhibition can be ob-served on a short-term basis (Sauseng et al. 2009). It isunknown whether a prolonged (several minutes) stimulationof, for instance, visual or auditory stimuli would lead tolonger-lasting changes in respective sensory brain regions. Ifthis was the case, however, then this massive sound stimulationat the IAF may have resulted in considerable inhibitory effects.It is important to emphasize that in both cases (associativelearning, IAF entrainment) sham cannot be considered as acompletely “inactive” control condition.

Another problem we had to face, especially concerning thedata analysis, was the application of TMS (and accompanyingthe application of the sound stimulation) on different sides,since we decided to stimulate contralateral to the tinnitus side.Our approach to divide the activity according to regions ofinterest ipsi- and contralateral to the rTMS stimulation sidefunctioned as a good compromise for the current study. Yet,statements for subgroups of tinnitus (e.g., laterality, gender)cannot be drawn. Furthermore, it still remains a matter ofdebate to what extent tinnitus-related changes are predomi-nantly located in the auditory cortex contralateral to the per-ceived tinnitus (Weisz et al. 2007b) or whether alterations ofneural activity in the central auditory system are independentfrom the perceived tinnitus laterality (Arnold et al. 1996;Langguth et al. 2006).

Moreover, it has not been possible to measure auditorycortical changes directly after rTMS since there was a delay ofabout 8 min until the measurement started again. The loudnessrating on the VAS has been conducted after the second MEGmeasurement; thus loudness has been gathered only 20 minafter rTMS, which clearly limits conclusions on the prompteffects of rTMS on tinnitus. However, studies regarding rTMSeffects on the human motor cortex (Chen et al. 1997; Huanget al. 2005) demonstrate that even effects of single rTMSsessions last for �15–60 min. Accordingly, we were still ableto demonstrate changes regarding the aSSR as well as thetinnitus loudness after active rTMS protocols compared withsham stimulation, which further argues for extended effectseven of single rTMS sessions. Nevertheless, differences be-tween burst and tonic stimulations have to be interpreted withcare, since burst stimulation was demonstrated to have longer-lasting effects on the human motor cortex (Huang et al. 2005).

Conclusions

Results of the current study demonstrate stronger effects ofrTMS on the aSSR compared with the N1, which possiblyargues for a greater influence on A1 using a coil placementapproach that was supposed to target the A1 (Langguth et al.2006).

Nonetheless, the findings of the present study are promising.Auditory cortex excitability (reflected in the aSSR) is reducedafter iTBS, cTBS, and 1 Hz and these particular protocols werefollowed by a reduction of tinnitus, thus confirming our as-sumptions outlined in the INTRODUCTION. Yet, the spatial reso-lution of rTMS regarding the frequency specificity of the

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auditory cortex is low, which is reflected in unspecific resultsregarding the stimulation with three different tone frequencies.

Since the current study does not claim to be a therapy studyregarding a treatment of tinnitus, further research concerninglonger rTMS periods distributed across several days is re-quired.

Besides the above-mentioned limitations the current study isthe first to demonstrate rTMS effects on evoked auditorycortical activity. A greater number of corresponding studieswill improve insights into possible mechanisms of differentTMS protocols on auditory activity, potentially leading toadvances in applying this technique as a treatment of chronictinnitus.

A C K N O W L E D G M E N T S

We thank F. Fernandes, H. Gorodetzky, and D. Laptinskaya for valuableassistance in data collection; T. Hartmann for technical support; and M.Dobbins for proofreading the manuscript.

G R A N T S

This work was supported by Deutsche Forschungsgemeinschaft Grant WE4156/2-1 to N. Weisz, the Tinnitus Research Initiative, and the Zukunftskollegof the University of Konstanz.

D I S C L O S U R E S

No conflicts of interest, financial or otherwise, are declared by the author(s).

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