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Efficacy of different protocols of transcranial

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 The World Journal of Biological Psychiatry, 2012; Early Online: 1–10

ORIGINAL INVESTIGATION

Efficacy of different protocols of transcranial magnetic stimulation

for the treatment of tinnitus: Pooled analysis of two randomized
controlled studies

B. LANGGUTH1,2, M. LANDGREBE1,2, E. FRANK1,2, M. SCHECKLMANN1,2,

World J Biol Psychiatry Downloaded from informahealthcare.com by University of Zuerich on 08/22/12

P. G. SAND1, V. VIELSMEIER2,3, G. HAJAK1 & T. KLEINJUNG2,3,4

1Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany, 2Interdisciplinary Tinnitus
Clinic, University of Regensburg, Regensburg, Germany, 3Department of Otorhinolaryngology, University of Regensburg,
Regensburg, Germany, and 4Department of Otorhinolaryngology, University of Zurich, Zurich, Switzerland

Abstract
Objectives. Tinnitus is related to alterations in neuronal activity of auditory and nonauditory brain areas. Targeted modu-
lation of these areas by repetitive transcranial magnetic stimulation (rTMS) has been proposed as a new therapeutic
approach for chronic tinnitus. Methods. Two randomized, double-blind, parallel-group, controlled clinical trials were
performed subsequently and pooled for analysis. A total of 192 tinnitus patients were randomly allocated to receive 10
stimulation sessions of either sham rTMS, PET-based neuronavigated 1 Hz rTMS, 1Hz r TMS over the left auditory
For personal use only.

cortex, or combined 20 Hz rTMS over the left frontal cortex, followed by 1 Hz rTMS over the left auditory cortex.
Results. rTMS treatment was well tolerated and no severe side effects were observed. All active rTMS treatments resulted
in significant reduction of the TQ as compared to baseline. The comparison between treatment groups failed to reach
significant differences. The number of treatment responders was higher for temporal rTMS(38%) and combined frontal
and temporal rTMS (43%), as compared to sham (6%). Conclusions. This large study demonstrates the safety and toler-
ability of rTMS treatment in patients with chronic tinnitus. While the overall effect did not prove superior to placebo,
secondary outcome parameters argue in favour of the active stimulation groups, and specifically the combined frontal
and temporal rTMS protocol.

Key words: Neuropsychiatry, transcranial magnetic stimulation, PET, tinnitus, randomized clinical trial

Introduction
Tinnitus, the perception of sound in the absence of
an auditory stimulus, severely impairs quality of life
in about 1–3% of the population (Axelsson and
Ringdahl 1989). These figures are expected to
increase due to increasing occupational and leisure
noise, warfare and demographic development. Severe
tinnitus is frequently associated with depression,
anxiety and insomnia (Langguth et al. 2011) and is
difficult to treat (Dobie 2004).
The majority of patients with tinnitus present with
a lesion in the peripheral auditory system which,
however, is not the direct substrate of tinnitus. It is
widely held that the neuroplastic changes which occur
in the brain following sensory deafferentiation lead to
changes in neuronal processing and, ultimately to tin-
nitus (Moller 2007). FDG-PET studies in tinnitus
patients have revealed abnormal asymmetry in the
auditory cortices of tinnitus patients with higher lev-
els of spontaneous metabolic activity predominantly
on the left side, irrespective of tinnitus laterality
(Arnold et al. 1996; Langguth et al. 2006a).
Transcranial magnetic stimulation (TMS) is a
non-invasive technique that applies a brief magnetic
pulse to the scalp and underlying cortex and changes
the pattern of neuronal firing (Allen et al. 2007).
Based on its ability to focally modulate cortical activ-
ity, repeated applications of repetitive transcranial
magnetic stimulation (rTMS) have been proposed as
a treatment approach for tinnitus (Kleinjung et al.
2005). Several placebo controlled clinical trials have
already shown beneficial effects of rTMS over
temporal or temporoparietal brain areas (Kleinjung
et al. 2005; Plewnia et al. 2007; Rossi et al. 2007;

Correspondence: Berthold Langguth, MD, Department of Psychiatry, University of Regensburg, Universitaetsstraße 84, 93053 Regensburg,
Germany. Tel: ⫹49 941 941 2099. Fax: ⫹49 941 941 2025. E-mail: Berthold.Langguth@medbo.de

(Received 14 June 2011; accepted 18 April 2012 )

ISSN 1562-2975 print/ISSN 1814-1412 online © 2012 Informa Healthcarev
DOI: 10.3109/15622975.2012.708438
 2 B. Langguth et al.
Khedr et al. 2008; Marcondes et al. 2010; Anders
et al. 2010; Mennemeier et al. 2011; Piccirillo et al.
2011). However, most studies are burdened by only
moderate sample size and high interindividual vari-
ability (Langguth et al. 2008). Therefore, evidence
for the efficacy of rTMS in the treatment of tinnitus
is still inconclusive.
As for stimulation protocols, no consensus has yet
been reached. While some authors advocate stimula-
tion according to individual neuroimaging findings
(Kleinjung et al. 2005; Plewnia et al. 2007) or con-
tralateral to the tinnitus (Khedr et al. 2010), others
routinely favour left sided stimulation (Langguth
et al. 2006b). According to a pilot study, combined
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stimulation of the frontal cortex and the auditory
cortex would appear to outperform simple temporal
stimulation (Kleinjung et al. 2008). A rationale for
the combined stimulation approach is provided by
visualization of tinnitus-related changes in neural
networks involving auditory and non-auditory
brain areas (Lanting et al. 2009; Schlee et al. 2009;
De Ridder et al. 2011).
The presented two large studies address the effects
of three different stimulation protocols, all of which
have shown promising effects in the past. These
For personal use only.
comprise (i) neuronavigated active and sham rTMS
over the area of increased metabolic activity in the
temporal cortex as revealed by individual positron
emission tomography (PET) scans (Kleinjung et al.
2005), (ii) low-frequency rTMS over the left tempo-
ral cortex with the coil positioned based on 10–20
EEG coordinates (Langguth et al. 2006b), and (iii)
combined high-frequency left frontal rTMS followed
by low-frequency left temporal rTMS (Kleinjung
et al. 2008).
Methods
Study design
Two randomised, double-blind, parallel-group stud-
ies were performed at the Tinnitus Center of the
University of Regensburg with identical inclusion
and exclusion criteria. From 2004 to 2006, patients
were randomly assigned to neuronavigated rTMS or
sham rTMS, and from 2007 to 2009, patients were
randomised to left temporal rTMS or to combined
temporal and frontal rTMS (see Figure 1).
Patients
Patients were eligible for the study if they were aged
18–80 years and suffered from subjective tinnitus
with duration of at least 3 months. All patients
underwent a complete ontological and audiolo-
gical examination. Exclusion criteria were Morbus
Meniere, conductive hearing loss, objective tinni-
tus, a history of seizures, a clinically relevant
psychiatric comorbidity, a suspected diagnosis of
organic brain damage, cardiac pacemakers or other
electrical implants, pregnancy and prior treatment
with rTMS.
Based on previous studies (Kleinjung et al. 2005)
an effect size of 0.6 was estimated. Power estimations
(1–β ⫽ 0.8; α ⫽ 0.05) resulted in a sample size of
45 per treatment arm to reveal significant group dif-
ferences. All patients gave written informed consent
before participating in the study which was approved
by the local institutional review board and performed
according to the declaration of Helsinki.
Randomisation and blinding
At the beginning of both studies treatment protocols
were randomly assigned to patient code numbers.
Both patients and investigators were blind to treat-
ment conditions (observer blind). The non-blinded
study staff applying rTMS was instructed not to
communicate the treatment arm to anybody involved
in patient management. To assess blinding success,
patients of the first study phase were asked at the
final visit for their best guess whether they received
real or sham rTMS.
Procedures
During the first study phase all patients underwent
FDG-PET and magnetic resonance imaging (MRI)
before they were randomized to active rTMS (neu-
ronavigated group) or to sham rTMS (sham group).
PET imaging was performed after injection of [18F]
deoxyglucose (FDG) (ECAT EXACT 47, Siemens).
After fusion with structural MRI-data (MPRAGE,
T1 weighted, 1.5 T Magnetom Symphony; Siemens)
the area of increased activation within the auditory
cortices was identified as target for rTMS (Figures
2 and 3) (Kleinjung et al. 2005). The coil was posi-
tioned over this area by using a neuronavigational
system (Vectorvision, BrainLAB AG, Germany) with
the handle of the coil pointing upwards. Repetitive
transcranial magnetic stimulation was applied with a
figure-of-eight coil, (90 mm outer diameter; coil
MC-B70, Medtronic, Minneapolis, MN) connected
to a stimulator (MagPro Option, Medtronic, Min-
neapolis, MN). Patients were enrolled into the study
on Mondays and received stimulation on 10 subse-
quent working days. The rTMS protocol consisted
of 2000 stimuli per session at a frequency of 1 Hz
and an intensity of 110% motor threshold. For sham
stimulation, a specific sham-coil system was used
(90 mm outer diameter; coil MC-B70, Medtronic,
Minneapolis, MN).

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For personal use only.
Figure 1. Patient flow.
During the second study phase patients were
randomised to receive either low-frequency rTMS
(2000 stimuli; 1 Hz; 110% motor threshold) over the
left temporal cortex (left temporal group) or a com-
bined protocol consisting of high-frequency rTMS
of the left dorsolateral prefrontal cortex (40 trains
with 50 stimuli; 25-s intertrain interval; 20 Hz; 110%
motor threshold) followed by low-frequency rTMS
(2000 stimuli; 1 Hz; 110% motor threshold) of the
left temporal cortex (in total 4000 stimuli per ses-
sion; combined group). Coil positioning over the
temporal cortex was based on 10–20 EEG coordi-
nates (Langguth et al. 2006b), over the left dorso-
lateral prefrontal cortex (DLPFC) on a standard
algorithm by moving the coil from the optimal posi-
tion for stimulation of the right abductor minimi
6 cm in anterior direction. In both groups (left tem-
poral and combined group) rTMS was administered
TMS for treating tinnitus 3
over the left hemisphere independently of handed-
ness or tinnitus laterality (Langguth et al. 2006b).
For temporal cortex stimulation the handle of the
coil was pointing upwards, for prefrontal stimulation
backwards 45° away from the midline.
During treatment patients were seated comfort-
ably in a reclining chair and the coil was held with
a mechanical arm. The motor threshold (RMT) was
determined for the right abductor digiti minimi and
defined as the lowest intensity at which at least four
of eight consecutive magnetically evoked potentials
were ⱖ 50 μV in amplitude while the investigated
muscle was at rest.
Assessment instruments
Tinnitus severity was assessed at screening, before
treatment (baseline), at the end of treatment (day 12)
 4 B. Langguth et al.
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Figure 2. FDG-PET of patient #1. [18F]Deoxyglucose (FDG)
positron emission tomography (PET) had been performed in
each patient before treatment. The area of hypermetabolic
activity in the temporal cortex was chosen as target for TMS
treatment. Here the FDG PET of patient #1 is displayed, where
For personal use only.
a transversal slice through the temporal brain region shows
unilaterally increased metabolic activity (arrow) in projection to
the left auditory cortex.
and during a follow-up period of 11 weeks after
rTMS treatment (days 18, 25, 59, 90) by using the
tinnitus questionnaire (TQ) (Goebel and Hiller
1994). For additional subjective assessment of treat-
ment effects, a self-rating scale for the measurement
of subjective well-being (BfS ⫽ Befindlichkeitsskala)
(Zerssen 1976) was used, which is especially suitable
for the assessment of rapid mood changes (Schwarz
and Strian 1972).
Statistical analysis
The primary efficacy endpoint was the absolute
change in the TQ total score from baseline to end of
treatment (day 12). Also the number of treatment
responders, defined as a minimum difference of five
points between pre- and post-treatment mean scores
(Kleinjung et al. 2007), were analysed. Secondary
efficacy endpoints were the TQ total score from pre
(mean value of screening and baseline) to post treat-
ment (mean value of days 12, 25, 59, and 90). Fur-
ther secondary efficacy endpoints were the change
in the Bf-S from pre (baseline) to post treatment
(mean value of days 12 and 25).
The statistical analysis was performed on an
intention-to-treat basis including all patients who
Figure 3. Site of stimulation on a 3-D brain reconstruction.
The red area approximates the magnetic field on the brain surface,
as computed by the neuronavigation system.
underwent at least one rTMS session and using a
last observation carried forward approach. Repeated-
measures analysis of variance (ANOVA) with time
as within factor (two levels: baseline vs. day 12 for
primary outcome; pre vs. post for secondary out-
comes) and treatment (four levels) as between factor
was used for estimation of primary and secondary
treatment effects. Furthermore, in exploratory anal-
yses separate within-group comparisons between
baseline and day 12 (primary outcome) and between
pre and post treatment (secondary outcome) mea-
surements were performed for the different treat-
ments by using paired Student’s t-tests. Additionally,
separate comparisons were performed between the
active groups and the sham group for baseline and
pre treatment corrected TQ changes (primary out-
come: day 12 minus baseline; secondary outcome:
mean post minus mean pre treatment) using unpaired
Student t-tests including calculation of effect sizes.
The secondary outcome “mean post (days 12, 25,
59, 90) minus mean pre (screening, baseline)” has
been performed to take into account the expected
variability of tinnitus measurements over time. Group
differences in the ratio of treatment responders were
calculated by chi-square tests.
Baseline clinical and demographic characteristics
between the different treatment groups were com-
pared by using one-way ANOVAs or by chi-square
tests. The second trial is registered with Clinical-
Trials.gov (NCT 00876720).
Role of the funding source
The study was funded by the Tinnitus Research
Initiative. The Tinnitus Research Initiative had no
 TMS for treating tinnitus 5

involvement in study design, data collection, analy-
sis, or interpretation of data. There was also no
involvement in the writing of the report or in the
decision to submit the paper for publication.
Results
Patient flow and rTMS side effects
Between 2004 and 2006, a total of 302 patients were
screened for enrolment in study one, between 2007
and 2009, a total of 287 patients were screened for
study two (Figure 1). In each study 96 patients were
enrolled and randomly allocated to one out of two
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age, tinnitus laterality, and mean hearing loss.
However, correlations of TQ changes with age and
mean hearing loss were weak (all r values
–0.049 ⬍ r ⬍ 0.241; all P values ⬎ 0.134), indicating
that these sample characteristics did not confound
treatment effects. ANOVAs with the factors treat-
ment groups (four levels) and tinnitus laterality
(three levels) revealed no significant main effect of
tinnitus laterality (F ⫽ 0.3; df ⫽ 2,68; P ⫽ 0.738).
Likewise, no significant group by laterality interac-
tion was seen (F ⫽ 1.6; df ⫽ 6,68; P ⫽ 0.138).
Primary outcome criterion

treatment arms. Four patients dropped out after ran-
domization, but before study start, because of with-
drawal of consent, resulting in 188 who received at
least one rTMS session. Three patients discontinued
rTMS treatment (one sham, one neuronavigated,
one combined). The reason for discontinuation was
transient worsening of tinnitus in all three cases.
Headache, site discomfort, and facial twitching
were reported by about 15% of the patients treated
with active rTMS (neuronavigated 7; left temporal
7; combined 8) and by three of the sham treated
For personal use only.
A descriptive overview of treatment effects on TQ
scores is given in Figure 4. Comparison between TQ
scores at baseline and at day 12 revealed a significant
effect of time (F ⫽ 19.2; df ⫽ 1,184; P ⬍ 0.001), how-
ever the interaction between time and group did not
reach statistical significance (F ⫽ 1.3; df ⫽ 3,184;
P ⫽ 0.271). Exploratory comparison of the TQ base-
line score and the TQ score at day 12 revealed a
significant difference for all active groups (neuro-
navigated: mean difference (MD), 1.88; confidence
interval (CI), 0.16–3.59; T ⫽ 2.2; df ⫽ 47; P ⫽ 0.032;

patients (7%). No patient discontinued rTMS treat-
ment because of these adverse effects. No seizures
or other serious adverse events occurred.
Table I shows clinical and demographical charac-
teristics of patients. Treatment groups were similar
with respect to gender, tinnitus duration, baseline
tinnitus scores, and baseline general well being
scores. Treatment groups differed significantly for
left temporal: MD, 2.00; CI, 0.18–3.82; T ⫽ 2.2;
df ⫽ 47; P ⫽ 0.032; combined: MD, 3.32; CI,
1.23–5.40; T ⫽ 3.2; df ⫽ 46; P ⫽ 0.002), but not for
the sham group (MD, 0.76; CI, –0.88–2.39; T ⫽ 0.9;
df ⫽ 44; P ⫽ 0.357).
Exploratory analyses of TQ changes (TQ at day
12 minus TQ at baseline) of the active groups vs. the
sham group revealed no significant contrasts with

Table I. Demographic and clinical characteristics of patients (intention-to-treat analysis set) (mean ⫾ SD).

sham neurons vieated left temporal combined

n 45 48 48 47 statistics
age (years) 50.3 ⫾ 12.9 44.9 ⫾ 11.5 50.4 ⫾ 12.5 52.7 ⫾ 11.4 F ⫽ 3.6; dt ⫽ 3,184; p ⫽ 0.015∗
women 14(31%) 13(27%) 16(33%) 15 (32%) χ2 ⫽ 0.5; df ⫽ 3: p ⫽ 0.922
healing function (mean dB 15.7 ⫾ 107 11.2 ⫾ 7.0 14.4 ⫾ 10.3 19.0 ⫾ 15.2 F ⫽ 3.0: df ⫽ 3,134:
HL over all tested (n ⫽ 40) (n ⫽ 40) (n ⫽ 31) (n ⫽ 27) p ⫽ 0.034∗∗
frequencies (125-8000Hz)
and over both ears)
tinnitus duration (months) 74.4 ⫾ 74.2 68.0 ⫾ 97.0 78.3 ⫾ 64.9 89.7 ⫾ 109.3 F ⫽ 0.5: df ⫽ 3,175:p ⫽ 0.702
(n ⫽ 45) (n ⫽ 45) (n ⫽ 46) (n ⫽ 43)
tinnitus laterality (left or 17; 20; 8 10; 23;12 21;12;14 21;9; 13 χ2⫽14.5; df ⫽ 6; p ⫽ 0.025∗∗∗
left ⬎ right; left ⫽ right or
in head; right or
right ⬎ left)
tinnitus questionnaire (TQ) 36.2 ⫾ 16.6 3 7.9 ⫾ 17.8 38.6 ⫾ 19.6 37.9 ⫾ 18.3 F ⫽ 0.2; df ⫽ 3,184: p ⫽ 0.933
baseline score
general wellbeing (BfS) 15.7 ⫾ 12.0 16.2 ⫾ 12.7 15.2 ⫾ 11.2 18.2 ⫾ 14.6 F ⫽ 04; df ⫽ 3,157; p ⫽ 0.722
baseline score (n ⫽ 36) (n ⫽ 41) (n ⫽ 43) (n ⫽ 41)

∗neuronavigated group significant younger than the other groups

∗∗neuronavigated group significant better hearing function than the combined group
∗∗∗significant, different ratio of tinnitus laterality of the neuronavigated group in contrast to the left temporal and combined group
 6 B. Langguth et al.

Figure 4. Changes of tinnitus questionnaire (TQ) scores after rTMS as compared to baseline (mean ⫾ SE).
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small effect sizes for the contrast neuronavigated vs.
sham (T ⫽ 1.0; df ⫽ 91; P ⫽ 0.345; d ⫽ 0.197) and left
temporal vs. sham (T ⫽ 1.0; df ⫽ 91; P ⫽ 0.311;
d ⫽ 0.211). As opposed to the sham group, the com-
bined group showed higher TQ changes with a trend
toward significance and a moderate effect size
(T ⫽ 1.9; df ⫽ 90; P ⫽ 0.056; d ⫽ 0.405).
Responders were defined as those patients with at
least 5 points reduction in the mean TQ score post
For personal use only.
corresponding to an effect size of 1.8. There were 10
responders in the neuronavigated group (21%), 18
in the left temporal group (38%), 20 (43%) in the
combined group, but only six (13%) in the sham
group. The difference in the responder rates across
stimulation conditions was significant (χ2 ⫽ 12.9;
df ⫽ 3; P ⫽ 0.005). Pairwise comparisons with sham
treatment by chi-square tests revealed a significantly
higher number of treatment responders for left tem-

rTMS as compared to the mean TQ score pre rTMS poral rTMS (χ2 ⫽ 7.1; df ⫽ 1; P ⫽ 0.008) and com-
(Kleinjung et al. 2007). The average improvement bined frontal and temporal rTMS (χ2 ⫽ 9.7; df ⫽ 1;
among responders was 27% reduction of the mean P ⫽ 0.002), but not for neuronavigated rTMS
TQ score post rTMS as compared to pre rTMS, (χ2 ⫽ 0.9; df ⫽ 1; P ⫽ 0.338) (Figure 5).

Figure 5. Individual changes of tinnitus questionnaire (TQ) scores after rTMS (mean of day 12, day 25, day 59, and day 90) as compared
to pre rTMS (mean of screening and baseline) indicating treatment response by a change of 5 points.

Secondary outcome criteria
Based on all time points (screening and baseline vs.
days 12, 25, 59, and 90) ANOVA demonstrated a
significant effect of time on TQ scores (F ⫽ 6.7;
df ⫽ 1,184; P ⫽ 0.010), but no significant interaction
of time and group (F ⫽ 1.4; df ⫽ 3,184; P ⫽ 0.243).
Separate within-group comparisons of the mean TQ
score post rTMS (days 12, 25, 59, and 90) and the
mean TQ score pre rTMS (screening and baseline)
revealed significant differences only for the left tem-
poral stimulation group (T ⫽ 2.3; df ⫽ 47; P ⫽ 0.028)
and the combined stimulation group (T ⫽ 2.0;
df ⫽ 46; P ⫽ 0.05), but neither for the neuronavigated
( T ⫽ 0.6; df ⫽ 47; P ⫽ 0.575) nor for the sham group
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(T ⬍ 0.1; df ⫽ 44; P ⫽ 0.990). Analyses of pre treat-
ment corrected post treatment TQ changes (days 12,
25, 59, and 90 minus screening and baseline) between
groups revealed no significant contrasts with small
effect sizes for the contrast neuronavigated vs. sham
(T ⫽ 0.4; df ⫽ 91; P ⫽ 0.665; d ⫽ 0.090), and medium
effect sizes for left temporal vs. sham (T ⫽ 1.8;
df ⫽ 91; P ⫽ 0.082; d ⫽ 0.366) and combined vs.
sham (T ⫽ 1.7; df ⫽ 90; P ⫽ 0.101; d ⫽ 0.348).
Comparison of wellbeing scores at baseline with
mean post treatment values for days 12 and 90
For personal use only.
revealed no significant effect of time (effect of time:
F ⫽ 0.6; df ⫽ 1,157; P ⫽ 0.440) and no significant
interaction between time and group (interaction
time ⫻ group: F ⫽ 1.5; df ⫽ 3,157; P ⫽ 0.217).
Blinding success in study phase one
During study phase one, patients were asked at the
last visit (day 90) about their guess which stimula-
tion they had received. Among those who thought to
be treated with active rTMS 63% received active
rTMS whereas 37% had sham treatment. Among
those patients who were convinced to be treated with
sham, 23% had active rTMS and 77% had sham.
This difference was significant (χ2 ⫽ 4.5; df ⫽ 1;
P ⫽ 0.034).
Discussion
In the performed studies, 192 patients received one
of four different treatment conditions: 1 Hz sham
rTMS, 1 Hz neuronavigated FDG-PET guided
rTMS, 1 Hz left temporal rTMS or combined 20 Hz
left frontal followed by 1 Hz left temporal rTMS.
A statistically significant reduction in TQ scores
immediately after rTMS in comparison to baseline
pre rTMS was found in all three active treatment
arms, but not for sham rTMS. However, the direct
comparison between the three active treatments
against the sham condition, which was chosen as
TMS for treating tinnitus 7
primary outcome criterium, did not reach statistical
significance. Effect size for the neuronavigated
(d ⫽ 0.197) and the left temporal (d ⫽ 0.211) group
was small, whereas effect size for the combined
group was medium (d ⫽ 0.405). Overall, the effect
size of rTMS for treatment of tinnitus severity in our
study was smaller than had been suggested by the
pilot study (d ⫽ 0.6) (Kleinjung et al. 2005) on which
the sample size estimation was based. Given the high
inter-individual variability in treatment outcome the
higher effect size in the pilot study may be explained
by its small sample size together with an accidentally
high proportion of treatment responders in that
sample.
The analysis of secondary outcome parameters
(all post vs. all pre treatment TQ scores) confirmed
significantly higher responder rates in left temporal
and combined frontal and temporal rTMS as com-
pared to the sham group (Figure 5). In the com-
parison between active and sham conditions, a
potential bias due to insufficient blinding has to be
considered. Correct estimation of treatment condi-
tion was significantly above chance level, indicating
the urgent need for more sophisticated sham condi-
tions (Rossi et al. 2007; Mennemeier et al. 2009) and
for controlling blinding success in rTMS trials
(Broadbent et al. 2011).
Comparing the three active rTMS protocols, the
treatment combining high-frequency left frontal
rTMS and 1 Hz left temporal rTMS was most
efficient. This is in line with results from a pilot
study which revealed longer lasting effects of such
a combined stimulation protocol as compared to
temporal rTMS alone (Kleinjung et al. 2008). The
DLPFC is well known to play an important role in
auditory processing. It is involved in auditory mem-
ory (Bodner et al. 1996) and auditory attention
(Alain et al. 1998). Functional imaging (De Ridder
et al. 2011) and magnetoencephalography (Schlee
et al. 2009) studies have confirmed the involvement
of the dorsolateral prefrontal cortex in tinnitus
pathophysiology. Since the DLPFC exerts an inhib-
itory top-down modulation on input to the audi-
tory cortex (Knight et al. 1989), high-frequency
rTMS of the DLPFC may exert beneficial effects
by normalizing this dysfunctional top-down inhibi-
tory process in tinnitus patients. Further studies
will be needed to confirm the advantage for com-
bined fronto-temporal stimulation and to demon-
strate that the beneficial effect is related to multi-site
network stimulation and not just to the higher
number of stimuli per day or frontal rTMS alone.
A pure effect of frontal stimulation on mood as an
explanation for the superiority of combined stimu-
lation seems rather unlikely since no significant
effects on wellbeing scores were observed.
 8 B. Langguth et al.
We also found that neuronavigated positioning
of the TMS coil over the area of maximal meta-
bolic activity in the auditory cortex was not supe-
rior to coil positioning over the left temporal
cortex based on EEG coordinates. This finding is
in line with very recent results questioning the
utility of PET for targeting rTMS. Specifically,
rTMS-induced tinnitus improvement does not
appear to correlate with changes in PET activity
at the treatment site (Mennemeier et al. 2011). In
this context, findings from rTMS over the motor
cortex for the treatment of pain may be of rele-
vance. There rTMS was more effective when the
stimulation was applied to an area adjacent to the
World J Biol Psychiatry Downloaded from informahealthcare.com by University of Zuerich on 08/22/12
cortical representation of the painful zone rather
than to the motor cortical area of the painful zone
itself (Lefaucheur et al. 2006). Another potential
explanation may be that rTMS interferes with tin-
nitus by modulating inhibitory function in the
thalamus (Langguth et al. 2007b; May et al. 2007)
and that the exact cortical area does not matter as
long as auditory corticothalamic loops are reached.
It is also possible that rTMS exerts its activity on
the primary auditory cortex (Lorenz et al. 2010)
via stimulation of the more superficial secondary
For personal use only.
auditory cortex, as suggested by findings from epi-
dural stimulation (De Ridder et al. 2007). Direct
comparison of the stimulated area and treatment
effects on an individual level could help to clarify
whether treatment response depends on exact
coil positioning and what would be the optimal
target (Langguth et al. 2010). Unfortunately the
neuronavigation system used in this study
did not allow to mark the stimulated area in the
individual MR dataset making such an analysis
impossible.
Moreover we cannot exclude that unspecific
effects of stimulation may account for the observed
treatment effects. Since cortical stimulation with
rTMS is always accompanied by some form of
auditory and somatosensory stimulation, these
effects may play a role in mediating the TMS effect
(Schecklmann et al. 2011; Zunhammer et al. 2011).
Since our sham condition involved auditory stimu-
lation, acoustic stimulation can be largely excluded
as an explanation of the observed effect. However
stimulation of superficial nerves may be partly
involved in the mediation of the rTMS effect on
tinnitus via modulation of afferent somatosensory
input, as suggested by a recent study that compared
the effects of single sessions of rTMS and trancu-
taneous electrical nerve stimulation on tinnitus
(Vanneste et al. 2011).
It should be noted that all comparisons between
the first (sham and PET guided) and the second
study (left temporal; combined left frontal and
temporal) have to be interpreted with caution since
the two studies were performed subsequently and
patients were selected and randomized at different
time-points. Nevertheless, we considered a pooled
analysis appropriate since the two studies were
planned together, performed at the same centre by
the same staff with the same equipment and with
identical inclusion and exclusion criteria. There were
differences in age and mean hearing loss of the
patient groups participating in the two studies, prob-
ably reflecting changes in the patient population
seeking help at our tinnitus clinic over the last years.
But these characteristics should not have confounded
results since they did not correlate significantly with
treatment outcome. However, further confounders
such as differences in the anticipation of the treat-
ment effect between study one and two or differ-
ences in the experience of the staff with rTMS
cannot be excluded.
In this study, treatment outcome was only
assessed by the tinnitus questionnaire (TQ), a well-
validated instrument for the assessment of tinnitus
severity (Goebel and Hiller 1994), which is widely
used in clinical practice. However since the time
when the presented trial was planned increasing
consensus emerged that, for comprehensive assess-
ment of treatment outcome, tinnitus questionnaires
should be complemented by additional instruments
such as visual analogue scales or instruments for
the assessment of depression, anxiety, quality of life
or clinical global impression (Langguth et al. 2007a;
Elgoyhen and Langguth 2010; Landgrebe et al.
2010). In summary, our study demonstrates that
active rTMS can alleviate tinnitus. However, the
magnitude of these effects is relatively low and calls
for further studies involving large sample sizes. Our
results further question the usefulness of PET-
guided neuronavigated coil positioning and under-
score the potential of stimulating non-auditory
targets.
Authors’ contributions
BL, ML, PGS, GH and TK designed the study, BL,
ML, EF, VV and TK performed the study, BL and
MS analysed the data and drafted the manuscript
and all authors approved the final version of the
manuscript
Statement of Interest
None of the authors has a conflict of interest in rela-
tion to the presented study.
The study was funded by the Tinnitus Research
Initative.

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