Download Review Experimental, Controversial, and Futuristic Treatments for

J Am Acad Audiol 25:106–125 (2014)
Review
Experimental, Controversial, and
Futuristic Treatments for Chronic Tinnitus
DOI: 10.3766/jaaa.25.1.7
Robert L. Folmer*†
Sarah M. Theodoroff*†
William Hal Martin†
Yongbing Shi†‡
Abstract
Background: Because chronic tinnitus is a condition that negatively impacts the quality of life
of millions of people worldwide, a safe and effective treatment for tinnitus has been sought for
millennia. However, effective treatments for tinnitus are greatly outnumbered by ineffective strategies, medications, devices, and surgeries that continue to be developed and promoted for the
condition.
Purpose: This article describes and critiques experimental, controversial, and potential treatments for
chronic tinnitus. The purpose of this review is to provide information that should help patients and clinicians to select tinnitus treatment and management strategies most likely to be effective for each set of
symptoms and circumstances.
Research Design: PubMed and MEDLINE databases (National Center for Biotechnology Information,
U.S. National Library of Medicine) were searched for the term tinnitus in articles published from 1940 to
2012. Other historical documents and publications were also reviewed as needed for particular topics.
Study Sample: Studies included in this review were selected to represent a sampling of treatment methodologies that have been used for tinnitus.
Data Collection and Analysis: Due to the heterogeneity of the studies reviewed, it was not appropriate
to perform a meta-analysis. A selective review of the literature was conducted to summarize and critique
published research results.
Results: Most invasive treatments for tinnitus should be avoided because (1) at best, there is scant
evidence that any of these treatments is effective, and (2) the risk to patients for most invasive
procedures is much greater than the risk posed by the tinnitus perception. Effective and noninvasive treatments for tinnitus include acoustic therapy (which includes hearing aids and
other types of environmental sound enrichment); cognitive-behavioral therapy; psychological
counseling; hypnosis; biofeedback; and relaxation training. Over-the-counter or prescription medications may be used as needed to facilitate sleep and to reduce anxiety, depression, or obsessivecompulsiveness.
Conclusions: Patients and clinicians should be especially cautious when considering invasive (and
potentially harmful) treatments for tinnitus, which is a non-life-threatening symptom. Unless welldesigned clinical trials verify that a tinnitus therapy demonstrates effectiveness above and beyond
*National Center for Rehabilitative Auditory Research, Portland VA Medical Center, Portland, OR; †Department of Otolaryngology, Oregon Health
and Science University, Portland, OR; ‡Currently Metokos LLC, Portland, OR
Robert L. Folmer, Ph.D., National Center for Rehabilitative Auditory Research, Portland VA Medical Center, 3710 SW U.S. Veterans Hospital Road
(NCRAR), Portland, OR 97239; E-mail: [email protected]
This research was supported by a grant from the U.S. Department of Veterans Affairs Rehabilitation Research and Development (RR&D) Service
(VA RR&D grant #C7448I). Additional support was provided by the National Center for Rehabilitative Auditory Research (funded by VA RR&D grant
#C9230C) at Portland VA Medical Center.
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Experimental and Controversial Treatments/Folmer et al
the placebo effect, consumers should be wary of medications, devices, or procedures promoted as a
“cure.” Although a true cure for tinnitus has not yet been found, effective and noninvasive tinnitus management strategies are available now. If progress is made to medically (or genetically) treat sensorineural
hearing loss in humans, this breakthrough should also help to simultaneously reduce the perception of
tinnitus for many patients.
Key Words: Auditory rehabilitation, management, tinnitus, therapy, treatment
Abbreviations: AlstR/AL 5 allatostatin receptor/allatostatin; BAHA 5 bone-anchored hearing aid;
CBT 5 cognitive-behavorial rehabilitation; DBS 5 deep brain stimulation; ECT 5 electroconvulsive therapy;
FDA 5 Food and Drug Administration; GABA 5 gamma-aminobutyric acid; LC 5 light chain; LTA 5
left temporoparietal area; MVD 5 microvascular decompression; RAIC 5 rostral agranular insular cortex;
rTMS 5 repetitive transcranial magnetic stimulation; tDCS 5 transcranial direct current stimulation; THI 5
Tinnitus Handicap Inventory; TMS 5 transcranial magnetic stimulation; SSRI 5 serotonin-specific
reuptake inhibitor; VAS 5 visual analog scale
INTRODUCTION
B
Study Selection
ecause chronic tinnitus is a condition that negatively impacts the quality of life for millions of
people worldwide, a safe and effective treatment for tinnitus has been sought for millennia. For
example, the Ebers Papyrus (an Egyptian medical
document originating in 3000 B.C.E.) recommended
intraural infusions of balanites oil and frankincense
as treatment for a “bewitched ear” (Dietrich, 2004).
Medical practitioners in Assyria (sixth century B.C.E.)
offered this advice: “If the hand of a ghost seizes on a
man and his ears sing, apply herbs, oils and salt
through a hollow reed” (Carey, 1988). The famous
physician Galen of Pergamon (130–200 C.E.) recommended the following for his tinnitus patients: “Dull
the senses with mandrake or opium” (Kraft, 1998). Such
potent substances may or may not affect tinnitus
directly, but they are likely to distract patients’ attention away from the symptom for a while.
More recent attempts to treat tinnitus have employed
a wide variety of methods, including electrical stimulation of the patient’s head; inserting magnets into the
ear canals; prefrontal leucotomy; and a plethora of
potions and pills that include exotic ingredients such
as lyophilized powder of enzymolyzed honeybee larvae
(Aoki et al, 2012). In spite of these creative approaches,
a true cure for the most common etiologies of tinnitus
(damage or degeneration within the auditory system)
remains elusive. This review describes and critiques
some tinnitus treatments that have been developed
or investigated.
Studies included in this review were selected to represent a sampling of treatment methodologies that have
been used for tinnitus. The purpose of this manuscript
is not to be an exhaustive review of tinnitus treatments
but, rather, to focus on experimental and controversial
treatments for chronic tinnitus.
Research Design
Alexander of Tralles (525–605 C.E.) suggested that
tinnitus sufferers could obtain relief by walking in
“sondry places.”
“Why is it that buzzing in the ears ceases if one makes
a sound? Is it because a greater sound drives out the
less?” (Salerno School, 12th–13th centuries C.E.)
Johan Jakob Wepfer (1620–1695) gave this account
of one patient’s technique: “He banged two pebbles
PubMed and MEDLINE databases (National Center
for Biotechnology Information, U.S. National Library of
Medicine) were searched for the term tinnitus in
articles published from 1940 to 2012. Other historical
documents and publications were also reviewed as
needed for particular topics.
Data Collection and Analysis
Due to the heterogeneity of the studies reviewed, it
was not appropriate to perform a meta-analysis. A selective review of the literature was conducted to summarize
and critique published research results.
Results
Some tinnitus treatment methods show potential to
offer tinnitus relief, while others lack evidence to support
their claims of being beneficial and should therefore be
avoided. This is not meant to be an exhaustive review;
the article reflects the authors’ professional biases and
prerogatives.
ACOUSTIC THERAPY
A
coustic therapy is often a component of effective
tinnitus management. One definition of acoustic
therapy is “using external sounds to provide relief from
tinnitus.” This is not a new concept, as the following
examples (recounted by Stephens, 1987) illustrate:
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Journal of the American Academy of Audiology/Volume 25, Number 1, 2014
together next to his ear so that the sound made by
these stones would solve his problem.”
Jean Marie Gaspard Itard (1821) wrote the following:
Producing a roaring fire in the grate considerably
relieves the disturbance resulting from tinnitus
which sounds like the distant murmuring of wind
and a river in flood. The same approach can be adopted with whistling tinnitus by putting green or
slightly damp wood on the fire. When the tinnitus
is like the sound of bells, as long as it is not too loud,
it may be masked by the resonance of a large copper
bowl into which falls a trickle of water from a vase.
Finally, in the case of tinnitus resembling the sound of
a set of wheels turning, one can place alongside the
bed a noisy spring-driven motor adapted to a mechanical organ, or a large watch, of which the movements
are speeded up by removal of the regulator.
During the last two centuries, numerous techniques
and devices have been developed to deliver acoustic
therapy to tinnitus sufferers. Urbantschitsch (1883)
used tuning forks; Wilson (1893) tried a telephone
transducer; Spaulding (1903) played a violin. Porter
and McBride (1916) suggested that tinnitus patients
should place a loud ticking clock near their beds. Saltzman
and Ersner (1947) recommended hearing aids for tinnitus
relief.
The rationale for all of these strategies is the same:
increase the level of external sounds in the patient’s
environment in order to decrease the patient’s perception of tinnitus. Acoustic therapy has been shown to be
an effective method to reduce tinnitus perception or
severity (Folmer and Carroll, 2006; Henry et al,
2008). In a quiet environment, the tinnitus signal is
prominent, and the level of background sound is low.
This phenomenon was demonstrated by Heller and
Bergman’s study published in 1953. They asked 80
adults who had normal hearing and no tinnitus to enter
a sound booth (one at a time) and make note of the
sounds they heard while in the booth. The interior of
the booth had a maximum background sound level
of 18 dB SPL. While they were in the booth, 75 (94%)
of these subjects reported that they heard sounds such
as buzzing, humming, ringing, insects, or pulsations.
Heller and Bergman (1953) concluded, “It appears that
tinnitus is present constantly, but is masked by the
ambient noise which floods our environment. This
ambient noise level for ordinary quiet living conditions
usually exceeds 35 dB SPL and is of sufficient intensity
to mask physiological tinnitus which remains subaudible. It would appear, then, that tinnitus will not be
eliminated by any treatment but at best can only
become subaudible.”
One of the goals of acoustic therapy is to increase the
level of background sound in order to decrease the
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tinnitus signal-to-noise ratio. When background sounds
are increased, the tinnitus signal-to-noise ratio becomes
smaller; therefore, tinnitus will then be less noticeable
and less bothersome or intrusive for most patients. In
this issue of JAAA, the article by Hoare et al (2014)
describes different methods and strategies of acoustic
therapies that can be implemented by clinicians and
patients. Here we describe two controversial methods
of acoustic therapy that have been promoted recently.
1. The “Inhibitor” ultrasonic tinnitus treatment device
(see Fig. 1) is being marketed by the Melmedtronics
Company (Colleyville, TX). This battery-powered
device is held against the patient’s mastoid and
delivers high-frequency stimulation via bone conduction. The idea that high-frequency stimulation
(i.e., frequencies near or above the upper range of
human hearing, which has a limit of 20 kHz) might
provide relief to tinnitus patients was pioneered by
the Hearing Innovations company that produced a
multifrequency device called “HiSonic.” Originally,
HiSonic technology was developed to deliver speech
stimuli via ultrasonic bone conduction (Lenhardt
et al, 1991) and was promoted as an alternative to
cochlear implantation. One major problem emerged:
although people with normal hearing or mild-tomoderate hearing loss could perceive speech signals
through the device, people with severe to profound
hearing loss (the target population) could not. Subsequently, the HiSonic device was promoted as a
form of acoustic therapy for tinnitus. Unfortunately,
the majority of patients who tried the device disliked
the sensations it produced, and they received
no relief from tinnitus. A similar fate befell the
Aurex-3 device (distributed by ADM Tronics, New
Jersey), another version of a high-frequency bone
stimulator that did not survive in the tinnitus treatment marketplace. Promoters of the Inhibitor are
attempting to rekindle interest in ultrasonic bone
conduction for tinnitus, but no well-designed research studies have been conducted to establish
or confirm the Inhibitor’s efficacy. Note: These
descriptions of the Inhibitor, HiSonic, and Aurex-3
are based on the authors’ experiences with the devices (and with patients who tried them) and therefore reflect the authors’ opinions.
Figure 1. Image of the Inhibitor device.
Experimental and Controversial Treatments/Folmer et al
2. A different type of acoustic therapy was described
by Reavis et al (2012), who presented a variety of
amplitude- and frequency-modulated tones for 3 min
at a time to 20 patients with chronic tinnitus. These
sounds, in addition to white noise, were presented
in a random order to all subjects and at intensities
that were just below the tinnitus loudness. The
authors concluded: “Our results suggest that, in
addition to a traditional masking approach using
unmodulated pure-tones and white noise, modulated
sounds should be used for tinnitus suppression
because they may be more effective in reducing
hyperactive neural activities associated with tinnitus.” However, the study described 13 of the 20 subjects as “poor responders” who experienced at most
50% suppression of perceived tinnitus loudness after
exposure to any masking sounds. The remaining
seven patients were designated as “good responders”
who reported 70% suppression of their tinnitus after
exposure to masking sounds.
Given these modest results, it is somewhat surprising
that Reavis et al recommend using modulated sounds
for tinnitus suppression. Independent clinical trials
that demonstrate treatment efficacy for this method
would help to dispel concerns of bias, given the financial
interests in the SoundCure Company disclosed by three
of the article’s authors. SoundCure (San Jose, CA) distributes a handheld device that produces modulated
tones for use by tinnitus patients (see Fig. 2). According
to the company’s Web site (www.soundcure.com),
The Serenade device consists of a handheld acoustic
stimuli generator, earphones, and pleasant treatment
sounds that are intended to address the underlying
cause of tinnitus. A suite of three different types of
sounds is included, enabling the audiologist to determine the specific clinical approach that is most likely
to be effective for each patient. Unlike most treatment
methodologies, Serenade is customizable and can be
programmed to meet the unique needs of each patient,
day or night. Studies suggest that S-Tonesä may offer
immediate relief.
Overstatements of a treatment’s efficacy, even in
light of modest research findings, are common in this
field and other clinical fields as well. Ioannidis (2011)
discusses how conflict of interest can influence medical
findings and stresses the importance of validating findings prior to implementing a new treatment. Independent research studies (i.e., performed by researchers who
are free of conflicts of interest) should be conducted to
validate test results prior to implementing a treatment
in clinical practice. Other examples of product development and marketing that occurred before efficacy was
fully documented by research include the “Inhibitor”
device mentioned previously and a vagus nerve stimulator (developed by Microtransponder, Inc.) described
Figure 2. Image of SoundCure’s Serenade device.
in a later section of this article. Perhaps some of these
products are effective treatments for tinnitus, even in a
subpopulation of patients. However, well-designed, placebo-controlled clinical trials should be conducted and
analyzed before claims of efficacy are made. In order
to establish whether a treatment is effective, research
must demonstrate that a significant change (clinical or
statistical) has occurred that can be attributed to the
treatment above and beyond the placebo effect. Performing clinically relevant research is part of conducting evidence-based medicine. By definition, “evidence
based medicine is the conscientious, explicit, and judicious use of current best evidence in making decisions
about the care of individual patients” (Sackett et al,
1996), which leads to an informed decision regarding
the results reported in the literature pertaining to a
specific treatment prior to implementation.
PSYCHOLOGICAL INTERVENTIONS
I
n this issue of JAAA, the article by Cima et al
(2014) describes psychological interventions—such as
cognitive-behavioral therapy (CBT) and acceptance and
commitment therapy (ACT)—that have demonstrated
efficacy for reducing patients’ distress, anxiety, depression, insomnia, and other negative consequences associated with tinnitus perception (Hesser et al, 2011).
Andersson and Lyttkens (1999) performed a metaanalysis review on psychological treatments (CBT,
relaxation, education, hypnosis, biofeedback, stress
management) and reported that these treatments benefit many tinnitus patients. Here we describe two additional psychological interventions that have helped
some tinnitus patients.
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Journal of the American Academy of Audiology/Volume 25, Number 1, 2014
Hypnosis
Reports of using hypnotherapy to help tinnitus
patients began in the 1940s (Pearson and Barnes,
1948) and have been published in every decade since,
including the current one (Yazici et al, 2012). Given
the fact that hypnotherapy can help to promote relaxation and reduce anxiety (Lee et al, 2007), and might alter
neural connectivity between brain regions (Hoeft et al,
2012), it is not surprising that this technique helps tinnitus patients since many studies have established the
correlation between tinnitus severity and anxiety/stress
(e.g., Folmer et al, 2001). Also, hypnotherapy can be used
to augment other behavioral therapies (such as CBT) by
encouraging patients to implement more productive coping strategies. Self-hypnosis techniques (Attias et al,
1993) might help to instill a “locus of control” for some
tinnitus patients who exhibit a deficiency of this trait.
Is hypnosis more effective than other psychological
interventions for tinnitus? Because no large-scale,
randomized clinical trials of hypnosis have been conducted with tinnitus patients, it is difficult to gauge
the efficacy of the method. Also, different types of hypnotherapy exist and have been used with this population. However, since the procedure carries minimal
risk for patients and usually promotes self-improvement
and relaxation, hypnotherapy would seem to be more beneficial than harmful in most cases.
Biofeedback
Biofeedback provides information to patients about a
physiological measure (such as electroencephalography
or muscle tension) while they engage in activities (such
as relaxation, meditation, or pleasant visualization)
designed to have a positive effect on the physiological
characteristic. Reports of clinicians using biofeedback
techniques with tinnitus patients date to the 1970s
(Grossan, 1976; House, 1978). In the study by House
(1978), 41 tinnitus patients attended 12 1 hr sessions
with a psychologist who provided instruction on relaxation techniques and strategies. During these sessions,
patients received constant feedback via electromyography (EMG) and skin temperature monitoring devices.
Successful implementation of relaxation techniques
would result in decreased muscle tension and increased
skin temperature. Patients were also encouraged to
practice the techniques at home between formal sessions in the clinic. House reported that 33 of the
patients reported reductions in tinnitus severity immediately after the last therapy session, and 23 patients
sustained some improvement 6 to 12 mo later. A majority of patients also reported improvements in general
well-being and enjoyment of life and less reliance on
anti-anxiety medications. Such positive results are typical of published studies of biofeedback for tinnitus. In
110
this study by House, no control group was included (e.g.,
one that received relaxation training but no biofeedback). It is likely that 12 1 hr sessions with a psychologist who provides relaxation training would benefit
most patients who experience tinnitus and/or anxiety.
So we do not know if the biofeedback procedure itself
provided additional benefits for these patients. But
like hypnosis, biofeedback therapy has helped many
patients to increase relaxation and decrease anxiety.
Therefore, the procedure is likely to benefit at least a
subpopulation of patients with bothersome tinnitus.
Additional references on the topic of neurofeedback
for tinnitus include Haller et al (2010) and Crocetti
et al (2011).
OTHER MINIMALLY INVASIVE
INTERVENTIONS
Soft Laser
The word soft is used to describe a low-powered laser
that can be focused into the patient’s ear canal. In a
study by Okhovat et al (2011), a 5 mW medical laser
transmitter (Tinnimed, German Medical Laser, Pforzheim,
Germany) was connected by a fiberoptic cable and an
adapter with a soft silicone tip to the patient’s ear.
The laser beam was then directed through the external
ear canal and tympanic membrane into the cochlea
(i.e., transmeatal). Okhovat et al (2011) irradiated
the ear canals of 61 tinnitus patients with a 650 nm,
5 mW soft laser for 20 min per day for 20 consecutive
days. The patients’ sensations of tinnitus were measured on a visual analog scale (VAS) before and 2 wk
after treatment. The authors reported that the VAS
mean difference before and after the treatment was
statistically significant ( p , 0.0001), and the best
treatment effect was in the youngest group. Okhovat
et al (2011) admit that “the therapeutic mechanism of
this method is not completely understood” (p. 33).
Siedentopf et al (2007) proposed that laser stimulation
might reduce tinnitus by increasing inner ear cell proliferation, adenosine triphosphate (ATP) and collagen production, and secretion of growth factors, and by improving
inner ear blood flow and activating hair cell mitochondria
that stimulate repair mechanisms.
One criticism of the study by Okhovat et al (2011) is
that a placebo control was not part of the research plan.
Cuda and De Caria (2008) did include a control group in
their study involving 46 tinnitus patients: 26 patients
received laser treatment (20 min per day every week
day for 3 mo), and 20 patients were assigned to a placebo
group. The authors reported that Tinnitus Handicap
Inventory (THI) scores improved in the entire sample
after treatment, but they changed more significantly
in the group receiving low-level laser stimulation.
Approximately 61% of irradiated patients had tinnitus
Experimental and Controversial Treatments/Folmer et al
severity decreased by one class, in comparison to 35% of
the placebo group.
However, other published studies failed to find efficacy of low-level laser stimulation for tinnitus. For
example, Teggi et al (2009) replicated much of the
experimental protocol used by Cuda and De Caria
(2008), which included a treatment group and a placebo
group of patients. Teggi et al reported that no significant difference was detected between the groups in
the THI total score (p 5 0.97) and the functional (p 5
0.89), emotional (p 5 0.89), and catastrophic (p 5
0.89) subscales. Also, a VAS for tinnitus loudness showed
no difference between the groups (p 5 0.69).
Nakashima et al (2002) conducted a study involving
45 tinnitus patients (n 5 25 in the treatment group, and
n 5 20 in the placebo group) and used a more powerful
(60 mW) soft laser to irradiate the patients’ ear canals.
Active or placebo laser treatment was administered transmeatally once per week for 6 min; irradiation was performed four times during a 4 wk period. Nakashima
et al (2002) reported that no significant difference was
observed between the active and placebo laser groups
with regard to loudness, duration, quality, and annoyance of tinnitus. In one patient who received active
laser treatment, acute hearing deterioration occurred
after the third irradiation. The authors concluded that
“transmeatal low-power laser irradiation with 60 mW
is not effective for the treatment of tinnitus” (Nakashima
et al, 2002, p. 296).
Why did some studies conclude that soft laser irradiation is an effective treatment for tinnitus, while other
studies found no efficacy for the procedure? The lack of a
placebo control in the study by Okhovat et al (2011) is a
serious experimental design flaw that occurs in many
tinnitus investigations. While Cuda and De Caria
(2008) did include a placebo group in their study, it is
possible that “blinding” of research subjects and clinical
staff was incomplete. The more rigorous placebocontrolled protocol employed by Teggi et al (2009)
reduced clinician bias and influence on research subjects, resulting in no significant treatment effects for this
type of laser irradiation.
Wearable Magnets
Wearable magnets have been touted as treatments
for a variety of conditions, including arthritis, diabetes,
gout, chronic pain, even cancer (Philpott and Kalita,
2000; Rose, 2001). The devices are available in many
shapes and sizes and can be worn as bracelets or necklaces; also, magnetic appliqués can be attached to the skin
of the arm, leg, back, or head–wherever relief is desired.
Takeda (1987) inserted small round (4 mm diameter, 2
mm thick) magnets embedded in cotton into the ear
canals of 56 tinnitus patients. After one week, tinnitus
was reduced in 37 patients, did not change in 18
patients, and worsened for one patient. Takeda reported that the beneficial effects lasted at least 3 weeks,
and sometimes longer than 9 weeks.
However, a placebo control was not included in the
experimental design. In 1991, Coles et al conducted a
double-blind, placebo-controlled study of tinnitus patients
using the same types of magnets that Takeda employed.
Magnets or physically similar but nonmagnetic pieces of
metal were mounted on cotton and inserted into the ear
canal of patients on the side where tinnitus perception
was loudest; 26 patients received magnets, and 23 received
nonmagnetic metal “plugs”. Results were obtained after
4 wk (Table 1). Coles et al concluded, “it is self-evident that
this line of treatment is insufficiently effective to be clinically worthwhile, except perhaps as a form of placebo
treatment, and has to join the long list of claimed treatments for tinnitus that have not stood up to clinical trial”
(1991, p. 372).
Transcranial Magnetic Stimulation (TMS)
A much more powerful magnetic field—delivered to
the patient’s head by a technique called transcranial
magnetic stimulation (TMS)—is being assessed for its
potential to reduce tinnitus perception and severity.
TMS involves delivering electromagnetic pulses through
a coil that is in contact with the patient’s scalp (see
Fig. 3). Ultimately, some of this energy is transmitted
through the skull, inducing an electric current that affects
the activity of underlying neural tissue. Low-frequency
repetitive TMS (1 Hz or less) is known to reduce neural
activity in directly stimulated brain regions (Chen et al,
1997; Maeda et al, 2000; Siebner et al, 2003) as well as in
structurally connected remote brain regions (May et al,
2007). For this reason, repetitive TMS (rTMS) has been
investigated as a possible treatment for disorders related
to increased neural activity (Hoffman and Cavus, 2002),
including tinnitus. Several different functional imaging
studies have shown that, compared to control subjects,
people who experience tinnitus have increased activity
in the auditory cortex, even in the absence of external
auditory stimuli (Arnold et al, 1996; Lockwood et al,
1998; Folmer, 2007). Therefore, applying low frequency
TMS to auditory cortex, as well as the dorsolateral prefrontal cortex (De Ridder, Song, et al, 2012), may
reduce patients’ perceived severity or loudness of
Table 1. Effect of Wearable Magnets on Tinnitus
(Coles et al, 1991)
Tinnitus improved
No change
Tinnitus worsened
Magnet group
(n = 26)
Placebo group
(n = 23)
7 (27%)
12 (46%)
7 (27%)
4 (17%)
16 (70%)
3 (13%)
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Journal of the American Academy of Audiology/Volume 25, Number 1, 2014
management. One of these roles is to prescribe medications that might help tinnitus patients by alleviating
the severity of associated symptoms such as insomnia,
anxiety, depression, or obsessive-compulsiveness. This
section will provide an overview of over-the-counter,
prescription, and experimental medications that have
been advocated or used for tinnitus.
Over-the-Counter Substances
Figure 3. A transcranial magnetic stimulation (TMS) system.
tinnitus. A recent article by Theodoroff and Folmer
(2013) reviewed many TMS studies that have been conducted for tinnitus. While optimism for the clinical utility
of TMS as an effective treatment for tinnitus remains high
among many researchers, clinicians, and patients, several
key questions and procedural issues remain unresolved.
Additional studies are needed to identify the optimum
parameters for TMS coil placement, stimulation frequency
and intensity, and other basic procedural issues. Advancements of this kind are necessary to improve the effectiveness of rTMS as a viable method to treat chronic tinnitus.
Transcranial Direct Current Stimulation (tDCS)
Another promising treatment for tinnitus is transcranial direct current stimulation, or tDCS (Vanneste et al,
2013). This procedure involves attaching one end of
electrodes to the patient’s scalp and the other end to
a current source. Application of electrical current then
either increases or decreases the neuronal excitability
or activity beneath the stimulating electrode. In one
of the first published studies of tDCS for tinnitus,
Fregni et al (2006) reported that stimulation of the left
temporoparietal area (LTA) resulted in a significant
reduction of tinnitus, similar to that produced by 10 Hz
TMS. A review of subsequent tDCS studies for tinnitus
(Song et al, 2012) indicated that 39.5% of all patients
responded to active tDCS with a mean reduction in tinnitus intensity of 13.5%. Active tDCS was found to be
more effective than sham tDCS for tinnitus intensity
reduction (Hedges’ g 5 .77, 95% confidence interval 5
0.23–1.31). Therefore, Song et al concluded that tDCS
may be a promising tool for tinnitus management. To further assess the efficacy of the procedure, the authors recommended implementation of larger randomized clinical
trials (RCTs) as well as a comparison between LTA and
frontal tDCS electrode placement positions.
MEDICATIONS
T
he article by Shi et al (2014) in this issue of JAAA
describes the role of the physician in tinnitus
112
As stated in the introduction of this article, numerous
substances have been tried—with minimal success—
over the last few millennia by clinicians and patients
seeking a cure or treatment for tinnitus. Today, several
herbal and homeopathic products are marketed as “tinnitus remedies.” For example, the t-gone company
(Henderson, NV) distributes a line of ingestible tablets
that are purported to help with tinnitus due to cochlear
(or noise) damage, stress, sinus/allergy problems, and
tinnitus caused by Ménière’s disease. Ingredients of
the tablets include different combinations of thiosinaminum, carboneum sulphuratum, chininum sulphuricum,
pulsatilla vulgaris, cinchona officinalis, belladonna, calcarea carbonica, phosphorus, silicea, hydrastis and
kalium bichromate. Because such concoctions are not
well regulated by governmental agencies, it is difficult
to confirm the actual ingredients contained in the tablets
and at what dosages. Further, none of these substances
has been demonstrated by research to be an effective
treatment for tinnitus caused by cochlear damage, noise
exposure, stress, Ménière’s disease, or any other etiology
of the condition. No clinical trials of t-gone have been
published in peer-reviewed literature.
Another company, Arches Natural Products (Salt
Lake City, UT), distributes Tinnitus Formula capsules
that contain zinc, garlic, and ginkgo biloba extract. The
company Web site claims that the capsules were “Specifically formulated for ringing in the ears with clinically proven ingredients for tinnitus.” Arches claims
that the capsules have been “recommended by thousands of leading ENT specialists for their patients with
tinnitus.” Like the t-gone company Web site, the Arches
Web site contains numerous testimonials from “customers” reporting that the products helped them greatly by
reducing or eliminating their tinnitus.
Following is a discussion of each of the Tinnitus Formula ingredients to determine if any of them are effective treatments for tinnitus. Several studies assert that
tinnitus patients might have lower-than-recommended
blood levels of zinc (Ochi et al, 2003; Coelho et al, 2007).
However, few placebo-controlled studies of zinc for tinnitus have been conducted. One such investigation, by
Paaske et al (1991) concluded that neither zinc supplements nor placebo tablets had any significant effect on
tinnitus for 48 patients in the study. Arda et al (2003)
also performed a placebo-controlled study of zinc for
Experimental and Controversial Treatments/Folmer et al
tinnitus treatment and did not find any statistically significant results for the supplement. Garlic, the second
ingredient in Tinnitus Formula capsules, has not been
investigated in a placebo-controlled study of tinnitus.
Although it is usually a welcome ingredient in spaghetti
sauce, garlic has not been shown to affect cochlear or
neural damage that is the root cause of most cases of
tinnitus. Linde et al (2001) reviewed herbal medicine
used for health-related problems and found insufficient
evidence to draw any conclusion for garlic to be used as
an herbal remedy. Finally, ginkgo biloba has been
touted as an effective treatment for tinnitus and is
included in many over-the-counter “remedies.” However, in 2001, Drew and Davies (2001) conducted a
double-blind, placebo-controlled trial of ginkgo biloba
involving 1121 tinnitus patients. The authors concluded that 50 mg of ginkgo biloba extract given 3 times
daily for 12 wk was no more effective than placebo pills in
treating tinnitus. Therefore, none of the ingredients in
Arches Tinnitus Formula capsules has research support
for improving tinnitus symptoms beyond a placebo effect,
although the company Web site (www.tinnitusformula.
com) proclaims that the ingredients are “clinically proven
for tinnitus.”
The placebo effect is an important consideration in
assessing the effectiveness of tinnitus treatments
because this effect is significant in many clinical trials,
especially those involving tinnitus patients (Dobie,
1999). In his review of randomized clinical trials of tinnitus treatments, Dobie (1999) concluded that patients
in the placebo group often improved (usually as much as
patients did in the active treatment group) because of
interactions with clinicians and researchers who took
their problems seriously and sought to help them.
Therefore, with the exception of many psychological
interventions, evaluations of tinnitus treatments
should include a placebo group for comparison. As
described above, when carefully conducted, placebocontrolled studies of over-the-counter tinnitus “remedies” or ingredients have been conducted, the active
ingredients have not performed better than placebos.
Some over-the-counter substances (such as those that
improve sleep, depression, anxiety, or sinus congestion)
might provide some relief or improvement for tinnitus
patients and aggravating or coincident conditions
(Rosenberg et al, 1998; Megwalu et al, 2006). For example, a recent study conducted in Japan concluded that
“the lyophilized powder of enzymolyzed honeybee larvae represents an effective complementary medicine
to alleviate depression associated with tinnitus by regulating the activity of the hypothalamus-pituitaryadrenal axis” (Aoki et al, 2012). Until independent
studies have been conducted, all of these claims should
be considered with caution. Since the underlying mechanism(s) of tinnitus are not completely understood,
it seems unlikely any of these substances—including
enzymolyzed honeybee larvae—will “cure” tinnitus
or facilitate reparation of the underlying causes of the
condition.
Prescription Medications
The severity of tinnitus is positively correlated with
depression (Folmer et al, 1999), insomnia (Folmer and
Griest, 2000), anxiety (Folmer et al, 2001), and obsessivecompulsive behavior (Folmer et al, 2008). Previous
studies demonstrated that effective treatment of these
symptoms can help to reduce the severity of patients’
tinnitus (Folmer, 2002). Because most of these comorbid
conditions are psychological in nature, a combination of
effective psychotherapy and medication can help many
patients to improve (Folmer, 2002). However, most of
the medications used for this purpose are not prescribed
specifically for tinnitus but, instead, for treatment of
associated mental health symptoms. It is important
for patients to work with clinicians who have appropriate training and experience in behavioral health to find
the most appropriate medication and dosage schedule
to effectively treat the conditions listed above. Two
classes of medications, benzodiazepines and serotonin-specific reuptake inhibitors (SSRIs), were investigated specifically for their effects on tinnitus and are
discussed below.
In 1993, Johnson and colleagues conducted a study of
the anti-anxiety medication alprazolam, which is in a
class of drugs called benzodiazepines (common brand
names include Xanax, Valium, Klonopin, and Ativan).
The study was undertaken because several patients
seen in the investigators’ clinic (Tinnitus Clinic at
Oregon Health and Science University, Portland, OR)
reported that alprazolam seemed to reduce their perception of tinnitus. In the study by Johnson et al, 17 tinnitus patients took increasing dosages of alprazolam for
12 wk to a maximum dosage of 0.5 mg three times daily;
19 tinnitus patients took lactose pills according to the
same schedule for 12 wk. Results indicated a significant
reduction in the matched loudness of tinnitus (dB SL)
for the alprazolam group, with no similar effect for
the placebo group. In fact, the maximum dosage of
alprazolam reduced the matched loudness of tinnitus
for 13 of 17 subjects in the active treatment group. Also,
11 of these 13 alprazolam patients reported improved
sleep patterns, and 10 of these 13 patients experienced
reduced anxiety. The placebo patients did not experience improvements in tinnitus, sleep, or anxiety. These
findings are not surprising because alprazolam is an
anti-anxiety medication that has a sedating effect for
many patients. It is likely that the medication reduced
patients’ perception of tinnitus via its action as a GABA
(gamma-aminobutyric acid) agonist. GABA is one of the
major inhibitory neurotransmitters in the human central nervous system. By activating GABA receptors in
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Journal of the American Academy of Audiology/Volume 25, Number 1, 2014
the patients’ brain, alprazolam suppressed some of the
neural activity responsible for tinnitus perception and
also helped patients to relax and sleep.
This study by Johnson et al had a number of design
flaws and procedural problems, including small sample
size; no measures of tinnitus severity; no formal measures of anxiety; and no long-term follow-up. Also, it was
easy for subjects to differentiate between alprazolam
and placebo because the lactose pills had no sedating
effects. Although alprazolam exhibited some beneficial
effects for tinnitus patients, we must ask the following:
for which patients do the benefits of taking benzodiazepines (improved sleep; reduced anxiety and tinnitus)
outweigh the risks (dependence on medication and
sedation)? It is possible for patients to receive some benefits from alprazolam even if they do not take the maximum dosage (0.5 mg three times daily) achieved by
patients in the study by Johnson et al. Interested
patients should work with their physician to determine
if they are good candidates for this medication, which
can be used occasionally (daily administration is not
required) and in smaller dosages as needed.
A more recent study of alprazolam was conducted
among 36 tinnitus patients by Jalali et al (2009).
Patients with depressive or anxiety disorders were
excluded from the study, as were those who used hearing aids. Results indicated that, compared to placebo,
alprazolam did not result in statistically significantly
changes in THI score or matched tinnitus loudness.
However, there was a significant improvement in
VAS tinnitus loudness score for the alprazolam group
compared with the placebo group ( p , 0.001). The fact
that patients with depressive or anxiety disorders were
excluded makes it difficult to compare the findings in
this study to results obtained by Johnson et al.
A different class of prescription medications that has
been investigated for tinnitus is SSRIs—drugs that are
used to treat depression, anxiety, and obsessive-compulsive behavior. Case reports by Shemen (1998) and
Christensen (2001) claimed that use of SSRI medications fluoxetine and paroxetine resulted in “complete
resolution” of tinnitus in a total of four patients.
Encouraging reports such as these led Robinson et al
(2005) to conduct a study of paroxetine in a population
of 120 tinnitus patients. In this study, 60 patients took
the maximally tolerated dose (up to 50 mg/day) of paroxetine for 31 days, and 60 patients took placebo pills
according to the same schedule for 31 days. Results
indicated that paroxetine was not statistically superior
to placebo on measures including tinnitus loudness
matching and the Tinnitus Handicap Questionnaire.
Robinson et al concluded, “The majority of individuals
in this study did not benefit from paroxetine in a consistent fashion” (2005, p. 981). This negative result
probably occurred because of the study design: patients
with psychotic or substance use disorders or suicidal
114
ideation were excluded, as were those using psychoactive medications. Consequently, only one tinnitus
patient with major depression was included in the study
population.
Benzodiazepines and SSRI medications have helped
to reduce the severity of anxiety and depression for millions of patients throughout the world. Studies of these
medications that excluded patients with anxiety or
depression (e.g., Robinson et al, 2005; Jalali et al,
2009) concluded that they were not effective treatments
for tinnitus. However, these results should not be interpreted to mean that benzodiazepines and SSRIs are not
likely to benefit tinnitus patients. For many patients
who experience anxiety and depression in addition to
tinnitus, medications such as these in conjunction with
effective psychotherapy may help to improve their quality of life and reduce the severity of tinnitus.
“Off-Label” Use of Prescription Medications
for Tinnitus
In addition to benzodiazepines and SSRIs, many
other prescription medications have been tried by clinicians and tinnitus patients. The term off label refers to
using a medication for a purpose other than that originally approved by the Food and Drug Administration
(FDA). For example, a few studies reported that gabapentin (another GABA agonist that was developed as an
anticonvulsant) is effective for reducing the perception
or severity of tinnitus (Zapp, 2001; Bauer and Brozoski,
2006). However, double-blind randomized controlled
trials of gabapentin conducted by Witsell et al (2007)
and Piccirillo et al (2007) concluded that gabapentin
was not superior to placebo as a tinnitus treatment.
Azevedo and Figueiredo (2005) exhibited creative
thinking when they conducted a clinical trial of acamprosate for tinnitus. This study was creative because
acamprosate’s usual application is a treatment for alcoholism. Specifically, acamprosate helps patients to
abstain from alcohol by functioning as a glutamate
(excitatory neurotransmitter) antagonist and a GABA
agonist in the brain. Because over-activation of glutamatergic pathways and underactivation of GABA-ergic
pathways in the central auditory system are thought to
play roles in the generation and perception of tinnitus,
acamprosate would seem to be a logical choice that
might help patients with the condition. In the study
by Azevedo and Figueiredo, 23 tinnitus patients
received acamprosate, and 18 patients received placebo
pills for a period of 3 mo. For an outcome measure,
patients rated how “disturbed” they were by tinnitus
on a 1–10 scale. At 60 and 90 days postbaseline, the
acamprosate group exhibited significant decreases in
this measure compared to the placebo group, which
did not show significant changes in tinnitus disturbance. Concerns about this study include a small sample
Experimental and Controversial Treatments/Folmer et al
size, a single (and simplistic) outcome measure, and
questionable blinding of study participants. A larger,
double-blind, randomized controlled trial of acamprosate
conducted by W.H. Martin, S. Griest, and Y. Shi (unpublished) at Oregon Health and Science University concluded
that the effects of the medication were not significantly
different from placebo pills for tinnitus treatment.
Numerous other prescription medications have been
tried for tinnitus, with limited success (see Salvi et al,
2009; Savage et al, 2009, for reviews). In our opinion,
the medications most likely to help reduce tinnitusrelated distress are those that address comorbid symptoms (such as insomnia, anxiety, or depression) when
they are present. Also, patients and clinicians should
not expect a medication alone to effectively treat tinnitus or any of its cosymptoms. Because all of these conditions are complex in nature, they require integrated,
multidisciplinary management strategies. For example, most tinnitus patients benefit from some sort of
acoustic therapy (see the article by Hoare et al [2014]
in this issue of JAAA) that can include utilization of
hearing aids. Many tinnitus patients also benefit from
CBT or other types of psychological interventions that
help reduce tinnitus-related distress (see the article by
Cima et al [2014] in this issue of JAAA). Prescription
medications can thus be viewed as one category of treatment options that may be used in conjunction with
other management strategies to help tinnitus patients.
INVASIVE INTERVENTIONS
I
n modern times, one of the most controversial and
invasive procedures ever implemented to treat tinnitus was frontal leucotomy, also known as lobotomy
(Elithorn, 1953; Beard, 1965). Beard (1965) reported
that he performed 20 leucotomy procedures for tinnitus
between 1948 and 1957. Prior to surgery, 13 of these
patients received electroconvulsive therapy (ECT) for
severe depression and other psychiatric disorders. It
is now known that ECT can initiate tinnitus for a small
percentage of patients who undergo the procedure
(Folmer et al, 2011). The leucotomy operations involved
drilling holes in the top frontal region of the patient’s
skull, then cutting downward through neural tissue,
affecting Brodmann’s areas 9 and 10 of the frontal cortex. Regarding outcomes, Beard wrote the following, “of
the 19 patients who survived the operation, 11 felt that
their head noises were just the same but bothered them
less, and 8 felt that they had improved” (1965, p. 30).
Beard did not explain what happened to the patient
who did not survive surgery, but a 5% mortality rate
seems unjustifiable for tinnitus treatment. The author
followed up with these patients 5 yr postsurgery and
wrote, “only 14 of the 20 patients survived for formal
assessment, and of these 14, 5 were very glad they
had the operation, 7 were definitely glad, and only 1
regretted it. One patient was unable to say” (Beard,
1965, p. 30). Again, Beard did not explain what happened to the five patients who did not survive 5 yr postsurgery. Beard reported that 12 of the 14 surviving
patients found their tinnitus less distressing at the 5
yr follow-up, although the pitch and loudness of tinnitus
had not changed for most of them. Beard concluded, “we
found that leucotomy gave good results in people incapacitated by psychiatric symptoms reactive to tinnitus,
though it is likely that some of these patients could now
be helped by drugs not available when these operations
were carried out.” Indeed, since the 1950s, development
of effective medications for depression, anxiety, and
other psychiatric disorders hastened a decline in frontal
leucotomy surgeries. A small number of psychosurgeries are still performed today to treat cases of severe
mental illness that do not respond to other interventions. These surgeries usually target structures in
the limbic system, such as the amygdala, hippocampus,
certain thalamic and hypothalamic nuclei, prefrontal
and orbitofrontal cortex, and the cingulate gyrus. Functional imaging studies of tinnitus patients have shown
abnormal neural activity in the limbic system, suggesting that some of these structures might be associated
with certain forms of the condition (Lockwood et al,
1998; De Ridder, Fransen, et al, 2006). Fortunately,
we found no additional reports of psychosurgery for tinnitus that were published after Beard’s 1965 article.
Below we describe some other invasive treatments that
have been implemented for tinnitus.
Acupuncture
Insertion of needles into the patient’s skin to treat
medical conditions has been practiced in China for more
than 3000 yr (Robson, 2004). In Western medicine,
reports of using acupuncture to treat tinnitus date to
the 1960s (Bischko, 1963), and a clinical trial of the procedure was published in 1982 by Hansen et al. In this
double-blind, placebo-controlled trial, the effect of traditional Chinese acupuncture was evaluated among 17
patients with chronic (mean disease duration 5.3 yr),
unilateral tinnitus. Each patient received two acupuncture treatments per week for 3 wk. In the last phase of
the study, patients who first received active acupuncture switched to the placebo group, and vice versa. After
15 wk, Hansen et al reported that there was no significant difference in tinnitus perception or severity
between traditional Chinese acupuncture and placebo
(Wilcoxon test, P . 0.05, one-tailed).
Although some recent studies claim that acupuncture
is an effective treatment for tinnitus (Wang et al, 2010;
Rogha et al, 2011; Jeon et al, 2012), a similar number of
reports found no significant treatment effect when
active and placebo acupuncture procedures were compared (Hansen et al, 1982; Axelsson et al, 1994; Vilholm
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et al, 1998; Park et al, 2000). This conundrum seems to
plague other applications of acupuncture, including its
use in pain management. Since the risk of adverse outcomes (e.g., infection, blood vessel or nerve puncture)
resulting from professionally applied acupuncture is
low, our recommendation to tinnitus patients is this:
try it if you are inclined to do so, but have reasonable
expectations regarding symptomatic improvement.
Neurectomy
Surgical severance of the vestibular branch of the
VIIIth cranial nerve is sometimes performed as a treatment for extreme dizziness that does not respond
to other therapies (Colletti et al, 1994; Decat et al,
1997). Unfortunately, tinnitus and hearing loss sometimes result from these procedures (Pappas and
Pappas, 1997; Van de Heyning et al, 1997). By contrast,
Wazen et al (1997) described a cochlear neurectomy procedure that was performed on two patients who experienced severe tinnitus prior to surgery. Both of these
patients also exhibited unilateral profound sensorineural hearing loss in the ear that perceived tinnitus.
Because Wazen et al severed the cochlear branch of
the VIIIth cranial nerve and preserved the vestibular
branch, patients reported a reduction of tinnitus but
did not experience dizziness or vertigo. It is important
to note that this surgery is recommended only for
patients who present with profound sensorineural
hearing loss and tinnitus in the same ear. After conducting a retrospective study of surgical procedures
and outcomes involving cranial nerves, Silverstein
et al (1986) concluded, “when useful hearing is present,
a CVN [cochleovestibular neurectomy] is not usually
recommended for relief of tinnitus, since the actual cure
rates are only 35%. When vertigo is not a complaint,
there is currently no surgical procedure known that can
be recommended for the treatment of tinnitus” (p. 438).
et al (2010) are instructive: the mean preoperative VAS
for tinnitus intensity was 7.8 6 1.5; the mean postoperative VAS was 6.7 6 2.5, which does not represent a
statistically significant change. The mean preoperative Tinnitus Questionnaire (TQ) score was 55.1 6
17; the mean postoperative TQ score was 55.7 6 14,
which also does not reflect a significant change.
Despite this apparent lack of effectiveness, De Ridder
(2010) and other neurosurgeons continue to promote
microvascular decompression as a viable treatment
option for tinnitus. In fact, auditory nerve compression
is an exceedingly rare cause of tinnitus; therefore,
microvascular decompression surgery for tinnitus
should be undertaken in a similarly miniscule number
of cases (Folmer, 2010). In 2007, De Ridder at al admitted, “The outcome of operations for tinnitus, moving
the blood vessel off the nerve (microvascular decompression operations, MVD) is less successful than
microvascular decompression operations for other
vascular conflict syndromes” (p. 401). Consequently,
clinicians should not recommend MVD procedures for
tinnitus unless there is irrefutable evidence that vascular compression of the VIIIth cranial nerve is a causative factor for the symptom.
Implantable Devices
Some implantable devices can improve or partially
restore hearing, thereby improving patients’ communication abilities and contributing to increased socialization and quality of life; reduced anxiety, depression, and
tinnitus severity. Other types of implantable devices
that stimulate cranial nerves or specific brain regions
also have the potential to reduce patients’ perception
or severity of tinnitus. This section reviews several different classes of implantable devices that have been or
could be used to treat chronic tinnitus.
Deep Canal Hearing Aids
Microvascular Decompression
Microvascular decompression is a surgical technique
that is used to move blood vessels away from nerves on
which they are exerting excessive pressure. One of the
most common applications of the procedure is to move
blood vessels away from the trigeminal nerve in order to
relieve symptoms of trigeminal neuralgia (Broggi et al,
2012; Zhang et al, 2012). During the last 30 yr, microvascular decompression of the VIIIth cranial nerve has
been performed occasionally to treat chronic tinnitus (Kudo
and Ito, 1984; Møller et al, 1993; De Ridder, Vanneste,
Adriaenssens, et al, 2010). The majority of published
reports state that the procedure reduces or abolishes
tinnitus for most patients and usually does not result
in adverse effects. However, results from 20 such surgeries described by De Ridder, Vanneste, Adriaenssens,
116
Any treatment or procedure that improves patients’
hearing sensitivity is likely to reduce their perception of
tinnitus by reducing the tinnitus signal-to-noise ratio.
That is why conventional hearing aids benefit many tinnitus patients who also have significant hearing loss:
hearing aids improve patients’ hearing and communication abilities and simultaneously make tinnitus less
noticeable (Folmer and Carroll, 2006). A recent development in hearing aid technology is the “deep canal” or
“implantable” aid distributed by Phonak (Warrenville,
IL). This hearing aid (brand name: Lyric) is placed deep
into the patient’s ear canal (within 4 mm of the tympanic membrane) by a clinician and can be left in place
up to 4 mo (see Fig. 4). Advantages of this device include
reduced handling and adjustment; improved sound
localization; and external invisibility. Because the Lyric
Experimental and Controversial Treatments/Folmer et al
before cochlear implantation. When the implant was
activated, seven patients (33%) experienced total suppression of tinnitus, and eight (39%) reported partial
relief. Cochlear implantation usually improves hearing
and tinnitus on the side of implantation in patients with
bilateral deafness, but tinnitus sometimes persists,
becomes noticeable, or worsens on the side contralateral to the implant. Bilateral cochlear implantation
should be considered for some patients who suffer these
effects.
Middle Ear Implant
Figure 4. Image of deep ear canal insertion for the Lyric hearing
aid.
hearing aid remains in the patient’s ear canal, it constantly increases background sound. For this reason,
the device might be of particular benefit to tinnitus
patients who need hearing aids. Although no formal
studies of the effectiveness of this hearing aid for tinnitus have yet been published, such studies are likely to
be conducted and published in the near future.
Stapes Prosthesis
Because the cochlea is extremely sensitive to physical
vibrations, the force applied during stapedectomy surgery sometimes transfers unnaturally large and harmful vibrations to the inner ear, resulting in permanent
hearing loss or tinnitus (Causse et al, 1983; Sancipriano
Hernández et al, 1999). Improved surgical techniques
such as lasers have reduced the likelihood of this negative outcome (Matkovic et al, 2003). In fact, successful
stapedectomy surgery can help to reduce the patient’s
perception of tinnitus. A study of 19 patients with preoperative severe tinnitus undergoing stapedectomy
resulted in 10 patients with complete remission of tinnitus and seven with significant improvement in tinnitus severity (Oliveira, 2007). Two patients had no
change, and none reported worsening of tinnitus after
surgery. Dost et al (2005) also reported significant
improvement in hearing status and tinnitus levels for
a majority of 49 otosclerosis patients who underwent
stapes prosthesis surgery.
Cochlear Implant
Numerous publications have reported that cochlear
implantation reduces patients’ perception of tinnitus
(Arts et al, 2012; Kim et al, 2013; Kompis et al,
2012). Yonehara et al (2006) reported on 29 cochlear
implant candidates, 21 of whom experienced tinnitus
The Vibrant Soundbridge (distributed by Med-El,
Durham, NC) was approved by the FDA for adults
with moderate to severe sensorineural hearing
loss who wanted an alternative to acoustic hearing
aids. Unlike conventional hearing aids, this device
bypasses the ear canal and eardrum by directly
vibrating the small bones in the middle ear. No portion of the device is placed in the ear canal. Biesinger
(2006) studied eight patients with hearing loss and
severe tinnitus who were fitted with a Vibrant Soundbridge. He reported that the device improved hearing
and reduced the perception of tinnitus in patients for
whom conventional sound stimulation treatments
were not helpful.
Bone-Anchored Hearing Aid (BAHA)
BAHAs were designed to help people who have
chronic inflammation or infection of the ear canal
and cannot wear conventional hearing aids, those with
conductive hearing loss or with malformed or absent
outer ear and ear canals (as occurs in Treacher-Collins
syndrome or microtia), and those with unilateral deafness. Holgers and Håkansson (2002) reported that the
majority of eight patients with significant hearing loss
and tinnitus who received BAHAs stated that sound
amplified by the aid helped to make their tinnitus less
noticeable.
Auditory Brainstem Implant
In the United States, auditory brainstem implants
are approved only for patients who suffer from neurofibromatosis type 2. Soussi and Otto (1994) reported
that six of seven patients with neurofibromatosis type
2 who received an auditory brainstem implant experienced noticeable tinnitus reduction; the seventh patient
reported no effect. Three other patients used the implant
only during laboratory testing; one reported complete
suppression of tinnitus; one described worse tinnitus;
and one reported no effect. More recently, Behr et al
(2007) reported that auditory brainstem implants
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Journal of the American Academy of Audiology/Volume 25, Number 1, 2014
improved hearing and reduced the perception of tinnitus for a majority of neurofibromatosis type 2 patients.
Deep Brain Stimulation (DBS)
DBS involves surgical implantation of long electrodes
into the brain to deliver electrical impulses to specific
regions. A stimulator unit is implanted beneath the
patient’s skin, usually below the clavicle. An external
device is used to control the stimulator, which delivers
electrical current through wires to the electrodes. This
procedure has provided therapeutic benefits for otherwise treatment-resistant disorders such as chronic
pain, Parkinson’s disease, tremor, and dystonia.
Shi et al (2009) tested four patients who were implanted with deep brain electrodes in the ventral intermedius nucleus of the thalamus for movement
disorders. All patients experienced chronic tinnitus, and
although the electrodes were not positioned in auditory
regions of the brain, two of these patients reported
reduced tinnitus loudness when deep brain stimulation
was activated. Cheung and Larson (2010) took a more
proactive approach to test the efficacy of deep brain
stimulation for tinnitus. They enlisted six patients with
tinnitus who were scheduled to undergo deep brain
stimulation surgery for Parkinson’s disease and essential tremor. Although the final target for electrode
implantation was the subthalamic nucleus or the ventral intermediate nucleus, the electrode was paused
during surgery in the caudate region to deliver electrical stimulation there. The electrode tip traversed the
caudate in five patients for whom tinnitus loudness
in both ears was suppressed to a level 2 or lower on a
0–10 rating scale. Tinnitus did not change for one
patient in whom the DBS electrode was outside of
the caudate region.
These reports are encouraging, but it is important
to consider the risks and benefits of this invasive procedure for a symptom such as tinnitus that is not lifethreatening. If DBS was performed for tinnitus specifically, how would a target for stimulation in the brain be
selected? Based on their experience, Cheung and Larson
(2010) might argue for the caudate region, but other
candidates could be the auditory cortex (Arnold
et al, 1996; Folmer, 2007; Friedland et al, 2007), the
medial geniculate region of the thalamus (De Ridder,
Vanneste, et al, 2012), the inferior colliculi (Melcher
et al, 2009), or the cochlear nucleus in the brainstem
(De Ridder, Vanneste, et al, 2012). These vital details
need to be investigated and understood before DBS
should be recommended as a tinnitus treatment.
electrodes, for example, have been implanted in
patients to reduce epileptic seizures or neuropathic
pain. De Ridder, Vanneste, van der Loo, et al (2010)
implanted an array of extradural electrodes over secondary auditory cortex in five patients with chronic tinnitus (see Fig. 5). The patients were asked to rate their
tinnitus distress and loudness on a VAS before and after
40 Hz tonic and 40 Hz burst (5 pulses at 500 Hz) stimulation. Patients reported significantly better suppression for
narrowband noise tinnitus with burst stimulation compared with tonic stimulation. No difference was found
between tonic and burst stimulation for pure-tone tinnitus.
Friedland et al (2007) implanted epidural electrodes over
auditory cortex in eight tinnitus patients. Two patients had
persistent reduction of pure-tone tinnitus, and six patients
had short periods of total tinnitus suppression with continuous stimulation. Significant improvements in the Beck
Depression Inventory and tinnitus questionnaires (Tinnitus
Reaction Questionnaire and Tinnitus Handicap Questionnaire) were also reported, although more objective
measures of tinnitus loudness remained fairly stable.
Since neurosurgery carries significant risks, is implantation of brain surface electrodes a viable treatment for
tinnitus? Many questions need to be addressed, for example, Which side of the patient’s brain should receive the
implant? De Ridder, DeMulder, et al (2006) claimed that
unilateral tinnitus is generated by contralateral auditory
cortex, so his team surgically implanted stimulating electrodes over this area in attempts to suppress tinnitus.
However, neural imaging studies by Arnold et al (1996),
Folmer (2007), and other researchers demonstrated that
the perception of tinnitus is sometimes associated with
activity in ipsilateral auditory cortex. Therefore, the optimal location for cortical stimulation remains uncertain.
Brain Surface Implants/Stimulation
Electrode arrays near the surface of the brain also
can be used to affect specific neural regions. Subdural
118
Figure 5. Diagram of a brain stimulation system.
Experimental and Controversial Treatments/Folmer et al
Vagus Nerve Stimulation
The FDA approved the use of vagus nerve stimulation as an adjunctive therapy for partial-onset epilepsy
in 1997 and for treatment-resistant depression in 2005.
Researchers associated with MicroTransponder Inc. in
Dallas, TX, recently published a study stating that electrical stimulation of the vagus nerve “completely eliminated the physiological and behavioural correlates of
tinnitus in noise-exposed rats” (Engineer et al, 2011,
p. 101). This publication and subsequent media reports
generated a great deal of interest in vagus nerve stimulation among clinicians, researchers, and tinnitus
patients, but we must remember that the original
experiments were conducted on rats. It seems reasonable to question whether the rats truly experienced tinnitus and what effect vagus nerve stimulation had on
their supposed tinnitus.
Engineer et al (2011) hypothesized that vagus nerve
stimulation eliminated the perception of tinnitus in rats,
but they do not know if stimulation directly affects the
perception of tinnitus at all. Because the vagus nerve
has such wide-ranging roles and paths of innervation
in the body (human and rat), stimulating it will produce
a variety of effects. Some of the efferent effects (bronchoconstriction, reduced heart rate, and increased gastrointestinal tract activity) are predictable, and might affect
the ways in which patients perceive or react to tinnitus.
The afferent effects of vagus nerve stimulation on central
nervous system activity are less well known but could
affect patients’ mood, disposition, motivation, and, indirectly, ways in which they perceive or react to tinnitus.
Although the FDA approved vagus nerve stimulation
for treatment-resistant depression, a randomized controlled trial of 235 patients by Rush et al (2005) concluded that no definitive evidence of efficacy for the
method was apparent. In light of this finding, we should
be wary of initial reports that proclaim the efficacy of
vagus nerve stimulation for tinnitus. Of note, these
reports were generated by scientists employed by a
company that is developing devices for commercial
distribution. The article by Engineer et al (2011,
online, under “Competing financial interests”) states,
“[Author] N.D.E. is a full-time employee of MicroTransponder Inc (Austin, Texas), which develops therapies
using neurostimulation. [Author] M.P.K. is a consultant and shareholder of MicroTransponder Inc.” On
the day Nature published the online letter by Engineer
et al, MicroTransponder Inc. released a media announcement titled, “Nature Study Shows That Nerve Stimulation Therapy Can Eliminate Tinnitus in an Animal
Model.” The company Web site also states that MicroTransponder is developing an implantable system
“for a pipeline of additional indications based on Vagus
Nerve Stimulation, including stroke rehabilitation,
tinnitus, and anxiety.” Companies disseminating media
releases or developing new products is standard practice.
However, it is essential that independent research is conducted prior to corporations (or their employees) making
claims as to benefits of their products.
One problem is inherent with all implanted electronic
devices: they do not last forever. Eventually, the device will
stop functioning because of aging components, failing electronics, or encroachment of the patient’s tissues/fluids,
sometimes necessitating device replacement or removal.
Researchers, clinicians, and medical device companies continue to develop and test various types of implants that
strive to improve hearing and reduce the perception of tinnitus, but patients should thoroughly explore noninvasive
strategies for tinnitus relief before undergoing surgery,
which includes a hospital stay and associated expenses,
especially for implantation of experimental devices. We
all look forward to technological advances, but we should
not allow patients’ zeal for a quick fix to put them at risk for
unproven and potentially harmful procedures.
FUTURE THERAPIES
A
s we stated earlier, any treatment or procedure
that improves patients’ hearing sensitivity is
likely to reduce their perception of tinnitus by reducing
the tinnitus signal-to-noise ratio. A current line of
investigation that aims to restore sensorineural hearing loss is “hair cell regeneration.” Usually, hair cells
in the mammalian cochlea do not regenerate if they
have been lost due to aging or disease processes or
are irreparably damaged by exposure to ototoxic substances or excessively loud sounds. In the 1980s, Cotanche
(1987) and Cruz et al (1987,) among others, demonstrated that elements of hair cells in the cochleae of some
birds can regenerate after severe damage by ototoxic
compounds and loud sound exposure. During the last
25 yr, laboratories around the world have studied this
phenomenon in birds (see Ryals et al, 2013, for a recent
review), and several investigators have attempted to
induce regeneration of hair cells or auditory neurons
in the mammalian cochlea. For example, in China,
Yang et al (2012) used a viral vector to deliver Atoh1
(a gene critical for hair cell differentiation) into the
cochleae of guinea pigs that were exposed to loud
sounds. Scanning electron microscopy revealed that
damaged/lost stereocilia bundles were repaired or regenerated after Atoh1 treatment. In England, Chen
et al (2012) implanted human embryonic stem cells into
the cochleae of gerbils that served as models for auditory neuropathy. The investigators reported that stem
cells were able to differentiate into hair-cell-like cells
and auditory neurons that displayed expected electrophysiological properties. Moreover, transplantation of
stem cells resulted in significant improvements in the
gerbils’ auditory-evoked response thresholds. If any
119
Journal of the American Academy of Audiology/Volume 25, Number 1, 2014
of the various methods now being studied eventually
succeeds in restoring functional hair cells (and hearing)
in humans, the treatment should also help to reduce the
perception of tinnitus for many individuals who experience this symptom in conjunction with hearing loss.
In addition to treatments designed to restore sensorineural hearing loss, several other procedures are being
investigated that might someday be used to reduce
patients’ perception of tinnitus.
Genetic Therapy: Viral Vector Inhibition
of Neural Activity
light-activated ion channels and pumps) can be genetically targeted into specific neural populations using
viral vectors. When exposed to light with the appropriate wavelength, action potentials can be triggered in
specific populations of neurons, and inhibition of action
potentials can be induced in other neuronal populations,
thus allowing for powerful control of neural activity.
Restoration of dopamine-related movement dysfunction
in Parkinson’s disease, amelioration of blindness, and suppression of neural activity associated with tinnitus are but
a few potential applications for this new procedure.
Targeted Drug Delivery
Because the generation and perception of tinnitus is
often associated with superfluous neural activity, procedures that can suppress such activity in narrowly targeted regions of the central auditory system have the
potential to be effective treatments for tinnitus. One
such procedure used a viral vector to deliver the gene
for the light chain (LC) fragment of tetanus toxin (that
induces synaptic inhibition by preventing the release of
synaptic vesicles) to discreet regions of the midbrain in
rats (Zhao et al, 2006). Expression of the LC gene
inhibited the increase in startle amplitude seen with
the control viral infection, and blocked context-dependent
potentiation of startle induced by fear conditioning in
treated rats. A different research group (Nielsen et al,
2012) used a viral vector to deliver an allatostatin receptor/allatostatin (AlstR/AL) system (which has previously
been shown to induce inactivation of neurons in vivo) to
a region of visual cortex in macaque monkeys. Expression
of the AlstR/AL system resulted in suppression of a visual
detection task by treated monkeys.
Jasmin et al (2003) described yet another mode of
genetic therapy that affects neural activity: locally
increasing GABA by using an enzyme inhibitor or gene
transfer mediated by a viral vector inhibited activity in
the rostral agranular insular cortex (RAIC) of rats.
Selectively manipulating GABA(B)-receptor-bearing
RAIC neurons produced hyperalgesia or analgesia
through projections to the amygdala, a brain region
involved in pain and fear.
Taken together, these genetic therapy methods have
the potential to help tinnitus patients by (1) reducing
neural activity responsible for tinnitus generation
and perception and (2) reducing patients’ negative reaction to tinnitus (including fear and anxiety). Of course,
many years of additional research are required before
these techniques can be applied in human populations.
Optogenetics
Kokaia and Sørensen (2011) described optogenetics
as a new method of controlling neural activity by delivering light impulses to specific brain regions. Derived
from microbial organisms, opsin genes (encoding
120
GABA agonists, such as benzodiazepine medications
or gabapentin, help some patients by reducing the perception or severity of tinnitus. Lidocaine has also provided relief for tinnitus patients (Marzo et al, 2004;
Kallio et al, 2008), although its intravenous delivery
and relatively short duration of action limit its practical
use. Another problem that plagues medications for tinnitus is their lack of specificity for particular neural targets. In fact, medications such as benzodiazepines,
gabapentin, and lidocaine have effects—including unwanted side effects—throughout the patient’s brain
and body. Jain (2012) describes a potential solution:
nanoparticle-based methods that could enhance and
improve drug delivery to the brain. When perfected,
these methods could enable delivery of effective medication to specific brain sites to reduce the perception and
severity of tinnitus. At the same time, negative side
effects and effective dosages of beneficial medications
could be reduced.
CONCLUSIONS
F
ortunately, most people who perceive chronic tinnitus do not require any treatment interventions for
the condition. However, effective and noninvasive management strategies are now available for patients who
require them (Andersson and Lyttkens, 1999; Henry
et al, 2008, 2009; Hesser et al, 2011; Cima et al, 2014;
Hoare et al, 2014) even though a true “cure” for tinnitus
has not yet emerged. Duckro et al (1984) stated, “As with
chronic pain, the treatment of chronic tinnitus is more
accurately described in terms of management rather than
cure” (p. 460). This is an important concept for patients
and clinicians to understand because most cases of
chronic tinnitus (which are associated with sensorineural
hearing loss) are likely to persist. Our goal should be to
help patients obtain relief from the condition so their quality of life improves and is not affected by the symptom.
Effective tinnitus management strategies described
in this issue of JAAA and elsewhere can help patients
to reduce their negative reaction to tinnitus; reduce the
percentage of time they are aware of or bothered by
Experimental and Controversial Treatments/Folmer et al
tinnitus; gain more control over their tinnitus; reduce
anxiety, depression, and insomnia; and reduce tinnitus
severity and its negative impact on their lives. Regarding new treatments for tinnitus that will continue to
appear in news articles and other media: let the patient
beware, because if it seems too good to be true, it probably is. Invasive treatments—especially surgical procedures—should be considered with extreme caution, and
a risk/benefit assessment should be conducted before
clinicians and patients decide to implement such procedures. When possible, studies of tinnitus treatments
should adhere to the requirements of randomized clinical trials (Dobie, 1999) and should include a welldesigned control condition to distinguish treatment
effects from placebo effects. The great majority of clinical trials that have been conducted for tinnitus treatments suffer from several experimental design flaws,
including lack of appropriate controls; lack of adequate
sample size; absence of valid outcomes measures; lack of
monitoring participant compliance during the study; and
inadequate inclusion/exclusion criteria for participants.
Recently, an international consortium of researchers
made the following recommendations to facilitate
improvement and standardization of tinnitus clinical
trials (Landgrebe et al, 2012, p. 119, table 2):
Trial planning
‐Clear formulation of the research question
‐Choice of adequate trial design
‐Definition of one or more main outcome measure(s)
(i.e., a validated tinnitus questionnaire)
‐THI should be included in every trial at least as
secondary outcome to improve interstudy comparability
‐Sample size estimation based on power calculations
(e.g., based on data from pilot studies)
‐Ethical approval
‐Informed consent
‐Establishment of a statistical analysis plan
‐Registration in a clinical trials registry
Study performance
‐The clinical trial should be performed according
to good clinical practice (GCP) and CONSORT
guidelines
Reporting of results
‐All clinical trials should be published
‐Results should be reported according to CONSORT
guidelines
Because of the heterogeneity exhibited by tinnitus
patients and their symptoms, tinnitus treatment stud-
ies should include as many participants as possible to
allow meaningful analyses of subgroups that do or do
not respond favorably to specific treatment methods.
Due to the variability seen in the tinnitus population,
it is important to perform statistical analyses to detect
such subgroups and to evaluate how they affect outcomes
or respond to a particular treatment. Also, greater standardization of tinnitus outcome measures would facilitate more meaningful comparisons of treatments for
the condition.
REFERENCES
Andersson G, Lyttkens L. (1999) A meta-analytic review of psychological treatments for tinnitus. Br J Audiol 33(4):201–210.
Aoki M, Wakaoka Y, Hayashi H, Kuze B, Mizuta K, Ito Y. (2012)
Effect of lyophilized powder made from enzymolyzed honeybee larvae on tinnitus-related symptoms, hearing levels, and hypothalamuspituitary-adrenal axis-related hormones. Ear Hear 33(3):
430–436.
Arda HN, Tuncel U, Akdogan O, Ozluoglu LN. (2003) The role of
zinc in the treatment of tinnitus. Otol Neurotol 24(1):86–89.
Arnold W, Bartenstein P, Oestreicher E, Römer W, Schwaiger M.
(1996) Focal metabolic activation in the predominant left auditory
cortex in patients suffering from tinnitus: a PET study with [18F]
deoxyglucose. ORL J Otorhinolaryngol Relat Spec 58(4):195–199.
Arts RA, George EL, Stokroos RJ, Vermeire K. (2012) Review:
cochlear implants as a treatment of tinnitus in single-sided deafness. Curr Opin Otolaryngol Head Neck Surg 20(5):398–403.
Attias J, Shemesh Z, Sohmer H, Gold S, Shoham C, Faraggi D.
(1993) Comparison between self-hypnosis, masking and attentiveness for alleviation of chronic tinnitus. Audiology 32(3):205–212.
Axelsson A, Andersson S, Gu LD. (1994) Acupuncture in the management of tinnitus: a placebo-controlled study. Audiology 33(6):
351–360.
Azevedo AA, Figueiredo RR. (2005) Tinnitus treatment with acamprosate: double-blind study. Braz J Otorhinolaryngol 71(5):618–623.
Bauer CA, Brozoski TJ. (2006) Effect of gabapentin on the sensation and impact of tinnitus. Laryngoscope 116(5):675–681.
Beard AW. (1965) Results of leucotomy operations for tinnitus.
J Psychosom Res 9(1):29–32.
Behr R, Müller J, Shehata-Dieler W, et al. (2007) The high rate
CIS auditory brainstem implant for restoration of hearing in
NF-2 patients. Skull Base 17(2):91–107.
Biesinger E. (2006) The Vibrant Soundbridge: amplification of the
high frequencies and its effect on tinnitus. Tinnitus Research Initiative Meeting, Regensburg, Germany, July 27–29.
Bischko J. (1963) The possibility of acupuncture in the ear, nose
and throat area. [In German.] Monatsschr Ohrenheilkd Laryngorhinol 97:464–466.
Broggi G, Broggi M, Ferroli P, Franzini A. (2012) Surgical technique for trigeminal microvascular decompression. Acta Neurochir
(Wien) 154(6):1089–1095.
Carey J. (1988) Tinnitus–puzzler ailment gets a new hearing. Los
Angeles Times July 4.
121
Journal of the American Academy of Audiology/Volume 25, Number 1, 2014
Causse JB, Causse JR, Wiet RJ, Yoo TJ. (1983) Complications of
stapedectomies. Am J Otol 4(4):275–280.
Chen R, Classen J, Gerloff C, et al. (1997) Depression of motor cortex excitability by low-frequency transcranial magnetic stimulation. Neurology 48(5):1398–1403.
Chen W, Jongkamonwiwat N, Abbas L, et al. (2012) Restoration of
auditory evoked responses by human ES-cell-derived otic progenitors. Nature 490(7419):278–282.
Cheung SW, Larson PS. (2010) Tinnitus modulation by deep brain
stimulation in locus of caudate neurons (area LC). Neuroscience
169(4):1768–1778.
Christensen RC. (2001) Paroxetine in the treatment of tinnitus.
Otolaryngol Head Neck Surg 125(4):436–438.
Cima RFF, Andersson G, Schmidt CJ, Henry JA. (2014) Cognitivebehavorial treatments for tinnitus: a review of the literature. J Am
Acad Audiol 25(1):29–61.
Coelho CB, Tyler R, Hansen M. (2007) Zinc as a possible treatment
for tinnitus. Prog Brain Res 166:279–285.
Coles R, Bradley P, Donaldson I, Dingle A. (1991) A trial of tinnitus
therapy with ear-canal magnets. Clin Otolaryngol Allied Sci 16(4):
371–372.
Colletti V, Fiorino FG, Carner M, Turazzi S. (1994) Vestibular
neurectomy and microvascular decompression of the cochlear
nerve in Meniere’s disease. Skull Base Surg 4(2):65–71.
Cotanche DA. (1987) Regeneration of hair cell stereociliary bundles in the chick cochlea following severe acoustic trauma. Hear
Res 30(2–3):181–195.
Crocetti A, Forti S, Del Bo L. (2011) Neurofeedback for subjective
tinnitus patients. Auris Nasus Larynx 38(6):735–738.
Cruz RM, Lambert PR, Rubel EW. (1987) Light microscopic
evidence of hair cell regeneration after gentamicin toxicity
in chick cochlea. Arch Otolaryngol Head Neck Surg 113(10):
1058–1062.
Cuda D, De Caria A. (2008) Effectiveness of combined counseling
and low-level laser stimulation in the treatment of disturbing
chronic tinnitus. Int Tinnitus J 14(2):175–180.
Decat M, Delvaux J, Deggouj N, Gersdorff M. (1997) The vestibular neurectomy by retrosigmoid approach: operative technique
and results. Acta Otorhinolaryngol Belg 51(2):123–126.
De Ridder D. (2010) Auditory nerve compression: a forgotten treatable cause for tinnitus. J Neurol Neurosurg Psychiatry 81(4):355.
De Ridder D, De Mulder G, Verstraeten E, et al. (2006) Primary and
secondary auditory cortex stimulation for intractable tinnitus.
ORL J Otorhinolaryngol Relat Spec 68(1):48–54, discussion 54–55.
De Ridder D, Fransen H, Francois O, Sunaert S, Kovacs S, Van De
Heyning P. (2006) Amygdalohippocampal involvement in tinnitus
and auditory memory. Acta Otolaryngol Suppl 126(556):50–53.
De Ridder D, Heijneman K, Haarman B, van der Loo E. (2007) Tinnitus in vascular conflict of the eighth cranial nerve: a surgical
pathophysiological approach to ABR changes. Prog Brain Res
166:401–411.
De Ridder D, Song JJ, Vanneste S. (2012) Frontal cortex TMS for
tinnitus. Brain Stimul 6(3):355–362.
122
De Ridder D, Vanneste S, Adriaenssens I, et al. (2010) Microvascular decompression for tinnitus: significant improvement for tinnitus intensity without improvement for distress. A 4-year limit.
Neurosurgery 66(4):656–660.
De Ridder D, Vanneste S, Menovsky T, Langguth B. (2012) Surgical brain modulation for tinnitus: the past, present and future.
J Neurosurg Sci 56(4):323–340.
De Ridder D, Vanneste S, van der Loo E, Plazier M, Menovsky T,
van de Heyning P. (2010) Burst stimulation of the auditory cortex:
a new form of neurostimulation for noise-like tinnitus suppression. J Neurosurg 112(6):1289–1294.
Dietrich S. (2004) Earliest historic reference of ‘tinnitus’ is controversial. J Laryngol Otol 118(7):487–488.
Dobie RA. (1999) A review of randomized clinical trials in tinnitus.
Laryngoscope 109(8):1202–1211.
Dost P, Arweiler-Harbeck D, Jahnke K. (2005) A prospective evaluation of the Essen titanium stapes prosthesis. Clin Otolaryngol
30(1):21–24.
Drew S, Davies E. (2001) Effectiveness of Ginkgo biloba in treating tinnitus: double blind, placebo controlled trial. BMJ 322
(7278):73.
Duckro PN, Pollard CA, Bray HD, Scheiter L. (1984) Comprehensive behavioral management of complex tinnitus: a case illustration. Biofeedback Self Regul 9(4):459–469.
Elithorn A. (1953) Prefrontal leucotomy in the treatment of tinnitus. Proc R Soc Med 46(10):832–833.
Engineer ND, Riley JR, Seale JD, et al. (2011) Reversing pathological neural activity using targeted plasticity. Nature 470
(7332):101–104.
Folmer RL. (2002) Long-term reductions in tinnitus severity. BMC
Ear Nose Throat Disord 2:3. www.biomedcentral.com/1472-6815/2/3.
Folmer RL. (2007) Lateralization of neural activity associated with
tinnitus. Neuroradiology 49(8):689–691, author reply 693–696.
Folmer RL. (2010) Forget auditory nerve compression as a treatable cause for tinnitus. J Neurol Neurosurg Psychiatry. http://
jnnp.bmj.com/content/81/4/355.full/reply#jnnp_el_6706.
Folmer RL, Carroll JR. (2006) Long-term effectiveness of earlevel devices for tinnitus. Otolaryngol Head Neck Surg 134(1):
132–137.
Folmer RL, Griest SE. (2000) Tinnitus and insomnia. Am J Otolaryngol 21(5):287–293.
Folmer RL, Griest SE, Martin WH. (2001) Chronic tinnitus as
phantom auditory pain. Otolaryngol Head Neck Surg 124(4):
394–400.
Folmer RL, Griest SE, Martin WH. (2008) Obsessive-compulsiveness in a population of tinnitus patients. Int Tinnitus J 14(2):
127–130.
Folmer RL, Griest SE, Meikle MB, Martin WH. (1999) Tinnitus
severity, loudness, and depression. Otolaryngol Head Neck Surg
121(1):48–51.
Folmer RL, Shi Y, Theodoroff S. (2011) Chronic tinnitus following
electroconvulsive therapy. Case Rep Psychiatry 2011:607061.
Fregni F, Marcondes R, Boggio PS, et al. (2006) Transient tinnitus
suppression induced by repetitive transcranial magnetic stimulation
Experimental and Controversial Treatments/Folmer et al
and transcranial direct current stimulation. Eur J Neurol 13
(9):996–1001.
Friedland DR, Gaggl W, Runge-Samuelson C, Ulmer JL, Kopell BH.
(2007) Feasibility of auditory cortical stimulation for the treatment of tinnitus. Otol Neurotol 28(8):1005–1012.
Grossan M. (1976) Treatment of subjective tinnitus with biofeedback. Ear Nose Throat J 55(10):314–318.
Haller S, Birbaumer N, Veit R. (2010) Real-time fMRI feedback
training may improve chronic tinnitus. Eur Radiol 20(3):696–703.
Hansen PE, Hansen JH, Bentzen O. (1982) Acupuncture treatment of chronic unilateral tinnitus—a double-blind cross-over
trial. Clin Otolaryngol Allied Sci 7(5):325–329.
Heller MF, Bergman M. (1953) Tinnitus aurium in normally hearing persons. Ann Otol Rhinol Laryngol 62(1):73–83.
Henry JA, Zaugg TL, Myers PJ, Kendall CJ, Turbin MB. (2009) Principles and application of educational counseling used in progressive
audiologic tinnitus management. Noise Health 11(42):33–48.
Henry JA, Zaugg TL, Myers PJ, Schechter MA. (2008) Using therapeutic sound with progressive audiologic tinnitus management.
Trends Amplif 12(3):188–209.
Hesser H, Weise C, Westin VZ, Andersson G. (2011) A systematic
review and meta-analysis of randomized controlled trials of cognitive-behavioral therapy for tinnitus distress. Clin Psychol Rev 31
(4):545–553.
Hoare DJ, Searchfield GD, El Refaie A, Henry JA. (2014) Sound
therapy for tinnitus management: practicable options. J Am Acad
Audiol 25(1):62–75.
Hoeft F, Gabrieli JD, Whitfield-Gabrieli S, et al. (2012) Functional
brain basis of hypnotizability. Arch Gen Psychiatry 69(10):1064–1072.
Hoffman RE, Cavus I. (2002) Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders. Am J Psychiatry 159(7):1093–1102.
Holgers KM, Håkansson BE. (2002) Sound stimulation via bone conduction for tinnitus relief: a pilot study. Int J Audiol 41(5):293–300.
House JW. (1978) Treatment of severe tinnitus with biofeedback
training. Laryngoscope 88(3):406–412.
Ioannidis JP. (2011) An epidemic of false claims. Competition and conflicts of interest distort too many medical findings. Sci Am 304(6):16.
Itard JMG. (1821) Traite´ des maladies de l’oreille et de l’audition.
Paris: Mequignon-Marvis.
Jain KK. (2012) Nanobiotechnology-based strategies for crossing
the blood-brain barrier. Nanomedicine (Lond) 7(8):1225–1233.
Jalali MM, Kousha A, Naghavi SE, Soleimani R, Banan R. (2009)
The effects of alprazolam on tinnitus: a cross-over randomized
clinical trial. Med Sci Monit 15(11):PI55–60.
Jasmin L, Rabkin SD, Granato A, Boudah A, Ohara PT. (2003)
Analgesia and hyperalgesia from GABA-mediated modulation of
the cerebral cortex. Nature 424(6946):316–320.
Jeon SW, Kim KS, Nam HJ. (2012) Long-term effect of acupuncture for treatment of tinnitus: a randomized, patient- and assessor-blind, sham-acupuncture-controlled, pilot trial. J Altern
Complement Med 18(7):693–699.
Johnson RM, Brummett R, Schleuning A. (1993) Use of alprazolam for relief of tinnitus. A double-blind study. Arch Otolaryngol
Head Neck Surg 119(8):842–845.
Kallio H, Niskanen ML, Havia M, Neuvonen PJ, Rosenberg PH,
Kentala E. (2008) I.V. ropivacaine compared with lidocaine for
the treatment of tinnitus. Br J Anaesth 101(2):261–265.
Kim DK, Bae SC, Park KH, et al. (2013) Tinnitus in patients with
profound hearing loss and the effect of cochlear implantation. Eur
Arch Otorhinolaryngol 270(6):1803–1808.
Kokaia M, Sørensen AT. (2011) The treatment of neurological diseases under a new light: the importance of optogenetics. Drugs
Today (Barc) 47(1):53–62.
Kompis M, Pelizzone M, Dillier N, Allum J, DeMin N, Senn P.
(2012) Tinnitus before and 6 months after cochlear implantation.
Audiol Neurootol 17(3):161–168.
Kraft JR. (1998) Hyperinsulinemia: a merging history with idiopathic tinnitus, vertigo, and hearing loss. Int Tinnitus J 4(2):
127–130.
Kudo T, Ito K. (1984) Microvascular decompression of the eighth
cranial nerve for disabling tinnitus without vertigo: a case report.
Neurosurgery 14(3):338–340.
Landgrebe M, Azevedo A, Baguley D, et al. (2012) Methodological
aspects of clinical trials in tinnitus: a proposal for an international standard. J Psychosom Res 73(2):112–121.
Lee JS, Spiegel D, Kim SB, et al. (2007) Fractal analysis of EEG
in hypnosis and its relationship with hypnotizability. Int J Clin
Exp Hypn 55(1):14–31.
Lenhardt ML, Skellett R, Wang P, Clarke AM. (1991) Human
ultrasonic speech perception. Science 253(5015):82–85.
Linde K, ter Riet G, Hondras M, Vickers A, Saller R, Melchart D.
(2001) Systematic reviews of complementary therapies –an annotated bibliography. Part 2: herbal medicine. BMC Complement
Altern Med 1:5.
Lockwood AH, Salvi RJ, Coad ML, Towsley ML, Wack DS,
Murphy BW. (1998) The functional neuroanatomy of tinnitus: evidence for limbic system links and neural plasticity. Neurology 50
(1):114–120.
Maeda F, Keenan JP, Tormos JM, Topka H, Pascual-Leone A.
(2000) Interindividual variability of the modulatory effects of
repetitive transcranial magnetic stimulation on cortical excitability. Exp Brain Res 133(4):425–430.
Marzo S, Stankiewicz JA, Consiglio AP. (2004) Lidocaine for the
relief of incapacitating tinnitus. Ear Nose Throat J 83(4):
236–238.
Matković S, Kitanoski B, Malicević Z. (2003) Advantages of CO2
laser use in surgical management of otosclerosis. Vojnosanit Pregl
60(3):273–278.
May A, Hajak G, Gänssbauer S, et al. (2007) Structural brain
alterations following 5 days of intervention: dynamic aspects of
neuroplasticity. Cereb Cortex 17(1):205–210.
Megwalu UC, Finnell JE, Piccirillo JF. (2006) The effects of melatonin on tinnitus and sleep. Otolaryngol Head Neck Surg 134(2):
210–213.
Melcher JR, Levine RA, Bergevin C, Norris B. (2009) The auditory
midbrain of people with tinnitus: abnormal sound-evoked activity
revisited. Hear Res 257(1–2):63–74.
123
Journal of the American Academy of Audiology/Volume 25, Number 1, 2014
Møller MB, Møller AR, Jannetta PJ, Jho HD. (1993) Vascular
decompression surgery for severe tinnitus: selection criteria and
results. Laryngoscope 103(4, Pt. 1):421–427.
Nakashima T, Ueda H, Misawa H, et al. (2002) Transmeatal lowpower laser irradiation for tinnitus. Otol Neurotol 23(3):
296–300.
Nielsen KJ, Callaway EM, Krauzlis RJ. (2012) Viral vector-based
reversible neuronal inactivation and behavioral manipulation in
the macaque monkey. Front Syst Neurosci 6:48.
Ochi K, Kinoshita H, Kenmochi M, Nishino H, Ohashi T. (2003)
Zinc deficiency and tinnitus. Auris Nasus Larynx 30(Suppl):
S25–S28.
Okhovat A, Berjis N, Okhovat H, Malekpour A, Abtahi H. (2011)
Low-level laser for treatment of tinnitus: a self-controlled clinical
trial. J Res Med Sci 16(1):33–38.
Oliveira CA. (2007) How does stapes surgery influence severe disabling tinnitus in otosclerosis patients? Adv Otorhinolaryngol 65:
343–347.
Paaske PB, Pedersen CB, Kjems G, Sam IL. (1991) Zinc in the
management of tinnitus. Placebo-controlled trial. Ann Otol Rhinol
Laryngol 100(8):647–649.
Pappas DG, Jr, Pappas DG, Sr. (1997) Vestibular nerve section:
long-term follow-up. Laryngoscope 107(9):1203–1209.
Park J, White AR, Ernst E. (2000) Efficacy of acupuncture as a
treatment for tinnitus: a systematic review. Arch Otolaryngol
Head Neck Surg 126(4):489–492.
Pearson M, Barnes LJ. (1948) Objective tinnitus aurium; report of
a case with recovery after hypnosis. Arch Neurol Psychiatry 59(2):
265–267.
Philpott WH, Kalita DK. (2000) Magnet Therapy: An Alternative
Medicine Definitive Guide.Alternativemedicine.com Books.
Piccirillo JF, Finnell J, Vlahiotis A, Chole RA, Spitznagel E, Jr.
(2007) Relief of idiopathic subjective tinnitus: is gabapentin effective? Arch Otolaryngol Head Neck Surg 133(4):390–397.
randomized, controlled acute phase trial. Biol Psychiatry
58(5):347–354.
Ryals BM, Dent ML, Dooling RJ. (2013) Return of function after
hair cell regeneration. Hear Res 297:113–120.
Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS.
(1996) Evidence based medicine: what it is and what it isn’t. BMJ
312(7023):71–72.
Saltzman M, Ersner MS. (1947) A hearing aid for the relief of tinnitus aurium. Laryngoscope 57(5):358–366.
Salvi R, Lobarinas E, Sun W. (2009) Pharmacological treatments
for tinnitus: new and old. Drugs Future 34(5):381–400.
Sancipriano Hernández JA, Calvo Boizas E, Diego Pérez C,
Rodrı́guez Gutiérrez A, Rincón Esteban L, Gómez Toranzo F.
(1999) Postoperative complication in stapedectomy: excessive
introduction of the prosthesis in the oval window. [In Spanish.]
Acta Otorrinolaringol Esp 50(3):219–222.
Savage J, Cook S, Waddell A. (2009) Tinnitus. Clin Evid (Online)
Nov 12. pii: 0506.
Shemen L. (1998) Fluoxetine for treatment of tinnitus. Otolaryngol Head Neck Surg 118(3, Pt. 1):421.
Shi Y, Burchiel KJ, Anderson VC, Martin WH. (2009) Deep brain
stimulation effects in patients with tinnitus. Otolaryngol Head
Neck Surg 141(2):285–287.
Shi Y, Robb MJA, Michaelides EM. (2014) Medical management of
tinnitus: role of the physician. J Am Acad Audiol 25(1):23–28.
Siebner HR, Filipovic SR, Rowe JB, et al. (2003) Patients with
focal arm dystonia have increased sensitivity to slow-frequency
repetitive TMS of the dorsal premotor cortex. Brain 126(Pt. 12):
2710–2725.
Siedentopf CM, Ischebeck A, Haala IA, et al. (2007) Neural correlates of transmeatal cochlear laser (TCL) stimulation in healthy
human subjects. Neurosci Lett 411(3):189–193.
Porter WG, McBride P. (1916) Diseases of the Throat, Nose and
Ears for Practitioners and Students. Bristol, UK: Wright.
Silverstein H, Haberkamp T, Smouha E. (1986) The state of tinnitus after inner ear surgery. Otolaryngol Head Neck Surg 95(4):
438–441.
Reavis KM, Rothholtz VS, Tang Q, Carroll JA, Djalilian H,
Zeng FG. (2012) Temporary suppression of tinnitus by modulated
sounds. J Assoc Res Otolaryngol 13(4):561–571.
Song JJ, Vanneste S, Van de Heyning P, De Ridder D. (2012) Transcranial direct current stimulation in tinnitus patients: a systemic
review and meta-analysis. ScientificWorldJournal 2012:427941.
Robinson SK, Viirre ES, Bailey KA, Gerke MA, Harris JP,
Stein MB. (2005) Randomized placebo-controlled trial of a selective serotonin reuptake inhibitor in the treatment of nondepressed
tinnitus subjects. Psychosom Med 67(6):981–988.
Robson T. (2004) An Introduction to Complementary Medicine.
Sydney, Australia: Allen and Unwin.
Rogha M, Rezvani M, Khodami AR. (2011) The effects of acupuncture on the inner ear originated tinnitus. J Res Med Sci 16(9):
1217–1223.
Rose P. (2001) Magnet Therapy Illustrated: Natural Healing and
Pain Relief Using Magnets. Berkeley, CA: Ulysses Press.
Rosenberg SI, Silverstein H, Rowan PT, Olds MJ. (1998) Effect of
melatonin on tinnitus. Laryngoscope 108(3):305–310.
Rush AJ, Marangell LB, Sackeim HA, et al. (2005) Vagus
nerve stimulation for treatment-resistant depression: a
124
Soussi T, Otto SR. (1994) Effects of electrical brainstem stimulation on tinnitus. Acta Otolaryngol 114(2):135–140.
Spaulding JA. (1903) Tinnitus, with a plea for its more accurate
musical notation. Ann Otol 32:272.
Stephens SDG. (1987) Historical aspects of tinnitus. In:
Hazell JWP, ed. Tinnitus. London: Churchill Livingstone, 1–19.
Takeda H. (1987) Magnetic therapy for tinnitus. Otologia Fukuoka
33:700–706.
Teggi R, Bellini C, Piccioni LO, Palonta F, Bussi M. (2009) Transmeatal low-level laser therapy for chronic tinnitus with cochlear
dysfunction. Audiol Neurootol 14(2):115–120.
Theodoroff SM, Folmer RL. (2013) Repetitive transcranial magnetic stimulation as a treatment for chronic tinnitus: a critical
review. Otol Neurotol 34(2):199–208.
Experimental and Controversial Treatments/Folmer et al
Urbantschitsch V. (1883) Ueber die Wechselwirkungen der innerhalb eines Sinnesgebietes gesetzten Erregungen. Archiv für die
gesamte Physiologie des Menschen und der Tiere 31(1):280–309.
Van de Heyning PH, Verlooy J, Schatteman I, Wuyts FL. (1997)
Selective vestibular neurectomy in Ménière’s disease: a review.
Acta Otolaryngol Suppl 526:58–66.
Vanneste S, Walsh V, Van De Heyning P, De Ridder D. (2013)
Comparing immediate transient tinnitus suppression using tACS
and tDCS: a placebo-controlled study. Exp Brain Res 226(1):25–31.
Vilholm OJ, Møller K, Jørgensen K. (1998) Effect of traditional
Chinese acupuncture on severe tinnitus: a double-blind, placebo-controlled, clinical investigation with open therapeutic control. Br J Audiol 32(3):197–204.
Wang K, Bugge J, Bugge S. (2010) A randomised, placebocontrolled trial of manual and electrical acupuncture for
the treatment of tinnitus. Complement Ther Med 18(6):249–255.
Wazen JJ, Foyt D, Sisti M. (1997) Selective cochlear neurectomy for
debilitating tinnitus. Ann Otol Rhinol Laryngol 106(7, Pt. 1):568–570.
Wilson H. (1893) Vibratory massage of the middle ear by means of
the telephone. N Y Med J 57:221–222.
Witsell DL, Hannley MT, Stinnet S, Tucci DL. (2007) Treatment of
tinnitus with gabapentin: a pilot study. Otol Neurotol 28(1):11–15.
Yang SM, Chen W, Guo WW, et al. (2012) Regeneration of stereocilia of hair cells by forced Atoh1 expression in the adult mammalian cochlea. PLoS ONE 7(9):e46355.
Yazici ZM, Sayin I, Gökkusx G, Alatas E, Kaya H, Kayhan FT.
(2012) Effectiveness of Ericksonian hypnosis in tinnitus therapy:
preliminary results. B-ENT 8(1):7–12.
Yonehara E, Mezzalira R, Porto PR, et al. (2006) Can cochlear
implants decrease tinnitus? Int Tinnitus J 12(2):172–174.
Zapp JJ. (2001) Gabapentin for the treatment of tinnitus: a case
report. Ear Nose Throat J 80(2):114–116.
Zhang H, Lei D, You C, Mao BY, Wu B, Fang Y. (2012) The longterm outcome predictors of pure microvascular decompression
for primary trigeminal neuralgia. World Neurosurg 79(5–6):
756–762.
Zhao Z, Krishnaney A, Teng Q, et al. (2006) Anatomically discrete functional effects of adenoviral clostridial light chain
gene-based synaptic inhibition in the midbrain. Gene Ther 13
(12):942–952.
125