Original Article - The International Tinnitus Journal (2018) Volume 22, Issue 2
The Effects of Acute Multisession Bifrontal Transcranial Direct Current Stimulation on Intractable Tinnitus and comorbid depression and anxiety: A Study Protocol for Randomized Controlled Trial
1Bioelectromagnetic Clinic, Imam Khomeini Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2Department of Medical Physics, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
3Department of Clinical Pharmacy, College of Pharmacy, Najran University, Kingdom of Saudi Arabia
4Department of Pharmaceutics and Pharmacy Practice, School of Pharmacy, Mount Kenya University, Thika, Kenya
5Graduate and Research Department, Polytechnic University of Pachuca, Zempoala, Mexico
6Information Technologies and Communications Department, Technological University of Huasteca Hidalguense, Huejutla, Mexico
- *Corresponding Author:
- Ali Yadollahpour
Department of Medical Physics and Bioelectromagnetic Clinic-Imam Khomeini Hospital
Ahvaz Jundishapur University of Medical Sciences
E-mail: [email protected]
Paper submitted to the ITJ-EM (Editorial Manager System) on November 22, 2018; and accepted on January 20, 2019.
Citation: Rashidi S, Yadollahpour A, Alkahtani SA, kunwar PS, Robles-Camarillo D, Meneses-Flores A, Trejo-Macotela F. Int Tinnitus J. 2018;22(2):181-187.
Background and Objective: Transcranial Direct Current Stimulation (tDCS) may exert therapeutic effects on tinnitus. This Randomized Control Trial (RCT) with double blind and placebo design investigates the potential therapeutic effects of Transcranial Direct Current Stimulation on chronic and intractable tinnitus using a new protocol. Acute repeated sessions of bifrontal Transcranial Direct Current Stimulation with two months follow up will be used for treatment of tinnitus symptoms and comorbid anxiety and depression. To best of our knowledge, this is the first randomized control trial investigating the effects of acute Transcranial Direct Current Stimulation exposure in intractable tinnitus.
Methods: This randomized control trial is conducted as double blinded placebo controlled with parallel group in patients with chronic intractable tinnitus. The patients will be randomly divided into two real or intervention and sham or placebo Transcranial Direct Current Stimulation. The real Transcranial Direct Current Stimulation group will receive two sessions per day with intersession interval of 6 hours for 5 consecutive days per week for one week (total 10 sessions). The Transcranial Direct Current Stimulation parameters include bifrontal (anode/cathode over right/left dorsolateral prefrontal cortex (DLPFC) 2 mA current (current density 57.1 μA/cm2), each session 20 min through 35 cm2 electrodes. The sham group will receive the same Transcranial Direct Current Stimulation parameters and electrode montage and after 30 seconds, the device will be turned off without informing the patient. The primary outcome is the score of Tinnitus Handicap Inventory (THI) measured at baseline (pre-intervention) and post-intervention at immediately, one, and two months after last session. The secondary outcomes are tinnitus loudness, tinnitus distress, depression, and anxiety scores. The tinnitus loudness and distress are measured with a 0-10 Numerical Rating Scale (NRS) preintervention and post-intervention at immediately, one hour, one week, one, and two months after the last Transcranial Direct Current Stimulation session. Beck Depression (BDI-II) and Anxiety Inventories (BAI) is respectively used for measuring depression and anxiety score pre- and post-intervention. Finally, the adverse effects of and tolerability to Transcranial Direct Current Stimulation will be assessed in both real and sham groups using customized questionnaire.
Discussion: To the best of our knowledge this is the first RCT investigating the effects of daily two sessions of Transcranial Direct Current Stimulation in repeated regime on chronic intractable tinnitus symptoms, depression, anxiety, and adverse effects in a long term study of two months follow-up.
transcranial direct current stimulation, chronic tinnitus, depression, anxiety, acute stimulation.
ISI: Intersession Interval; tDCS: Transcranial Direct Current Stimulation; DLPFC: Dorsolateral Prefrontal
Cortex; THI: Tinnitus Handicap Inventory; BDI-II: Beck Depression Inventory; BAI: Beck Anxiety Inventory; dBHL:
Decibels Hearing Level.
Tinnitus is the conscious perception of an auditory
phantom sensation without any corresponding external
sound source . The perception is usually elementary such
as ringing, hissing, and buzzing, but in some cases is of
more complex nature such as voices or music. Tinnitus
is sometimes be a rhythmical or pulsatile sound . The
global prevalence ranges 10%-15% among adults and is
usually accompanied by various comorbidities such as
depression, anxiety, and sleep disturbances, making it a
debilitating condition that can severely affect the quality
of life . Neuroimaging and electrophysiological evidence
indicate that tinnitus is a heterogeneous disorder
characterized by abnormal neural activities in primary
and secondary auditory pathways as well as in nonauditory
regions such as frontal cortex [3,4]. A mal-adaptive
plasticity in the primary and secondary auditory networks
may be the main cause of tinnitus. However, other regions
particularly frontal cortex is involved in the tinnitus etiology.
Frontal cortex, particularly Dorsolateral Prefrontal Cortex
(DLPFC) plays important role in attentional and emotional
aspects of tinnitus [5,7].
Despite of different medications administrated for
tinnitus, there is no definitive cure for the disorder so that
a significant portion of patients do not respond to the
medications [1,3]. Therefore, studies are ongoing to develop
new medications for tinnitus. However, considering
the side effects of the medications, a line of studies are
seeking to develop non-medication modalities for tinnitus
treatment. In this regard, different modalities such as
cognitive behavioral therapy, noise-masking, hearing
aids, neuro feedback training, and brain stimulation
techniques have been developed [8,10].
Transcranial Direct Current Stimulation (tDCS) is a noninvasive
and safe neuromodulation technique that has
been recently introduced as a potential treatment for
different neuropsychiatric disorders such as depression ,
addictions [12,13], traumatic brain injury , attention deficit
hyperactivity disorder , auditory hallucinations , and
chronic pain . Moreover, different studies have shown
that tDCS could improve different cognitive functions in
healthy individuals .
Considering the pathology of tinnitus and the
neurophysiological effects of tDCS, we could expect
therapeutic effects from tDCS in tinnitus. There are two
main hypotheses explaining the therapeutic effects of
tDCS in different neuropsychiatric disorders. The first
hypothesis says that tDCS exerts disturbance in the
ongoing abnormal neural activities responsible for the
impaired function or dysfunction. According to this
hypothesis, tDCS should target the areas with abnormal
activities to alter the impaired function. The second
hypothesis claims that tDCS alters the maladaptive
plasticity induced by the disorder in specific regions
through inducing plastic changes in the target sites. The hyperactivity and maladaptive plasticity in auditory cortex
and anomalies in non-auditory regions particularly DLPFC
are the main causes of tinnitus [2,3,19]. Therefore, the two
main targeting sites in the tDCS studies on studies were
AC and DLPFC [20,23]. In line with these hypotheses, several
studies have investigated the effects of tDCS in different
protocols and electrode montages on tinnitus [17,22,23-27].
Findings of these studies were promising, though
Different neural pathways or networks are involved in
tinnitus in which each network constitutes a clinical aspect
of tinnitus. In this regard, we can expect modulating one
of these networks would affect one of these aspects [3,19,27].
The main clinical aspects of tinnitus are loudness,
distress, and laterality.
The first line of tDCS studies focused on AC or left
temporoparietal area. DLPFC is involved in different
aspects of tinnitus considering its role in the regulating
the auditory processing, perception, and auditory
attention [6,7,28,29]. Therefore, one can expect that modulating
the DLPFC would influence the tinnitus loudness
perception or tinnitus related distress.
Previous clinical trials have studied the therapeutic
outcomes of tDCS over frontal and prefrontal regions in
chronic tinnitus [20,21]. However, the main drawback of these
studies was that most of them investigated the effects of
single tDCS session and the outcomes were assessed
for a very short time ranging some hours to few days.
Considering the mechanism of action of tDCS and also
the mal-adaptive plasticity in tinnitus, repeated sessions
of tDCS may have therapeutic value through inducing
plastic changes in the impaired regions. Based on the
literature search we performed, no RCT has investigated
the therapeutic effects of long term protocol of tDCS
in repeated sessions on tinnitus. In addition, most of
the studies conducted so far, used a single-sessionper-
day protocol. Therefore, this RCT aims to study
the treatment effectiveness of twice daily (intersession
interval: 6 hours) bifrontal tDCS in repeated sessions on
tinnitus symptoms, its loudness and distress as well as on
comorbid depression and anxiety in a two-month followup.
We hypothesized that acute repeated sessions would
result in aggregative therapeutic effects on tinnitus. Also,
we expect that bifrontal tDCS will reduce the depression
and anxiety scores in the patients. We will evaluate the
interactions of tDCS factors and disease characteristics
including gender, THI basal score, laterality, tinnitus
quality, and duration with the response to the treatment.
This study is a section of a big project we designed in
our clinic to comprehensively investigates the therapeutic
value of tDCS in tinnitus. During this project we will
study the efficacy of tDCS in different protocols applied in different brain sites for the treatment of tinnitus. The
studies will be conducted in the Bioelectromagnetic
Clinic in Ahvaz Imam Hospital, Ahvaz, Iran. The patients
with chronic tinnitus (>2 years) who were resistant to
the medications are enrolled in this clinical trial. This is a
double blind RCT with parallel allocation of two groups.
Ethics approval and study registration
The procedures of this clinical trial were approved by
the ethics committee in the human studies of Ahvaz
Jundishapur University of Medical Sciences (AJUMS),
Ahvaz, Iran (Ethic code: IR.AJUMS.REC.1394.639). The
regulations of the ethics committee were completely
coincide with regulations of human studies set by the
Helsinki declaration . The researchers will clearly explain
the main objectives, experiments, and the assessments
of the study and also the possible benefits and risks of
participation to all subjects before the intervention and
then the written consent form will be collected from all
participants. This RCT was registered in the Iranian
registry of clinical trials (IRCT2016110124635N5).
Inclusion and exclusion criteria
After the enrolment of the subjects, the inclusion and
exclusion criteria will be evaluated through predefined
neurological and audiological examinations by expert
specialists. The patients are selected from the tinnitus
patients referred to the Tinnitus Clinic in the Khuzestan
Cochlear Implant Center, Ahvaz, Iran. The participants
have the right to terminate the participation anytime
during the study. Moreover, researchers will terminate
the procedures for any patients who would report
significant Adverse Effects (AEs). The inclusion criteria
include idiopathic chronic (with more than 2 years) and
medication-resistant tinnitus, age range of 18 to 65
years old, no concurrent administration of medication.
The exclusion criteria include history of epileptic
seizures, brain trauma, psychotic, severe psychiatric
disorders, severe vertigo, Meniere's disease, severe
organic comorbidity, using pacemaker or defibrillator,
present pregnancy, neurologic disorders such as brain
tumors, concurrent treatment administered for mental
disorders, and receiving previous treatments with
rTMS or tDCS within 6 months. The audiometric and
neurologic examinations are performed in the Khuzestan
Cochlear Center, Ahvaz, Iran. The intervention and
outcome assessments and follow up evaluations will be
conducted in the Bio electromagnetic Clinic in Ahvaz
Imam Hospital, Ahvaz, Iran.
Study design and intervention
This is a double-blind RCT in which the patients are
randomly assigned into two groups of real tDCS and
sham tDCS. To reduce the inter-individual variability and
considering the parallel allocation of the two groups, the
real and sham groups will be matched for age, gender,
ethnicity, and the main audiometric characteristics. In addition, to reduce the subjective bias, the study will be
double blinded in which the patients and the researchers
who collect and analyze the data are blinded on the type
of the intervention. Furthermore, the both real and sham
tDCS groups will be assessed for the blinding quality
following the last tDCS session. The random allocation
is performed using computer software generating
random numbers with blocking approach. The allocation
concealment is secured using sequentially numbered,
opaque, sealed envelopes.
For tDCS session, we will use a battery-driven constant
current stimulator (OASIS ProTM device by Mind Alive
Inc., Edmonton, Alberta, Canada) that delivers electric
direct current up to 2 mA using a pair of saline-soaked
surface electrodes (35 cm2). The exposure protocol in the
real tDCS consists of two sessions per day, each session
20 min with inter-stimulation interval (ISI) of 6 hours for
five consecutive days (10 sessions in total). The current is
2 mA and the anode/cathode will be centered right (F4)/
left (F3) DLPFC according to the international 10-20 EEG
placement system. The sham tDCS will undergo the same
electrode montage and the same session parameters
of that the real tDCS, except that the tDCS device will
be turned off after 30 seconds without the knowledge
of the patients to blind them on the type of the tDCS
intervention. The rationale for choosing the 30 seconds
at the beginning of the session as the fade out period is
that previous studies have demonstrated that the AEs and
sensations due to tDCS such as skin burning, itching, and
tingling disappear after 30 seconds of the active tDCS [31,32].
The dose-response and safety studies have shown that
the tDCS protocols with 1-2 mA current and duration
of 15-20 min in single session to few sessions result
in no serious AEs [31,33]. The common reported AEs are
itching, pinching, tingling, fatigue, headache, and local
burn under the electrodes. In overall, the AEs of tDCS
were mild and the technique has been reported as a
safe modality. However, this should be noted that most
of the studies that assessed the AEs of tolerability to
tDCS have been conducted on single tDCS session of
20-30 min duration and 1 to 2 mA current and electrode
size of 35 cm2. In this line, few studies have assessed
the safety and tolerability profiles of few sessions (three
to five sessions) that showed the same level AEs as of
the single session protocols. The patients will undergo
repeated sessions of tDCS (10 sessions) that may lead to
more severe AEs than the previous studies with single to
five sessions. Therefore, we will evaluate the AEs of and
tolerability to the tDCS intervention using a researcher
built questionnaire (Supplementary Table 1). AEs and
tolerability of all patients will be assessed after each tDCS
session in both real and sham tDCS (Table 1)
||Anode right (F4) , Cathode left (F3) DLPFS
||Anode right (F4) , Cathode left (F3) DLPFS
Table 1. Setting for real and sham tDCS [Note: *30 seconds after the start of the stimulation the device will be turned off without informing the patient].
The data of this clinical trial comprise of three main
groups: (1) patients’ specific data, (2) response variables,
and (3) AEs and tolerability. The patients’ specific data
are assessed and recorded at the baseline prior to the
intervention. The response variables include primary
and secondary outcomes and are assessed at baseline
and at different time points after tDCS intervention. The
AEs and tolerability data are collected after each tDCS
session. The SPIRIT schematic protocol of this trial
including the patients’ specific data and the response
variables along with the time course of the assessments
for each outcome is represented in Table 2. The data are
measured and recorded at two main time points of preand
post-intervention. The pre-intervention assessments
are performed before the first tDCS session on the first day
of intervention (T0). The post-intervention assessments
are performed at five time points including immediately
(T1), one hour (T2) one week (T3), one month (T4), and
two months (T5) after the last tDCS session (Table 2).
||Treatment (5 consecutive days)
|Patient specific variable
|AEs and Tolerability
Table 2. Standard Protocol Items: Recommendations for interventional trials of this study [Note: THI: tinnitus handicap inventory, BDI: beck depression inventory, BAI: beck anxiety inventory, T0: before intervention, T1: immediately after last session, T2: one hour after last session, T3: one week T4: one month, and T5: two months after last tDCS session].
Patients’ specific data
After the enrolment, the patients will undergo complete
neurological and audiometric assessments by expert
specialties. The hearing threshold and hearing loss type,
tinnitus duration, quality, and laterality as well as the
age and gender of all patients will be recorded. Tinnitus
quality is categorized in different classes including buzzing, cicadas and high pitch whistling, hissing,
humming, ringing, pulsating, thumping, and ticking.
Audiometric assessments are performed inside an
acoustically isolated room (ISO 8253-1:2010). Pure-tone
Audiometry (PTA), conducted by an AC 40 dual channel
audiometer (Intracoustics Co., Denmark) is used to
determine the hearing threshold. The modified Hughson-
Westlake method recommended by ANSI 1997 is used to
determine hearing thresholds over 250-8000 Hz and 500-
4000 Hz frequency ranges respectively for air conduction
and bone conduction pathways . The hearing class is
defined as the averaged threshold at 250 Hz, 1000, 2000,
and 4000 Hz. The PTA outcome or hearing threshold is
normal when the hearing threshold of all frequencies
is below 20 dBHL. The class of hearing loss for both
ears of all patients is determined according to the type
and degree follows: normal (<20 dB), mild (20-40 dB),
moderate (41-70 dB), severe (70-90 dB), and profound
hearing loss (>90 dB) .
The response variables comprised of primary and
secondary outcomes as well as the data of the AEs and
tolerability Tinnitus Handicap Inventory (THI) score is
defined as the primary outcome. The THI is widely used
as the primary outcome measure in double-blind RCT
to study the efficacy of medications or non-medication
modalities in tinnitus patients . In this RCT, we will
measure the THI scores at pre-intervention (T0) and at
immediately (T1), one month (T4), and two months (T5)
after the last tDCS session. For the primary outcome (THI
score) we will use the clinical improvement rather than
statistical improvement so that a reduction ≥ 20 points
in the THI score (Pre-treatment THI–Post-treatment THI ≥
20) is defined as the treatment response. The 20 point
cut-off value of THI is generally accepted as significant clinical improvement in tinnitus treatment [26,37,38].
In addition to the primary outcome, four secondary
outcomes are defined for this study including tinnitus
loudness (intensity), tinnitus related distress, depression,
and anxiety. The tinnitus loudness and distress are
assessed with a 0-10 NRS at pre-intervention (T0) and at
five time points of post-intervention including immediately
(T1), one hour (T2) one week (T3), one month (T4), and
two months (T5) after the last tDCS session (Table 2). A
reduction of 10 percent in the baseline score of loudness
and distress, 1 point reduction in the 0-10 NRS, is
considered as treatment response [39,40]. The depression and
anxiety comorbid with tinnitus are assessed respectively
with Beck Depression Inventory-II (BDI-II) and Beck
Anxiety Inventories (BAI) at pre- (T0) and immediately
post intervention (T1). The treatment response for the BAI
and BDI scores is defined the reduction of equal or higher
than 50% of the baseline (pre-treatment) score [40,41].
The AEs of and tolerability to the tDCS sessions
will be assessed using a customized questionnaire
(Supplementary Table 1) after each tDCS session.
For defining the blinding condition for the patients in the
sham group, the tDCS device will be turned on for the
initial 30 seconds of tDCS session and then without the
knowledge of the patient it becomes turned off. This period
is based on the previous findings that demonstrated that
the perceived tDCS induced sensations usually persist
30 seconds and after that fade out. To assess the quality
of the blinding, we will ask all patients in both groups to
determine which type of stimulation, real or sham tDCS,
they have received. This assessment is conducted along
with the AEs after the last tDCS session.
All statistical tests are conducted with Statistical
Package for the Social Sciences (SPSS) (version 20,
IBM Corporation, New York, USA). Independent samples
t-tests are used to compare the differences of age, sex,
tinnitus quality tinnitus laterality, THI score, duration,
and severity of hearing loss as the dependent variables
between the real and sham tDCS groups to evaluate the
level of match between the two groups.
For nominal variables such as gender and tinnitus class,
the two groups will be compared using Chi-square test.
Independent sample t-tests are used to assess whether
individual baseline variables including THI, BDI, BAI,
and tinnitus loudness and distress differ between the
two groups. Levene’s test will be used before t-tests to
evaluate the equality of variances So that if the Levene’s
test is not violated, then equality of variances is assumed.
The number of female and male participants and the
tinnitus quality, across each group will be compared
using Pearson Chi-square tests. Mixed repeated-measure
ANOVAs with the within-subject factor Time and the between-subject factor Stimulation are used to assess
the changes in the primary and secondary outcomes
including THI, tinnitus loudness, tinnitus distress, BDI,
and BAI scores. For the ANOVAs, sphericity will be tested
using the Mauchly's test and if it is violated, then the
Greenhouse-Geisser correction is performed. In case
of significant effects, follow-up post-hoc t-tests will be
conducted with LSD adjustments for multiple comparisons
to examine if tDCS caused a significant difference relative
to sham or baseline. In addition, the Pearson’s correlation
coefficients will be calculated between the pre- to postintervention
changes of THI and BDI values.
The number of responders versus non-responders for
both real and sham groups will be evaluated through
calculating pre- to post-intervention changes of THI
scores (Vanneste et al. 2010; Vanneste et al. 2011).
Responders are those patients who show ≥ 20 points in
THI score (Pre-treatment THI–Post-treatment THI ≥ 20).
To determine the differences between the proportions
of responders versus non-responders under each
condition, we will use the Pearson’s chi-square tests.
For all statistical analyses, the statistically significance
level is set at p-value=0.05.
Sample size calculation
We calculated the sample size of this clinical trial with the
standard sample size formula (Eq.1). Considering the
study of Garin et al.  as the base study, power of 85%
and confidence interval of 95 percent, we calculated the
sample size as 25. To count for any attrition due to long
run of the study, we will enroll 30 patients in each group.
This clinical trial is designed to investigate the treatment
effects of multi-session tDCS (anodal/cathodal over the
right/left DLPFC) on tinnitus symptoms and comorbid
depression and anxiety in patients with medication
resistant tinnitus. The tDCS has shown beneficial
effects in improving cognitive functions in healthy  and
cognitive impaired individuals [11,16,43-46]. Moreover, it has
shown beneficial effects for different neuropsychiatric
disorders such as depression , obsessive compulsive
disorder , auditory-verbal hallucinations , and chronic
pain . Several studies have reported potential treatment
efficacies of tDCS for chronic tinnitus [20,23,24,26,47]. However,
the findings are inconsistent and majority of them have
focused on single session protocol investigating transient
and short term effects. The main advantages of this
study are its double blinded design and the relatively
long term follow up period of two months. Moreover, it
will concurrently evaluate the effects of the tDCS on the
comorbid depression and anxiety in the patients. To
the best of our knowledge this will be the first study of multisession tDCS with two months follow-up.
Ethics approval and consent to participate
The study was approved by the local ethics committee
of AJUMS, Ahvaz, Iran (registration code: IR.AJUMS.
REC.1394.639). After enrolment and before the start of
the study, researcher will clearly explain the experimental
procedures, the objectives, possible benefits, and side
effects of the study to the patients and then all participants
will fill and sign a written consent form for participation in
The present study was registered at Iranian Registry of
Clinical Trials (http://www.irct.ir:IRCT2016110124635N5).
Availability of data and material
The datasets generated and/or analyzed during the
current study are available from the corresponding author
on reasonable request. Furthermore, the authors will
publish the dataset of this study in the appropriate journal
following the completion of this study.
The authors declare that they have no competing interests.
The authors would like to thank the staff of the Khuzestan
cochlear center, Ahvaz, Iran for their assistance in
performing the audiometric assessments.
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