1

Master thesis part 1

The effect of bimodal stimulation on

tinnitus severity in patients with
tinnitus: a systematic review
Academic year
2019 - 2020

Aktepe Özlem
Happé Yentl
Westerterp Stèphanie

Supervisor: Prof. dr. Michiels Sarah

Disclaimer Master Thesis
This master thesis is an exam document that was not corrected for any possible mistakes. It
is not permitted to reproduce, copy, use or adapt (parts of) this publication without written
permission from both the promotor(s) and the author(s). Requests for obtaining the right to
reproduce or utilize parts of this publication should be addressed to the university where the
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A written permission from the supervisor(s) is also required to use the (original) methods,
products, schematics and programs described in this work for industrial or commercial use,
and for submitting this publication to participate in scientific prizes or contests.
This document complies with the faculty regulations and the master of epidemiology
guidelines and has been checked by the supervisor and/or coach of the master thesis.

Checklist
 Name: Stèphanie

Surname: Westerterp

Title master thesis: “The effect of bimodal stimulation on tinnitus severity in patients with tinnitus.”

Promotor and guidance team: Michiels Sarah

Not Fulfilled
fulfilled
I know the guidelines of the faculty regulations for master’s theses. X
I know the guidelines of the educational guidebook for master’s theses. X
I have delivered the version that I will submit, to my supervisor. X
I have informed my supervisors that I will submit my master thesis. X

Date: 14-5-2020

Signature student:

Acknowledgement
We would like to express our deep and sincere gratitude to our supervisor Prof. dr. Michiels Sarah, for giving us
the opportunity to do research and providing us with invaluable guidance throughout this research.
This assignment could not have been completed without the effort and cooperation of our group members.
Thank you for your enthusiasm and collegiality.
Finally, special thanks to our family and friends for all the help and support during these research times.

Table of Contents

List of figures and tables...........................................................................................................................................5

List of abbreviations..................................................................................................................................................6
Background...............................................................................................................................................................7
Abstract.....................................................................................................................................................................8
Introduction..............................................................................................................................................................9
Methods....................................................................................................................................................................9
Eligibility criteria and study selection.................................................................................................................10
Search strategy and study selection...................................................................................................................10
Data collection and analysis...............................................................................................................................10
The level of evidence and risk of bias in individual studies................................................................................10
Results of the search...........................................................................................................................................11
Study characteristics...........................................................................................................................................11
Risk of Bias Assessment......................................................................................................................................12
Results individual studies...................................................................................................................................12
Discussion................................................................................................................................................................13
Limitations..........................................................................................................................................................14
Conclusion...........................................................................................................................................................15
References...............................................................................................................................................................15
Plagiarism report.....................................................................................................................................................17
Research protocol...................................................................................................................................................18
Informed Consent...............................................................................................................................................22
Toestemmingsformulier.....................................................................................................................................25
Attachments............................................................................................................................................................26
Attachment 1: risk of bias table..........................................................................................................................26
Attachment 3: data-extraction table..................................................................................................................27

List of figures and tables  

Figures 1: flowchart: overview selection process
Table 1: characteristics of the selected studies
Table 2: risk of bias table  
Table 3: data-extraction table  
List of abbreviations  
BDI: Beck Depression Inventory
CAS: Compensatory Auditory Stimulation
CBT: Cognitive Behaviour Therapy
DLPFC: Dorsolateral Prefrontal Cortex
EBRO: Evidence-based Guideline Development
HD-tDCS: High-Definition Transcranial Direct Current Stimulation
LOCF: Last Observation Carried Forward
LTA: Left Temporoparietal Area
MDI: Major Depression Inventory
MML: Minimum Masking Level
PRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses
QoL: Quality of Life
RI: Residual Inhibition
ROBINS-I: Risk of Bias in Non-randomized Studies
rTMS: repetitive Transcranial Magnetic Stimulation
SF12: the 12-Item Short Form Health Survey
STAI: State-Trait Anxiety Inventory
tDCS: Transcranial Direct Current Stimulation
TFI: Tinnitus Functional Index
THI: Tinnitus Handicap Inventory
THQ: Tinnitus Handicap Questionnaire
TQ: Tinnitus Questionnaire
TRT: Tinnitus Retraining Therapy
VAS: Visual Analogue Scale
VNS: Vagus Nerve Stimulation
WHOQoL-BREF: World Health Organization Quality of Life – BREF questionnaire
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Background
This research was conducted within the Physical Therapy department of the Faculty of Medicine and Health
Sciences, of the University of Antwerp. The execution of this review was supervised and guided by promotor
Prof. dr. Sarah Michiels. The review was conducted by 3 Master students of the University of Antwerp, as part
of their master thesis.
The topic of tinnitus has been broadly studied by Prof. dr. Sarah Michiels, who has done research and published
several articles on this topic already. Follow up study is planned to be conducted in the fall of 2020 by the same
researchers. This systematic review provides an overview of the current evidence of the effect of bimodal
stimulation on tinnitus severity and forms a basis for further research on this subject.
The entire study, from literature search to writing the presented review, was conducted between October 2019
and May 2020. In the process of creating this review, all 3 students were involved. They each worked on
finetuning search strategy, collecting literature, discussing selection criteria and performing screening and risk
of bias assessment. The review was written by the 3 students and approved by the promotor.
 8

Abstract  
Introduction: Tinnitus is the perception of sound without the presence of an external acoustic stimulus. 1-2% of
all tinnitus patients experience severe impairments in their quality of life due to their tinnitus complaints.
Recently there has been an increasing interest in bimodal stimulation for the management of tinnitus. Electrical
stimulation or cranial nerve stimulation combined with sound stimulation may have a valuable effect in
normalizing the abnormal patterns of auditory neurons which are related to tinnitus complaints.
Objectives: To provide an overview of the evidence for the effect of bimodal stimulation on tinnitus severity.
Methods: We searched in PubMed, Web of Science and Scopus and an additional hand search was performed
in order not to miss any relevant articles. The most recent search was performed on October 24 th, 2019. Studies
in which tinnitus patients received a bimodal stimulation treatment and where the effect of the treatment on
tinnitus severity was assessed, were included.
Results: Five studies were included; two pilot studies, a single blind study, a cross-over study and a controlled
randomized trial. Three out of five studies reported a significant reduction in tinnitus severity after bimodal
stimulation using psychometrically validated questionnaires and outcome measures such as tinnitus rating
scale, visual analogue scale (VAS) and/or minimum masking level (MLL). Two studies that additionally assessed
the effect of their treatment on depression, anxiety and Quality of Life (QoL) could not report any significant
improvement.
Conclusions: Different types of bimodal stimulation may be effective in reducing tinnitus severity, regardless of
the large diversity of tinnitus patients, the different intervention protocols and outcome measures. In order to
draw a conclusion on long-term effects of bimodal stimulation, studies with a longer follow-up are
recommended. Further research with larger sample sizes to reach a more general conclusion about the effect
of bimodal stimulation are also recommended.

Keywords: tinnitus, electrical stimulation, auditory stimulation, bimodal, neuromodulation

 9

Introduction
Tinnitus is a common disorder, with a prevalence of 10-15%, which is defined as the perception of sound

without the presence of an external acoustic stimulus [15]. The perceived sound is often described as buzzing,
hissing, or ringing and can be intermittent or pulsatile [15]. Many tinnitus patients experience no restrictions in
their activities of daily life and therefor do not seek medical help [17]. However, 1-2% of all tinnitus patients
experience severe impairments in their quality of life [15]. The most commonly reported additional symptoms,

that can help define tinnitus severity [15], are frustration, annoyance, irritability, anxiety, depression, hearing
difficulties, insomnia and concentration difficulties [14].
For the treatment of tinnitus there is no golden standard that is effective for every patient [16]. Despite the
variation of treatment possibilities, therapy usually consists of learning to cope with and adjusting patients’
response to tinnitus-related symptoms [16]. The best evidence is currently available for cognitive behaviour

therapy (CBT) [3, 15]. The effectiveness of CBT in reducing tinnitus-related symptoms such as distress, anxiety
and depression has been proven several times [2]. Other possible treatment strategies are tinnitus retraining
therapy (TRT) and auditory stimulation (e.g. sound therapy, hearing aids and cochlear implants) [15]. Recently,
there has been an increased focus on the use of non-invasive neuromodulation techniques for the

management of tinnitus [12]. Several functional imaging studies report how patients with tinnitus show
increased activity in the auditory cortex and how co-activation of non-auditory brain regions could also lead to
tinnitus complaints [6, 9].
Neuromodulation intents to inhibit, stimulate or regulate the normal brain activity by influencing the electrical

activity in the central, peripheral or autonomic nervous system for therapeutic purposes [5]. Neuromodulation
techniques that can be used for the treatment of tinnitus patients are repetitive transcranial magnetic
stimulation (rTMS) and transcranial direct current stimulation (tDCS) of the temporoparietal and frontal brain
areas [5]. These techniques are based on the underlying concept of suppression of cortical activity by
stimulating the brain [12]. Repetitive transcranial magnetic stimulation can for instance be used to decrease
abnormal neural activity related to tinnitus [1, 15]. Some studies that assess the effectiveness of cranial nerve
stimulation (e.g. vagus nerve stimulation), have obtained promising results in animals while the results in

human studies were contrasting [5].

Based on several animal studies, combination therapy consisting of simultaneous electrical stimulation and
sound stimulation, seems promising in normalizing the abnormal patterns of auditory neurons which are

related to tinnitus complaints [4], resulting in an increasing interest in bimodal stimulation for the treatment of
tinnitus [11].
Therefore, the aim of this systematic review is to provide an overview of the available literature on the use and
effectiveness of bimodal stimulation on tinnitus severity in tinnitus patients.
 10

Methods  
This systematic review is reported according to the PRISMA (Preferred Reporting Items for Systematic reviews
and Meta-Analyses) guidelines [18].

Eligibility criteria and study selection

The aim of this systematic review was to report the evidence on the effectiveness of bimodal stimulation in
tinnitus patients. The main outcome of interest was the change in tinnitus severity and tinnitus loudness. To be
able to objectively assess this change, the search strategy was adjusted to target articles that used
questionnaires such as Tinnitus Handicap Inventory, Tinnitus Functional Index, amongst others. Animal studies,
case studies, studies that assess other treatment modalities than bimodal stimulation, single treatment,
surgery, pharmacological intervention or studies assessing the safety of electrical stimulation as main or only
outcome were excluded. An additional selection criterion was that articles had to be written in English or
Dutch.

Search strategy and study selection

A relevant research question was made to answer our research question: “What is the effect of bimodal
stimulation on tinnitus severity in patients with tinnitus?” Three databases were used (PubMed, Web of Science
and Scopus) to find the articles related to this topic, available on October 24 th, 2019. Based on the PICO-
question mentioned above, the following search strategy was used: tinnitus AND ((bimodal stimulation) OR
(combination OR bilateral OR mixed OR dual OR binaural) AND (treatment OR therapy)) AND (intensity OR
effect OR severity OR severeness OR tinnitus functional index OR tinnitus handicap inventory OR tinnitus
reaction questionnaire OR tinnitus handicap questionnaire). No filter was used in any database. Both screening
processes were carried out twice, each time by different researchers. In case of doubt, it was discussed
whether the article should be included or excluded between the three researchers. The articles that did not
meet the inclusion criteria were excluded from this review. An overview of the inclusion and selection process
can be found in the flowchart below (figure 1).

Data collection and analysis

A data-extraction table was used to summarize the relevant information for the included articles. Study design,
sample or eligibility criteria, the applied interventions, outcome and follow up, results and any remarks were
reported.

The level of evidence and risk of bias in individual studies

The level of evidence was determined according to the EBRO (evidence-based guideline development) method.
All articles included in this review were scored with a level B evidence. Risk of bias was assessed twice with
ROBINS-I tool by 3 independent researchers. After comparison, inconsistent domains were discussed until a
consensus was reached. The different domains and the final judgment of risk of bias were scored as low,
moderate, serious, critical or no information.
 11

Figures 1: flowchart: overview selection process

Results  
Results of the search
In PubMed the search strategy resulted in 398 articles. Web of Science and Scopus obtained respectively 325
and 74 articles. In addition, 2 articles were included that were obtained by hand searching. After the
elimination of the duplicates, a total of 665 relevant articles remained, which were screened on title and
abstract. After the first screening 24 articles remained which were further screened on full text. After screening
on full text, 5 relevant articles were included in the systematic review.

Study characteristics
Two pilot studies, a single blind study, a cross-over study and a randomized controlled trial were included.
Three out of the five studies were sham-controlled. A total of 119 tinnitus patients were included in the
selected studies. The characteristics of the individual studies are provided in table 1. Two studies investigated
the combination of tDCS and auditory stimulation [12, 19], a third investigated the effect of rTMS in
combination with auditory stimulation with the aim of relaxation [13], a fourth one used electrical
somatosensory stimulation in combination with auditory stimulation [16] and the fifth study investigated the
effect of vagus nerve stimulation in combination with tones [22]. Only the study of Tyler et al. (2017) included a
long-term follow-up of one year and the study of Kreuzer et al. (2016) had a shorter follow-up of 10 weeks.
Table 1: characteristics of the selected studies
 12

HD-tDCS = High Definition Transcranial Direct Current Stimulation; CAS = compensatory auditory stimulation: MML = minimum masking level; VAS = visual
analogue scale; rTMS = Repetitive Transcranial Magnetic Stimulation; TQ = Tinnitus Questionnaire; TFI = Tinnitus Functional Index. WHOQoL-BREF = World
Health Organization Quality of Life – BREF questionnaire; MDI = Major Depression Inventory; tDCS = Transcranial Direct Current Stimulation; LTA = left
temporoparietal area; VNS = vagus nerve stimulation; THI = Tinnitus Handicap Inventory; THQ = Tinnitus Handicap Questionnaire; BDI = Beck Depression
Inventory; STAI = State-Trait Anxiety Inventory; SF12 = the 12-Item Short Form Health Survey;

Risk of Bias Assessment

The Risk of Bias in Non-randomized Studies
Only the study of Marks et al. (2018) scored low for the final judgement of bias. The studies of Henin et al.
(2016), Shekhawat, Kobayashi and Searchfield et al. (2015) and Tyler et al. (2017) scored low to moderate for
the final judgement of bias while the study of Kreuzer et al. (2016) scored moderate. More detailed information
about the reason for assigning the degree of bias can be found in ‘attachment 2: risk of bias table’.

Results individual studies

The study of Shekhawat et al. (2015), one out of the two studies that assessed the effect of tDCS in
combination with auditory stimulation, could not show any significant changes in tinnitus loudness or a
significant suppression in MML. The second study of Henin et al. (2016) reported a synergistic effect on VAS
when both tDCS and CAS was applied compared to the single tDCS and single CAS intervention, however this
effect was also not significant.
The study of Kreuzer et al. (2016) that combined rTMS with auditory stimulation, using relaxation audio files,
reported a significant reduction in THI scores from baseline to week 2 (p=0.003) and from week 4 to week 12
(p=0.009) and a higher responder percentage (44.7%), based on a minimum reduction of 5 points on the TQ,
compared to the active control group (27.8%) and the sham stimulation group (21.7%). There was a significant
correlation between the degree of relaxation and the reduction in TQ scores.
The study of Tyler et al. (2017) that investigated the effect of vagus nerve stimulation (VNS) paired with tones,
was also able to show a positive effect of their treatment on tinnitus. A clinically significant improvement on
 13

the THI was reported in 50% of the participants after the treatment period of 6 weeks (p=0.023) and 56% of the
participants after the treatment period of 12 weeks (p=0.004) compared to baseline.
Finally, Marks et al. (2018) demonstrated the effectiveness of bimodal auditory somatosensory stimulation
compared to unimodal auditory somatosensory stimulation. The study reported a significant decrease in
tinnitus loudness (p=0.0035) and in the mean TFI scores (p=6.14 x 10 -5).
Two studies that additionally assessed the effect of their treatment on depression, anxiety and QoL could not
report any significant improvement [13, 22]. The effect of bimodal stimulation on psychological level fell
outside the scope of interest of this study but is not negligible given the impact of tinnitus complaints on the
emotional well-being of a patient.

Discussion 

This systematic review was conducted to assess the effectiveness of bimodal stimulation on
tinnitus severity and to provide an overview of the available literature on the subject. The
study has given insight in numerous possibilities with bimodal stimulation techniques. We
included 5 articles of which two pilot studies, a randomized sham-controlled single blind
study, a double-blinded cross-over study and a randomized controlled trial.
Two studies [12, 19], were unable to report significant changes in tinnitus complaints. Henin
et al. (2016) reported a synergistic effect in reducing VAS after applying HD-tDCS + CAS
treatment in patients with chronic tinnitus, compared to single HD-tDCS and single CAS.
However, this effect was not significant due to a small sample and insufficient practice of the
participants in the use of VAS [12]. The remaining three studies showed significant effects of
their treatment on tinnitus severity. Both Tyler et al. (2017) and Kreuzer et al. (2016)
reported a significant reduction in THI in participants with chronic tinnitus in a controlled
trial, the first by using VNS paired with tones and the second by combining rTMS with
relaxation. Marks et al. (2018) showed a significant decrease in TFI and tinnitus loudness on
somatic tinnitus as a result of bimodal auditory somatosensory stimulation compared to
unimodal auditory stimulation.
In a previous study, Shekhawat, Stinear and Searchfield (2013) reported that stimulation of
the left temporoparietal area (LTA) is effective for tinnitus suppression and the optimal
duration and intensity for tDCS was equal to respectively, 2 mA and 20 min. In the included
study of Shekhawat, Kobayashi and Searchfield (2015) in this systematic review, tDCS was
applied according to these stimulation settings in combination with 1-min auditory
stimulation and this resulted in immediate tinnitus suppression in 7 out of 9 participants
 14

based on the tinnitus rating scale. However, suppression in tinnitus loudness was not
significant [19]. In the study of Henin et al. (2016), HD-tDCS was also applied according to the
optimal stimulation settings (2mA and 20 min) [20]. A synergistic, but not significant effect
on VAS was found in combination with CAS. These two studies were thus unable to
demonstrate the effectiveness of the optimal stimulation settings reported in the study of
Shekhawat, Stinear and Searchfield (2013). This finding leads us to the question whether the
application of auditory stimulation in combination with tDCS may reduce the effectiveness of
electrical stimulation. Both Shekhawat, Kobayashi and Searchfield (2015) and Tyler et al.
(2017) reported limitations in the use and effectiveness of MML. In addition, no significant
effect for MML was found by Henin et al. (2016) in the bimodal stimulation group. This
suggests that MML might not be the best tool for measuring the effect of bimodal
stimulation in tinnitus patients. As suggested in Shekhawat’ discussion, it is hypothesized
that sound for monitoring MML may lead to recalibration of internal reference which
therefor does not show a decrease in MML [19].
However, Henin et al. (2016) was also unable to report a significant difference with the
single tDCS intervention. Two different interventions (HD-tDCS and CAS) were applied one
after the other in one treatment session. The limited wash out period between these two
interventions could have hidden possible positive effects of HD-tDCS due to interference
[12].
In another study Shekhawat and Vanneste (2018) reported a significant suppression in
tinnitus loudness after 15 min HD-tDCS of the dorsolateral prefrontal cortex (DLPFC) and
based on their findings that there is no difference between 15 min and 20 min of
stimulation, Shekhawat and Vanneste suggested that after 15 min of stimulation a plateau
phase is reached. Fregni et al. (2006) reported a significant, but short lasting (less than 5-6
minutes), effect on tinnitus reduction after both rTMS and anodal tDCS of LTA of short
duration. A frequency of 10 Hz and an intensity of 20% above the motor threshold was used
for the rTMS protocol. For the tDCS protocol a constant current with intensity of 1 mA was
applied for 3 minutes. The study of Kreuzer et al. (2016) reported that rTMS combined with
auditory stimulation forms an effective treatment and might be more effective than rTMS
alone for reducing tinnitus. But this statement could only be demonstrated by significant
differences in the THI scores. The difference with the study of Fregni et al. (2006) was that
high-frequency stimulation (20 Hz) of DLPFC was combined with low-frequency stimulation
 15

(1 Hz) of LTA with auditory stimulation for about 33 min. An intensity of 110 % of the resting
motor threshold was used in contrast to an intensity of 20% above the motor threshold in
the study of Fregni et al. (2006).
In addition, no responders were reported in the sham rTMS and sham tDCS interventions in
the study of Fregni et al. (2006), while De Ridder et al. (2005) who investigated the effect of
TMS, reported a placebo effect in 63% of the participants. This difference can be explained
by the variation in the intensity and duration of tinnitus of the participants that were
included in these two studies [7, 10]. The study of De Ridder et al. (2005) implemented
several sessions with longer duration of stimulation which can also be an influencing factor.
Both studies concluded that non-invasive brain stimulation resulted in a short-lasting
suppression of tinnitus and that tinnitus suppression was correlated with the duration of
tinnitus [7, 10].
Limitations
A possible limitation of our study is the limited amount of studies that were included in this
systematic review. The included studies had a small sample sizes and if present, a short
follow-up, apart from one study.
For the population sample we applied no other inclusion criteria besides being human and
experiencing tinnitus. Even though all participants in the studies met our criteria, the
individual studies had more specific inclusion criteria for their research. Considering all
included studies had their own way of selecting their participants, it is difficult to generalize
our findings for the entire tinnitus population, which is a very heterogeneous population.
In addition, 4 different study designs were applied in the 5 articles that were included. All of
them used different treatment protocols and most of them used different outcome
measures. This will make them less comparable because of the inability to draw a definite
conclusion about the effect of the design that was used or the optimal frequency of
treatment. Since tinnitus related complaints were assessed in several ways, it is not possible
to combine those outcomes without subjectively altering the results. Therefore, the only
way to generalize our findings is stating bimodal stimulation seems to have a positive effect
on tinnitus complaints in general, without specifying on which form of tinnitus. Considering
these limitations further research with larger sample sizes, comparing subgroups of tinnitus
patients and longer follow-up is recommended. Overall, more studies investigating the effect
 16

of bimodal stimulation are recommended in order to be able to compare both bimodal

stimulation of the same form among themselves and different forms of bimodal stimulation.
Conclusion
This systematic review showed that bimodal stimulation might be effective in reducing
tinnitus severity despite the large diversity of tinnitus patients, the different intervention
protocols and outcome measures. However, the limited number of included studies, small
sample sizes and short-term follow up within studies may significantly affect our findings,
resulting in a risk to overestimate the actual effect of bimodal stimulation. Further research
in larger samples and with a longer follow-up, to discuss long-term effects of bimodal
stimulation is recommended.

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Plagiarism report  
Plagiarism was checked via Blackboard SafeAssign on May 10 th, 2020.
This gave a 39% match on 9.309 words:
- 20% from institution database (8)
- 13% from internet (16)
- 6% from global database (11)
After checking the originality report, we could conclude that the similarities were mainly
based on references and referrals, titles, lists with the abbreviations used and a part of the
informed consent. Almost none of the self-written text was marked, allowing us to conclude
that there is a low risk of plagiarism in our work. The marked parts were checked and all
sources of the similarities in the self-written text were also mentioned in our reference list,
with the exception of parts corresponding to other students’ papers.
Research protocol
Research question
What is the effect of transcutaneous electrical nerve stimulation (TENS) combined with auditory stimulation on
tinnitus severity in patients with somatic tinnitus compared to the standard physical therapy intervention?

Objective
An increased activity in connecting fibers between the medullary somatosensory nuclei and the dorsal cochlear
nucleus (DCN), an important auditory nucleus in the brainstem, has been demonstrated in 20 to 40% of
patients with tinnitus. Increased spontaneous firing rate in the DCN as a result of the increased activity in these
connecting fibres leads to the perception of tinnitus. In this manner, altered somatosensory input from the
cervical spine or temporomandibular region can cause a tinnitus perception or an existing tinnitus can be
modulated. Zhan et al. demonstrated the existence of these connecting fibers in rats [14].
Koehler and Shore (2013) showed in animal experiments in guinea pigs that bimodal stimulation, consisting of
electrical stimulation of the spinal trigeminal nucleus and auditory stimulation, suppresses the spontaneous
firing rate of the DCN. In 2018, the same group of researchers demonstrated that this method of simultaneous
electrical stimulation at C2 or the jaw region and auditory stimulation also had a positive effect in humans on
the tinnitus loudness and tinnitus severity objectified by the TFI.
A previous pilot study of Sarah Michiels at UZA also showed that this treatment method is promising, especially
in patients with somatic tinnitus. However, it is not clear whether bimodal stimulation therapy has better
effects than the physical therapy that is currently applied as best evidence practice for these patients.
The aim of this study is therefore to investigate whether a combination of TENS at C2 or the jaw region, in
combination with auditory stimulation, has a positive effect on the tinnitus complaints of patients with somatic
tinnitus. In addition, it will be investigated whether bimodal stimulation provides a greater improvement in
tinnitus severity than the standard physical therapy currently provided.

Method
Research design
A randomized controlled trial to assess the therapeutic effect of bimodal stimulation compared to standard
physical therapy intervention.

Participants:
Patients diagnosed with chronic somatic tinnitus according to the diagnostic criteria for somatic tinnitus [11]
will be included in the study. In addition, tinnitus symptoms should be severe enough: a score between 25 and
90 points on the Tinnitus Functional Index (TFI). Patients with tinnitus as a result of Meniere's disease or other
active middle or inner ear diseases or tumoral processes will be excluded. Recruitment will take place at the
tinnitus consultation of the ENT department of UZA.
Intervention
Patients will be randomized before the start of the study in the bimodal stimulation group or in the physical
therapy group. This randomization will be done by Qminim randomization software. Both assessors and
patients will be aware of the group allocation.
Patients in the bimodal stimulation group will be treated for half an hour daily for 4 weeks with the bimodal
stimulation therapy using a take-home device. The bimodal stimulation consists of TENS treatment at C2 or jaw
region combined with auditory stimulation. TENS will be applied with an existing device: the EMPI TENS from
Chattanooga, which is approved according to the standard EN 60601-1 "Medical electrical equipment, Part 1:
General requirements for safety" and EN 60601-1-2 "Electromagnetic compatibility - medical electrical
equipment". A high-frequency burst-TENS with a frequency of 1000 Hz and an adjusted current (mA), so that
the current is clearly felt but not painful, will be used. This by analogy with the protocol of Marks et al. (2018)
[9].
Patients in the physiotherapy group will be treated by the physiotherapist for half an hour once a week for 9
weeks. In addition, they will perform a series of exercises daily. Within this treatment dysfunctions present at
the level of the cervical spine and the orofacial region will be treated by means of manual mobilisations and
exercise therapy.

Outcome measures:
The TFI will be used as the primary outcome measure because of its high responsiveness to
treatment-related change and high validity for scaling the severity of tinnitus [3, 10]. The
questionnaire consists of 25 items divided into 8 different subscales. Each item is rated by
the patient on a 10-point Likert scale [10], higher scores indicate greater limitations in daily
life activities [4]. A reduction of 13 points is necessary for a clinically significant improvement
[10]. TFI has a high internal consistency reliability (α=0,98) and a high test-retest reliability
(r=0,91) [10].

In addition, the patient will be asked to complete the following questionnaires:

- Neck Bournemouth Questionnaire: Consist of seven items [2, 13] with the aim of
questioning the pain intensity, experienced limitations in ADL, depression and the degree
of self-control in patients with neck complaints [12]. With a moderate test-retest
reliability (ICC=0,65) and tolerable construct validity (r=0,50 with NDI) [2,13]. A reduction
of 12 points is considered as a clinically relevant change [2, 13]. The diagnosis of
cervicogenic somatic tinnitus becomes more likely with a score of > 14/70 [12]
- TMD-pain screener: When the patient scores positive on 3 or more items of the 6 items
there is a suspicion of a temporomandibular disorder (sensitivity of 99% and a specificity
of 97% and a high internal consistency (α = 0.93) [6].
- Hospital Anxiety and Depression Scale: To identify clinically significant symptoms related
to anxiety and depression [7]. The two subscales (anxiety and depression) consist of 7
items [1]. Each item is scored with a 4-point Likert scale. The total score of each subscale
can range from 0 to 21 (0 = no anxiety/depression; 7 = severe anxiety/depression) [7].
The mean internal consistency for the anxiety and depression scales is respectively, 0.83
and 0.82 [1].
- VAS for tinnitus loudness in the past week: To detect reductions in tinnitus severity (test-
retest reliability r=0,8; validity r=0,67, p<0,05). Although the purpose of this scale is to
measure tinnitus loudness, the response of the patients correlates with the impact of the
tinnitus symptoms. Patients who experience more tinnitus related complaints tend to
give a higher score on the VAS scale [15].
- Hyperacusis questionnaire
- Big Five Index (BFI-2)

All questionnaires, except the BFI, will be completed at 3 different moments: baseline, after treatment and 8 to
12 weeks follow-up. The BFI will only be completed on baseline.

Statistical analysis
For data analysis SPSS will be used. To determine the difference in TFI scores from baseline to the end of
treatment, for both the intervention group and the control group, a one-sample t-test will be performed. In
addition, an independent t-test will be performed to investigate a significant difference in TFI scores after the
treatment and 8 to 12 weeks between the intervention group and control group. A repeated measure ANOVA
will be applied to determine whether bimodal stimulation versus physical therapy influences the outcome
measures and whether there is a significant interaction effect.

Sample size
The sample size was calculated using G*Power [5] by means of a T-test for two independent groups. The
required parameters were the significance level (α), power and the effect size. The effect size was calculated
using the standard deviation of the TFI scores in the study by Chandra et al. (2018) in which 318 male
participants were included. The required sample size to find a clinically significant difference of at least a
reduction of 13 points on the TFI with a significance level of 5% and a power of 80% is equal to 84 participants
(42 participants in both the intervention and the control group).
Planning
October/November 2020
Recruitment of participants
February/March 2021
Randomized allocation of participants in an intervention group
Start of the study: applying the interventions in each group
April 2021
Data collection
April-May 2021
Statistical analysis of the results
May 2021
Reporting the results of the study in context of master thesis part 2
Relevance of the research
Recent animal studies have demonstrated the positive effect of bimodal stimulation. This caused a growing
focus on bimodal stimulation for the treatment of tinnitus patients, however, our systematic review revealed
that there are currently a limited number of studies investigating the effect of bimodal stimulation in tinnitus
patients. Our study may help to encourage other researchers to conduct similar studies with a different form of
bimodal stimulation or with tinnitus patients with different characteristics. An increase in studies using
electrical stimulation combined with auditory stimulation will allow us to draw more specific conclusions about
the effect of bimodal stimulation. If a significant difference in treatment effect is found, this may also lead to a
gradual transition from standard physical therapy to bimodal stimulation in the clinical practice to give patients
with tinnitus the most effective treatment.

Reference list
1. Bjelland, I., et al., The validity of the Hospital Anxiety and Depression Scale. An updated literature review. J
Psychosom Res, 2002. 52(2): p. 69-77.
2. Bolton, J.E. and B.K. Humphreys, The Bournemouth Questionnaire: a short-form comprehensive outcome
measure. II. Psychometric properties in neck pain patients. J Manipulative Physiol Ther, 2002. 25(3): p. 141-
8.
3. Chandra, N., et al., Psychometric Validity, Reliability, and Responsiveness of the Tinnitus Functional Index. J
Am Acad Audiol, 2018. 29(7): p. 609-625.
4. Fackrell, K., et al., Psychometric properties of the Tinnitus Functional Index (TFI): Assessment in a UK
research volunteer population. Hear Res, 2016. 335: p. 220-235.
5. Faul, F., et al., Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses.
Behav Res Methods, 2009. 41(4): p. 1149-60.
6. Gonzalez, Y.M., et al., Development of a brief and effective temporomandibular disorder pain screening
questionnaire: reliability and validity. J Am Dent Assoc, 2011. 142(10): p. 1183-91.
7. Julian, L.J., Measures of anxiety: State-Trait Anxiety Inventory (STAI), Beck Anxiety Inventory (BAI), and
Hospital Anxiety and Depression Scale-Anxiety (HADS-A). Arthritis Care Res (Hoboken), 2011. 63 Suppl 11:
p. S467-72.
8. Koehler, S.D. and S.E. Shore, Stimulus-Timing Dependent Multisensory Plasticity in the Guinea Pig Dorsal
Cochlear Nucleus. Plos One, 2013. 8(3).
9. Marks, K.L., et al., Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce
tinnitus in Guinea pigs and humans. Science Translational Medicine, 2018. 10(422).
10. Meikle, M.B., et al., The tinnitus functional index: development of a new clinical measure for chronic,
intrusive tinnitus. Ear Hear, 2012. 33(2): p. 153-76.
11. Michiels, S., et al., Diagnostic Criteria for Somatosensory Tinnitus: A Delphi Process and Face-to-Face
Meeting to Establish Consensus. Trends Hear, 2018. 22: p. 2331216518796403.
12. Michiels, S., et al., Diagnostic Value of Clinical Cervical Spine Tests in Patients With Cervicogenic Somatic
Tinnitus. Phys Ther, 2015. 95(11): p. 1529-35.
13. Michiels, S., et al., Does multi-modal cervical physical therapy improve tinnitus in patients with
cervicogenic somatic tinnitus? Man Ther, 2016. 26: p. 125-131.
14. Zhan X, T.P.a.D.R., Projections of the second cervical dorsal root ganglion to the cochlear nucleus in rats. J.
Comp. Neurol., 2006. 496: p. 335–48.
15. Henry, J. A. (2016) "Measurement" of Tinnitus. Otol Neurotol, 37, e276-85.

Informed Consent

Patiënt Nummer: ______________

Bimodal stimulation treatment in patients with somatic tinnitus

Bimodale stimulatiebehandeling bij patiënten met somatische tinnitus

Hierbij nodigen wij u uit voor deelname aan een wetenschappelijke studie, die het effect van een nieuwe
therapie voor tinnitus zal onderzoeken.

Vooraleer u toestemt om aan deze studie deel te nemen, is het belangrijk dat u dit formulier leest. In dit
informatie- en toestemmingsformulier worden het doel, de onderzoeken, de voordelen, risico’s en
ongemakken gepaard gaande met de studie beschreven. Ook de voor u beschikbare alternatieven en het recht
om op elk ogenblik de studie te verlaten, zijn hieronder beschreven. Er kunnen geen beloften gedaan worden
noch waarborgen gegeven worden betreffende de resultaten van de klinische studie. U heeft het recht om op
elk ogenblik vragen te stellen over de mogelijke en/of bekende risico’s die deze studie inhoudt.

Doel en beschrijving van de studie

Dit is een medisch-wetenschappelijk onderzoek waaraan naar verwachting ongeveer 100 Belgische patiënten
zullen deelnemen.

De studie heeft tot doel het effect van een nieuwe therapie voor tinnitus te onderzoeken. Deze therapie
bestaat uit een combinatiebehandeling, waarbij uw nek- of kaakregio door middel van elektrische stimulatie
behandeld zal worden, terwijl u naar geluiden luistert via een hoofdtelefoon.
Indien u aanvaardt aan dit onderzoek deel te nemen, zal u deze 30 minuten durende behandeling dagelijks,
gedurende 4 weken ondergaan. De behandeling kan u thuis zelf uitvoeren aan de hand van het toestel dat u
van ons mee krijgt. De kosten van de behandeling worden door de opdrachtgever van de studie gedragen.
Om het effect van de therapie te kunnen meten, vragen wij om op 3 momenten een reeks vragenlijsten in te
vullen. Voor de start van de eerste behandeling, zal u 7 vragenlijsten invullen. Vlak na de laatste behandeling en
8 tot 12 weken na de laatste behandeling, zal u 6 vragenlijsten invullen. Indien u beslist deel te nemen aan deze
studie, geeft u toestemming aan de onderzoekers om de resultaten van deze vragenlijsten anoniem te
gebruiken. Naast de gegevens van de vragenlijsten, zullen ook andere gegevens, zoals uw leeftijd, geslacht en
uw gehoor anoniem verwerkt worden.

Opdrachtgever van de studie

De opdrachtgevers van de studie zijn het Universitair Ziekenhuis Antwerpen en de Universiteit Antwerpen.

Duur van de klinische studie

De behandeling zal 4 weken duren. U zal echter 8 tot 12 weken na de laatste behandelsessie nog een laatste
maal gevraagd worden om vragenlijsten in te vullen, zodat we ook de lange termijn effecten van de
behandeling kunnen onderzoeken.

Onderzoeken in het kader van de studie

Indien u aanvaardt aan de studie deel te nemen en u voldoet aan alle voorwaarden voor deelname, dan zal u
gevraagd worden om 7 vragenlijsten in te vullen: één vragenlijst over de ernst van uw tinnitus, één over de
luidheid van het oorsuizen, één vragenlijst die peilt naar eventuele aanwezigheid van overgevoeligheid aan
geluid, één vragenlijst om de mate van angstige of depressieve gevoelens die met tinnitus gepaard kunnen
gaan, één die de ernst van eventuele nekklachten nagaat, één die de ernst van eventuele kaakklachten nagaat
en één vragenlijst die bepaalde persoonlijkheidskenmerken beschrijft.

Vrijwillige deelname
U neemt geheel vrijwillig deel aan deze studie en u hebt het recht te weigeren eraan deel te nemen.
Indien u aanvaardt om eraan deel te nemen, zal u deze informatiefolder krijgen om te bewaren en zal er u
gevraagd worden het aangehechte toestemmingsformulier te ondertekenen.

De studiebegeleider kan op elk ogenblik een einde stellen aan uw deelname aan de studie, zelfs zonder dat
hij/zij hiervoor uw toestemming moet vragen, om één van de volgende redenen:
– u houdt zich niet aan de instructies voor deelname aan de studie;
– er wordt naderhand ontdekt dat u niet aan de studievoorwaarden voldoet;
– de opdrachtgever zet de studie overal of in dit centrum stop wegens andere, momenteel onbekende
redenen.

U hebt het recht om uw deelname aan de studie op elk ogenblik stop te zetten, zelfs nadat u het
toestemmingsformulier ondertekend heeft. U hoeft geen reden te geven voor het intrekken van uw
toestemming tot deelname. Het intrekken van uw toestemming zal geen enkel nadeel of verlies van voordelen
met zich meebrengen.

Risico’s en ongemakken
Zoals elke behandeling voor tinnitus kan ook deze nieuwe behandeling gedurende een korte tijd (meestal
enkele uren) voor een toename van de tinnitus zorgen. Belangrijk is te weten dat deze eventuele toename van
uw oorsuizen van voorbijgaande aard is.

Wat indien u zwanger bent, zwanger wenst te worden of borstvoeding geeft?

Indien u zwanger bent of zwanger zou kunnen worden gedurende de duur van de behandeling, mag u niet aan
de studie deelnemen. Dit, omdat de veiligheid van het gebruik van elektrische stroom onvoldoende
aangetoond is bij zwangere vrouwen. Indien u borstvoeding geeft, kan u wel zonder enig probleem deelnemen
aan de studie.

Voordelen
Indien u deelneemt aan de studie, zal de kostprijs van de behandeling door de opdrachtgever van de studie
gedragen worden.
Indien u toestemt om aan deze studie deel te nemen, kan de onderzochte behandeling al dan niet nuttig blijken
te zijn voor patiënten met tinnitus. De uit deze studie bekomen informatie kan bijdragen tot een betere kennis
over het effect van deze behandeling bij toekomstige patiënten.

Verzekering
Indien u of uw rechthebbenden (familie) meent schade te ondervinden die verband houdt met deze studie, zal
deze schade, indien bewezen, door de opdrachtgever van deze studie vergoed worden overeenkomstig de wet
inzake experimenten op de menselijke persoon van 7 mei 2004. U hoeft hiervoor geen fout aan te tonen. De
opdrachtgever heeft een burgerlijke aansprakelijkheidsverzekering afgesloten die de risico’s en de schade, die
zouden voorvloeien uit deze studie, dekken. U of uw rechthebbenden kunnen de verzekeraar rechtstreeks in
België dagvaarden.

Vergoeding
De opdrachtgever betaalt de behandeling die u krijgt.

Bescherming van de persoonlijke levenssfeer

Uw identiteit en uw deelname aan deze studie worden strikt vertrouwelijk behandeld. U zult niet bij naam of
op een andere herkenbare wijze geïdentificeerd worden in dossiers, resultaten of publicaties in verband met de
studie.

De informatie over u zal elektronisch (d.w.z. in de computer) of handmatig verwerkt en geanalyseerd worden
om de resultaten van deze studie te bepalen. U hebt het recht aan de studiebegeleider te vragen welke
gegevens er over u worden verzameld in het kader van de studie en wat de bedoeling ervan is. U hebt ook het
recht om aan de studiebegeleider te vragen u inzage in uw persoonlijke informatie te verlenen en er eventueel
de nodige verbeteringen in te laten aanbrengen. De bescherming van de persoonlijke gegevens is wettelijk
bepaald door de GDPR wetgeving.
Indien u toestemt in deelname aan dit onderzoek, betekent dit dat u ook toestemming geeft voor het gebruik
van uw gecodeerde medische gegevens voor de hierboven beschreven doelen.

Bescherming van uw persoonsgegevens

Indien u toestemt om deel te nemen aan dit onderzoek betekent dit dat u toestemming geeft tot het gebruik
van uw persoonsgegevens die in het kader van dit onderzoek worden verzameld.

U kan de toestemming om uw gegevens te verzamelen en te verwerken op elk moment intrekken. Indien uw

studiedeelname voortijdig gestopt wordt, zal uw oorspronkelijke toestemming het gebruik toelaten van de over
u verzamelde gegevens met betrekking tot de periode dat u in het onderzoek ingesloten was.
Enkel personen die rechtstreeks bij het onderzoek betrokken zijn, zullen toegang hebben tot uw
persoonsgegevens. Uw gegevens worden niet doorgegeven aan derden.

De onderzoekers zullen uw gegevens bewaren gedurende een periode van 20 jaar.

Daarnaast worden uw medische gegevens die opgeslagen zijn in uw patiëntendossier in het UZA gedurende 30
jaar bewaard.
U heeft het recht aan de onderzoeker te vragen welke gegevens er over u worden verzameld in het kader van
het onderzoek en wat de bedoeling ervan is. U kan vragen om bepaalde gegevens te verbeteren of te wissen, of
om uw gegevens niet meer te gebruiken.
Alle gegevens die van u verzameld worden, zullen behandeld worden in overeenstemming met de “Richtlijn tot
bescherming van individuen betreffende het verwerken van persoonlijke gegevens” en de Belgische wetgeving
die deze verordening verder uitwerkt.

Het Universitair Ziekenhuis Antwerpen is als opdrachtgever van de studie verantwoordelijk voor de verwerking
van uw persoonsgegevens. Zij heeft daartoe een functionaris voor de gegevensverwerking aangesteld. Vragen
betreffende het beheer van uw gegevens kan u stellen aan de onderzoeksarts, uw behandelend arts of aan de
functionaris voor de gegevensbescherming van het UZA via e-mail: dpo@uza.be

Wanneer u vindt dat uw rechten met betrekking tot uw persoonsgegevens onvoldoende worden
gerespecteerd, kan u steeds terecht bij de functionaris voor de gegevensbescherming die desgevallend de
nodige maatregelen zal treffen. U hebt ook het recht om een klacht in te dienen bij de Belgische
Gegevensbeschermingsautoriteit.

Meer informatie kan u nalezen op https://www.uza.be/privacy.html

Commissie voor ethiek

Deze klinische studie is beoordeeld door een onafhankelijke commissie voor ethiek, nl. de commissie van het
Universitair Ziekenhuis Antwerpen, die een gunstig advies heeft gegeven op 16/09/2019.

Contactpersonen in geval van vragen in verband met de studie

Indien u meent studie-gebonden schade te hebben opgelopen, of indien u vragen heeft over het onderzoek of
uw rechten als studiedeelnemer, nu of tijdens of na uw deelname, dan kan u contact opnemen met:

Behandelend geneesheer Telefoon: 03 821 30 00

Toestemmingsformulier

Bimodal stimulation treatment in patients with somatic tinnitus

Deel enkel bestemd voor de patiënt(e) of de wettelijke vertegenwoordig(st)er:

Hierbij bevestig ik, ondergetekende (naam & voornaam) __________________________________dat ik over de

studie ben ingelicht en een kopie van de “Informatie voor patiënten” en het “Toestemmingsformulier”
ontvangen heb. Ik heb de informatie gelezen en begrepen. De studiebegeleider heeft mij voldoende informatie
gegeven met betrekking tot de voorwaarden en de duur van de studie. Bovendien werd mij voldoende tijd
gegeven om de informatie te overwegen en om vragen te stellen, waarop ik bevredigende antwoorden
gekregen heb.

– Ik heb begrepen dat ik mijn deelname aan deze studie op elk ogenblik mag stopzetten nadat ik de
studiebegeleider hierover heb ingelicht, zonder dat dit mij enig nadeel kan berokkenen.
– Ik ga akkoord met de verzameling, de verwerking en het gebruik van de studiegegevens, zoals beschreven in
het informatieblad voor de patiënt.
– Ik stem geheel vrijwillig toe om deel te nemen aan deze studie en om mee te werken aan de gevraagde
onderzoeken. Ik ben bereid informatie te verstrekken i.v.m. mijn medische geschiedenis, mijn
geneesmiddelengebruik en eventuele deelname aan andere studies.

Datum: ____________________

Handtekening patiënt(e) (of wettelijk vertegenwoordig(st)er):_____________________________

Deel enkel bestemd voor het onderzoeksteam (het is niet noodzakelijk de studiebegeleider die de informatie
en IC-procedure met de patiënt doorloopt; dit wordt soms ook door een ander lid van het onderzoeksteam
gedaan):

Ik, ondergetekende, _______________________, bevestig hierbij dat ik, ________________________

(naam van de patiënt(e) voluit) of zijn wettelijke gegevens vertegenwoordig(st)er) heb ingelicht en dat hij (zij)
zijn (haar) toestemming heeft gegeven om deel te nemen aan de studie.

Datum: ____________

Handtekening: __________________
Attachments  
Attachment 1: risk of bias table  
 
Judgement of Level of
Studies Domain
bias evidence
ROBINS-I* 1 2 3 4 5 6 7     
Low – Low –
Henin et al. (2016)  Low Low Low Low Moderate Moderate B
moderate Moderate
Kreuzer et al. (2016) 
Moderate Low Low Moderate Low Moderate Moderate Moderate B
Low –
Marks et al. (2018)  Low Low Low Low Low Moderate Low B
Moderate
Shekhawat et al. Low – Low –
Low Moderate Low Low Moderate Low B
(2015)  Moderate Moderate
Low – Low – Low –
Tyler et al. (2017)  Low Low Low Low Low –Moderate B
Moderate Moderate Moderate
Legend  ROBINS-I 
1. Bias due to confounding  
2. Bias in selection of participants into the study 
3. Bias in classification of interventions 
4. Bias in deviations from intended interventions           
5. Bias in missing data 
6. Bias in measurement of outcomes 
7. Bias in selection of the reported result  

 * The Risk of Bias in Non-randomized Studies

Attachment 3: data-extraction table  

Sample / eligibility Experimental Control Outcome +

Reference Study design Results Remarks
criteria intervention intervention follow-up
A randomized N = 17 4 groups and 2 treatment sessions: Changes in CAS treatment: tDCS did not
Henin et al. sham- chronic tinnitus each group received two different tinnitus severity: significant ↓ in MML, reduce tinnitus
(2016)  controlled, trend towards
single blind 16 ♂ / 1 ♀
treatments per session of 20’  MML significance for VAS
severity,
study age: 28-73y  VAS further
 first CAS, then HD-tDCS tDCS: numerical research is
 first HD-tDCS, then CAS Before and after improvement on MLL recommended
 first CAS + HD-tDCS, then sham the 4 + VAS, but not to assess
significant
 first sham, then CAS + HD-tDCS interventions whether tDCS
reduction in VAS: would have a
HD-tDCS+CAS > HD- long-term
tDCS/CAS alone effect,
especially in
combination
with CAT
Pilot study N = 42 10 sessions: high- Same rTMS protocol Primary outcome:  rTMS/relaxatio LOCF was used
Kreuzer et chronic subjective frequency (n = 18) and sham TQ n > placebo for replacing the
al. (2016)  tinnitus stimulation left rTMS (n = 46) missing values of
≥ 6 months DLPFC + low- without relaxation
control group the 4 dropouts
Secondary  active control
frequency
age: 18-70y stimulation left
outcomes: group =
tempo-parietal  THI placebo group
cortex, while  Tinnitus  rTMS/relaxatio
patients were numeric
listening to relaxing
n = rTMS
rating scale without
audio files
 WHOQoL- relaxation
N = 38 BREF  rTMS/relaxatio
(31 ♂ / 7 ♀)  MDI n: significant ↓
 in THI
T0: first day of  Degree of
treatment relaxation
T1: week 2 during the 2nd
T2: week 4 week
T3: week 12 correlated
significantly
with TQ
improvement
Double- N = 20 Bimodal auditory Unimodal auditory Weekly: TinnTester 2/20: complete All subjects
Marks et al. blinded, sham- somatic tinnitus somatosensory stimulation (sham) + TFI elimination of tinnitus received both
(2018)  controlled, stimulation 10/20: clinically active and sham
cross-over significant reduction in treatment: cross-
study (n = 10) (n = 10) TFI scores over to receive
30 min / day 30 min / day the other
TFI scores ↓ in active treatment for the
treatment, but 2nd four-week
unchanged during period after a
sham washout period
of 4 weeks
Sham- N = 10 (♂) tDCS of LTA + auditory stimulation (RI) Audiometry: at tDCS + acoustic 1 drop-out after 2
Shekhawat controlled, chronic tinnitus 60 min / session baseline stimulation: maximum sessions due to
et al. randomized > 2y  5 min monitoring MML wit no suppression of tinnitus worsening of the
(2015)  pilot study min. score of 25 on stimulation  Tinnitus loudness symptoms
the TFI  20 min tDCS + MML monitoring loudness
 30 min MML monitoring post tDCS no significant MML
age: 50-68y
rating scale suppression in the four
before (2x) different test
4 sessions for 4 different test and after protocols
protocols testing
 1 min acoustic stimulation before,
during, immediately after 20 min tDCS
 MML
stimulation or during 20 min sham
stimulation
 Two-arm, N = 30 VNS paired with First 6w VNS  Audiometry + THI: 50% after 6 weeks
Tyler et al. double (25 ♂ / 5 ♀) tones (n = 16) unpaired with tinnitus pitch and 56% after 12
(2017)  blinded, chronic 12 weeks tones, after 6w
matching weeks in paired VNS
controlled sensorineural paired VNS
 THI, THQ, TFI group showed
randomized tinnitus > 1y (n = 14) clinically meaningful
study  Tinnitus improvements
age: 22 – 65y loudness
Paired VNS > control
 MML group
 Loudness
matching
 BDI
 STAI
 SF12

T0: 3 baseline
visits prior to
starting therapy
T1: week 6
T2: week 12

Follow-up: every
three months for
one year

CAS = compensatory auditory stimulation; (HD)-tDCS = (high-definition) transcranial direct current stimulation; MML = minimum masking level;
VAS = visual analogue scale; DLPFC = dorsolateral prefrontal cortex; rTMS = repetitive transcranial magnetic stimulation; TQ = Tinnitus
Questionnaire; THI = Tinnitus Handicap Inventory; WHOQoL-BREF = World Health Organization Quality of Life – BREF questionnaire; MDI =
Major Depression Inventory; LOCF = last observation carried forward; TFI = Tinnitus Functional Index; LTA = left temporoparietal area; RI =
auditory residual inhibition; VNS = vagus nerve stimulation; THQ = Tinnitus Handicap Questionnaire; BDI = Beck Depression Inventory; STAI =
State-Trait Anxiety Inventory; SF12 = the 12-Item Short Form Health Survey