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ISSN 1463-1741
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Noise & Health • Volume 15 • Issue 63 • March-April 2013 • Pages 81-152
A Bi-monthly Inter-disciplinary International Journal
www.noiseandhealth.org
March-April 2013 | Volume 15 | Issue 63
Recent technological advances in sound‑based approaches
to tinnitus treatment: A review of efficacy considered
against putative physiological mechanisms
Derek J. Hoare1,2, Peyman Adjamian3, Magdalena Sereda1,2, Deborah A. Hall1,2
NIHR Nottingham Hearing Biomedical Research Unit, Ropewalk House, 113 The Ropewalk, Nottingham, NG1 5DU, UK, 2School of
Clinical Sciences, University of Nottingham, 3MRC Institute of Hearing Research, University Park, Nottingham, NG7 2RD, UK
1
Abstract
The past decade has seen an escalating enthusiasm to comprehend chronic tinnitus from the perspective of both scientific
understanding and clinical management. At the same time, there is a significant interest and commercial investment
in providing targeted and individualized approaches to care, which incorporate novel sound‑based technologies, with
standard audiological and psychological strategies. Commercially produced sound‑based devices for the tinnitus
market include Co‑ordinated Reset Neuromodulation®, Neuromonics©, Serenade®, and Widex® Zen. Additionally,
experimental interventions such as those based on frequency‑discrimination training are of current interest. Many of
these interventions overtly claim to target the underlying neurological causes of tinnitus. Here, we briefly summarize
current perspectives on the pathophysiology of tinnitus and evaluate claims made by the device supporters from a critical
point of view. We provide an opinion on how future research in the field of individualized sound‑based interventions
might best provide a reliable evidence‑base in this growing area of translational medicine.
Keywords: Electroencephalography, frequency discrimination, magnetoencephalography, plasticity, reorganization, sound therapy
Introduction
Self‑reported tinnitus affects around 4.4‑15.1% of the adult
population.[1] Tinnitus is a symptom of diverse pathologies,
including otologic, neurologic, infectious, and drug‑related
effects and evidence suggests that various levels of the
nervous system are involved in its manifestation.[2,3] Although
often co‑morbid with peripheral hearing loss, chronic tinnitus
persists after auditory nerve transection demonstrating
involvement of central mechanisms.[4] The current consensus
is that damage to the afferent input to the auditory pathway
initiates events that results in plastic changes at the central
level giving rise to the percept of tinnitus.
As well as being co‑morbid with hearing loss, for a subset
of people, tinnitus impairs quality of life and is associated
with symptoms of anxiety, depression, insomnia, and
stress.[5] Tinnitus care, therefore, can demand a multi‑faceted
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approach to patient assessment and management that can
be highly individual.[6] Traditional methods for the clinical
management of tinnitus involve three core elements: (i)
education and counseling, (ii) stress reduction and relaxation,
and (iii) use of therapeutic sound. Such approaches often
combine sound enrichment and counseling elements such
as in Tinnitus Retraining Therapy[7] or other less formalized
“habituation” therapies. That therapeutic sound can affect
changes in tinnitus percept has been appreciated for centuries.
In recent decades, the use of sound or sound enrichment has
become a central part of many tinnitus management programs
delivered by clinicians, whether the intention is to mask
tinnitus, suppress tinnitus, or interrupt the tinnitus generating
neural activity. In the UK, the most popular audiological
management approaches include hearing‑aid fitting and/or
the provision of white noise generators.[8] Specific discussion
of these particular devices is beyond the scope of this paper.
Here, we introduce the primary physiological mechanisms
hypothesized to underlie tinnitus. We also review a number
of innovative individualized sound‑based interventions,
considering their proposed physiological mechanisms of
action, and conclude on future directions in the field.
Pathophysiology of tinnitus
Hearing loss causes dramatic functional and structural
changes in the peripheral and central auditory system. The
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Hoare, et al.: Sound‑based tinnitus treatment
main cause of high‑frequency sensorineural hearing loss is
ageing, such that, the prevalence of tinnitus increases with
age.[1] High‑frequency hearing loss has been shown to induce
an increase in stimulus‑driven activity, a reorganization
of the tonotopic map, and an increase of the spontaneous
activity at virtually all levels in the central auditory
system, and synchrony in auditory cortex (An extensive
review of the neurophysiological evidence, predominantly
from the animal model, is provided by Noreña.[9]) As
these changes are not accompanied by enhanced outputs
from the auditory nerve, they probably result from neural
mechanisms intrinsic to the central auditory system. It has
been suggested that this overall hyperactivity could result
from an increase in central gain (or sensitivity). The general
purpose of such gain might be to adapt neural sensitivity
to the reduced sensory inputs, preserving a stable mean
firing and neural coding efficiency.[9] However, maintaining
neural homeostasis is achieved at the cost of amplifying
“neural noise” due to the overall increase of gain, ultimately
resulting in the generation of tinnitus.
The utility of auditory cortical evoked responses as an objective
indicator of tinnitus is still debated. Conflicting results may
reflect differences in choice of control group or experimental
parameters. For example, inter‑stimulus interval is known
to affect the amplitude of the evoked response with shorter
intervals leading to smaller amplitudes and hence a smaller
dynamic range within which to reveal differences across
groups.[19] Another issue is that of comorbid symptoms such
as hyperacusis. This condition refers to an abnormal sensitivity
to everyday sounds[20] and may be a manifestation of increased
neural excitability in the auditory system.[21] Hyperacusis is
often associated with tinnitus. Recent evidence using
functional magnetic resonance imaging (fMRI) suggests that
diminished sound‑level tolerance (as in hyperacusis) might
be sufficient on its own to enhance the stimulus‑evoked
response, irrespective of tinnitus.[22] This was especially
true in inferior colliculus and medical geniculate body. This
finding illustrates the importance of screening all tinnitus
patients for sound‑level tolerance and interpreting many of
the preceding results with due care.
Increased stimulus‑induced activity
Reorganisation of the tonotopic map
Hearing loss can lead to dramatic changes in
stimulus‑induced activity. Research in this field has
been particularly informed by animal recordings made
in dorsal cochlear nucleus. A number of human studies
have examined hyperexcitability in tinnitus and have
reported an abnormally elevated neural response to external
sounds. Given that electroencephalography (EEG) and
magnetoencephalography (MEG) reflect neural events on a
macroscopic scale, hyperexcitability could be a measure of
recruitment of a population of neurons provided that sufficient
synchrony exists within that ensemble. A comprehensive
review of the neuroimaging studies in tinnitus is given in
Adjamian et al.,[10] and here we briefly discuss some of the
relevant studies conducted in humans.
Long‑term sensorineural hearing loss can lead to dramatic
changes in the frequency‑based organization within central
auditory structures. When peripheral hearing loss deprives
central auditory neurons of their normal input they begin to
show responsiveness to the characteristic frequency of less
affected “neighbors’ rather than their original place in the
tonotopic map (see review by Eggermont and Roberts[23]).
The normal threshold at the new characteristic frequency of
neurons suggests that these changes have been induced by
plasticity mechanisms, perhaps through a process of rewiring
in the cortex, or the unmasking of latent cochlear inputs
to regions newly deprived of direct inputs. Neurons in the
affected region also show increased spontaneous activity
and synchrony.[24] Changes in response properties of neurons
and tonotopic map reorganization are therefore not isolated
events. Evidence for neuroplasticity after hearing loss and/
or tinnitus in the frequency organization of primary auditory
cortex has been reported using both animal electrophysiology
and human neuroimaging (see reviews by Eggermont and
Roberts;[23] Adjamian et al.[10]).
Increments of evoked signal amplitude have been reported
for several components of the acoustically evoked signal; the
middle latency response,[11] the steady‑state response[12] and
the N1/N1m.[13‑15] Using MEG, Diesch and colleagues recently
demonstrated that responses to the super‑position of three
amplitude‑modulated tones were reduced in healthy controls
(indicative of reciprocal inhibition), but increased in patients
with tinnitus (indicative of abnormal reciprocal facilitation).
This finding is compatible with the interpretation that tinnitus
is associated with a reduced lateral or surround inhibition
compared to control subjects. Similarly, a number of early
studies reported abnormally enhanced transient N1 (N1m)
responses to a 1‑kHz tone in a group of tinnitus patients,[13‑15]
although these studies have not always been replicated.[16‑18]
One might expect such hyperexcitability to be greatest at
frequencies corresponding to the tinnitus pitch and/or to the
region of hearing loss. However, this was not explicitly tested
or supported by previous experimental findings.
Noise & Health, March-April 2013, Volume 15
Neuroplastic reorganization has also been reported in
the normal hearing system driven by auditory perceptual
learning for pure tones.[25] In this study using owl monkeys,
the changes reported were again predominantly in terms
of an expanded representation of the trained frequency in
primary auditory cortex (A1) of trained animals, compared
to the corresponding area in animals that were untrained or
were trained on tones of a different frequency. Tonotopic
map reorganization in juvenile cat auditory cortex has
also been observed as a result of long‑term exposure to a
spectrally‑enhanced acoustic environment, without inducing
hearing loss.[26]
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Hoare, et al.: Sound‑based tinnitus treatment
In our view, most convincing pieces of evidence in humans
for an over‑representation of frequencies corresponding
to the edge of the hearing loss are from behavioral, not
neuroimaging, studies. Thai‑Van et al.,[27] demonstrated
enhanced frequency discrimination at the edge frequency in
individuals with steeply sloping hearing loss, suggesting that
an expansion of the cortical area with specificity around this
frequency would give the increase in computational power
required for better performance at frequency discrimination.
Moore and Vinay[28] also reported enhanced frequency
discrimination at low frequencies, in individuals with
cochlear dead regions at high frequencies.
Increased spontaneous activity
In the absence of external sound input, neural firing is randomly
generated, and hearing loss may alter the synchronous neural
discharge patterns in the central auditory system resulting in
tinnitus. Animals with induced hearing loss show an increase
in spontaneous synchronous firing of primary auditory cortical
neurons.[24,29,30] The greatest increase in synchrony occurs in
the deafferented region, which is most likely to reflect changes
in lateral connectivity. Chronic tinnitus has been associated
with increased oscillatory brain rhythm activity in the delta
band (1.5‑4 Hz) and the gamma band (e.g., 25‑80 Hz) and
decreased activity in the alpha band (8‑13 Hz).[31‑34]
Abnormal increase in slow‑wave (delta/theta) oscillatory
activity has been reported in a number of MEG/EEG studies
providing the strongest evidence for the involvement of
central auditory structures in tinnitus.[32,35,36] An example of
this effect is illustrated in Figure 1 where cortical power in the
delta band is shown as a function of time from two participants
one with and one without tinnitus. Using MEG, spontaneous
brain activity was recorded while participants listened to
their tinnitus. Power in the delta band was estimated at each
point in the brain volume using a beam former technique and
superimposed on the anatomical MRI of each participant.
In the participant with tinnitus, there was an increase in
delta activity localized to the left auditory cortex while the
participant with no tinnitus did not show such increase.
For the tinnitus participant, the waveform corresponding
to the peak location was extracted (solid blue line) while
for the participant with no tinnitus, a corresponding point
in the auditory cortex was chosen to extract the MEG time
course (dotted red line). As can be seen, delta band power
was enhanced for the tinnitus participant indicative of the
tinnitus percept. This enhanced slow wave activity is likely
to reflect a disruption of coherent activity between thalamus
and cortex.[31]
All the above models consider the pathophysiology of tinnitus
purely from the point of view of changes happening within
the central auditory system. However, this approach could
be criticized for being somewhat reductionist in its focus
because the primary complaints of tinnitus from the patient
perspective relate to the psychosocial aspects of the condition
(distress, depression, social withdrawal, etc.) rather than the
perceptual aspects of the condition (i.e., the auditory attributes
Figure 1: Power estimate of spontaneous activity from the auditory cortex in the delta band from a participant with tinnitus (right,
solid blue line) and one without tinnitus (left, dotted red line). This illustrative figure shows the abnormal enhancement of delta activity
in tinnitus which has been reported in various studies
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Hoare, et al.: Sound‑based tinnitus treatment
of the sound percept itself). While hearing loss is commonly
implicated in tinnitus, for most people, deafness does not lead
to tinnitus. Therefore, activity outside the classical central
auditory pathway is likely to play an important role in turning
tinnitus on or off, perhaps via a gating mechanism.
Role of emotional processing
Several recent theoretical models have proposed a central role
of the amygdala in tinnitus.[37,38] The basic assertion is that
tinnitus is continuously associated with aversive emotional
states through a process of learning. Rauschecker et al.,[38] have
asserted that the amygdala is part of a larger circuit in limbic
and paralimbic regions, responsible for a “noise cancellation
system” that is disordered in tinnitus [Figure 2]. The proposed
mechanism occurs via the projection of the tinnitus signal for
emotional evaluation along the auditory pathway through the
amygdala to the subcallosal area (nucleus accumbens, dorsal
raphe nucleus, and ventromedial prefrontal cortex) that sends
excitatory projections to the thalamic reticular nucleus. The
thalamic reticular nucleus has a frequency‑selective inhibitory
input to the medial subdivision of the medial geniculate body.
In Rauschecker’s model, limbic and paralimbic structures play
an active role in tinnitus. For example, the tinnitus signal can
be “cancelled” when the subcallosal relay acts appropriately
on the thalamic reticular nucleus to inhibit the tinnitus percept
before it reaches the cortex. Preliminary spontaneous EEG
data are generally supportive of a role for limbic regions.
Support for enhanced activity in the amygdala during tinnitus
comes from EEG measures of resting‑state oscillatory
electrical activity in the brain.[39] Greater synchronous alpha
band activity was found in a cohort of patients more distressed
by their tinnitus, and these signals were attributed to the
amygdala, parahippocampal gyrus, anterior cingulate cortex,
and insula (see also De Ridder et al.[37]). Such differences in
Figure 2: Putative brain networks involved in tinnitus. [36]
Paralimbic networks in the ventromedial prefrontal cortex linked
to the nucleus accumbens play an important role in evaluating
the sound’s emotional content and in the long‑term habituation to
continuous unpleasant sounds. Dashed circles indicate amygdala
(medial view) and auditory cortex, AC (lateral view)
Noise & Health, March-April 2013, Volume 15
neural activity suggest that neural systems or mechanisms
associated with chronic tinnitus are distinct from those
responsible for a person’s tinnitus‑related distress. Indeed
even in a population of healthy participants without tinnitus,
Irwin et al.,[40] found evidence for two functionally different
neural networks associated with either the acoustic attributes
of an external sound, or its emotional content. Evidence from
current anatomical studies comparing people with tinnitus to
controls lacks consensus on this issue. For example, Mühlau
et al.,[41] found decreased grey matter volume only in the
subcallosal area and an increase in grey matter volume in
the right posterior thalamus, including medical geniculate
nucleus, in people with tinnitus compared to healthy controls.
However, a more recent study from Melcher et al.,[42] found no
significant difference in grey matter volume between people
with tinnitus and healthy controls. Instead, Melcher et al.,[42]
reported a highly significant negative correlation between
grey matter volume in the subcallosal area (ventromedial
prefrontal cortex) and supra‑clinical audiometric thresholds
(≥8 kHz). This frequency range was not measured by Mühlau
et al.,[41] which may explain the discrepancy between the
two studies. At the same time, Leaver et al.,[43] also found
reduced grey matter volume in the ventromedial prefrontal
cortex of people with tinnitus compared to people without
tinnitus. Although no significant difference in audiometric
profiles were reported by Leaver et al.,[43] it is noted that
mean cut‑off frequency for normal hearing in their control
group was 6 kHz whereas for their tinnitus group, it was only
2 kHz, which may have influenced their result. This is clearly
an area that requires further research.
For an extensive review of fMRI evidence for the involvement
of limbic activity in patients with tinnitus see Adjamian et al.[10]
In his review of neurophysiological mechanisms, Noreña[9]
argues for a greater understanding of central changes within
the pattern of brain activity as a pre‑requisite to develop
efficient therapies for alleviating tinnitus. Focused on the
central auditory system, he outlines two potential strategies
depending on the individual neuropathology. First, one might
decrease the gain controlling neural sensitivity through the
restoration of a near‑normal distribution of sensory inputs
such as by amplification through a hearing aid. Second, one
might decrease spontaneous activity of the cochlear nerve
(the main driver of “neural noise” in the central auditory
system) such as by blocking pharmacologically the synaptic
transmission between inner hair cells and cochlear nerve
fibers. At present, we are some way off validating these
strategies, especially in the clinical context. Hence, we
believe that human neuroimaging can play an important
role in bridging the gap between animal and human models
of tinnitus in order to evaluate how some of the recent
sound‑based interventions might be effective. Let’s review
some of the current evidence here.
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Hoare, et al.: Sound‑based tinnitus treatment
Some recent sound‑based technological innovations
Acoustic co‑ordinated reset (CR) neuromodulation®
This technology is an intervention recently developed by the
German medical technology research company, Adaptive
Neuromodulation GmbH (ANM) (www.anm‑medical.com/).
The technology was first developed to treat Parkinson’s
disease using electrical stimulation of the cortical neurons
to disrupt (“reset”) pathological neuronal synchronization.
The pioneers of this technology consider both Parkinson’s
disease and tinnitus to be characterized by pathological nerve
cell hyperactivity and synchronization. Hence the acoustic
version of this intervention for tinnitus aims to disrupt
aberrant neural firing using sound stimulation, not electrical
stimulation as in the device for Parkinson’s disease. In
both cases, patient benefit is believed to be derived through
reduction of the pathological neural activity causing the
disorder.
The sound‑stimulation regime is tailored to each individual
patient and is a sequence of tones carefully selected to span
the frequency corresponding to the dominant tinnitus pitch.
The recommendation for treatment is that these tone sequences
are played at a low level for 4‑6 h and up to a maximum
of 8 h daily, while engaging in other daily activities. An
additional recommendation is that the treatment can be used
intermittently throughout the day but in block periods of at least
1 h. It is suggested that the sound sequence desynchronizes the
pathologically synchronous neuronal populations by decreasing
mean synaptic weight,[44] effectively “resetting” the population
from a stable synchronous state to a stable asynchronous state.
Evaluation of its efficacy and neurophysiological
mechanism of action
Behavioral results from an early‑phase trial conducted
in Germany indicate that 75% of participants reported
a reduction in tinnitus distress (≥6 points on the Goebel
Hiller Tinnitus Questionnaire) after using the device.[45]
The specific claims about the mechanism of action can be
objectively tested using neuroimaging techniques, which
are sensitive to measuring synchronous neural activity. Such
measures include the spontaneous oscillatory rhythms that
are well documented in the healthy resting brain[46] and in
tinnitus patients (see above). In the trial conducted by Tass
et al.,[45] EEG activity was measured before and after 12
weeks of Acoustic CR Neuromodulation® therapy. Using
the standardized low‑resolution brain electromagnetic
tomography (sLORETA) technique, 3 dimensional maps of
significant change in oscillatory activity were constructed
revealing an increase in alpha band power that was strongest
in temporal and prefrontal cortex, a widespread reduction in
delta that was strongest in primary and secondary auditory
cortices, and widespread reduction in gamma power after
treatment. Theta power was significantly reduced in frontal
regions and the anterior cingulate area, and beta power was
also significantly reduced in the temporal area, particularly
111
in the superior temporal gyrus. Overall, these neuroimaging
results support the notion that the sound‑based tinnitus
treatment modulates spontaneous brain activity in perceptual
(temporal lobe), cognitive (frontal lobe) and emotional
(sub‑cortical) regions of the human brain [consistent with
Figure 2].
The findings from this recently published work[45] are
promising, but at an early stage of evaluation, and thus
require more extensive and independent study. A large
scale, randomized, placebo‑controlled, double‑blind trial is
currently underway in the UK. Registration details of this trial
can be found on clinicaltrials.gov (identifier NCT01541969).
Serenade®
This sound‑based intervention was recently produced in the
US by SoundCure Inc. (www.soundcure.com). It is delivered
as part of a broader tinnitus treatment program, but the specific
mode of action of the sound device is purported to be that of
suppression where the patterned sounds modulate auditory
cortical activity and interrupt tinnitus generation.[47] The device
delivers multiple tracks of temporally patterned sounds (“S
tones”) that are again customized to each individual’s tinnitus so
that they span the frequency region of hearing loss and dominant
tinnitus pitch. Intermittent use of Serenade® is recommended by
its manufacturers to achieve an “instant” temporary relief, such
as for an hour in preparation for sleep.
Evaluation of its efficacy and neurophysiological
mechanism of action
The developers refer to the initial work of Zeng et al.,[48]
although this piece of research was a single‑case study
exploring protocols of electrical stimulation delivered by a
unilateral cochlear implant, for tinnitus benefit. In this study,
the electrophysiological measures revealed that a 100‑Hz
electrical stimulation pulse delivered to an apical electrode not
only provided total tinnitus suppression, but also reduced and
delayed the evoked N1 response to a frequency‑change stimulus.
The oscillatory brain rhythms during the stimulus also showed
an increase in alpha band (7‑9 Hz) power when tinnitus was
suppressed compared to when tinnitus was present. No benefits
were found for high‑rate (2‑5 kHz) electrical stimulation. From
these results, the authors conclude that low‑rate stimulation
maximally excites auditory cortex, which could interfere
or suppress the tinnitus‑induced abnormal central activity.
Indeed, animal electrophysiology has shown how sustained,
synchronized neural discharge rates occur for comparable
acoustic stimuli, such as click trains with longer (>40 ms)
inter‑click intervals[49] and continuous sounds amplitude
modulated at a slow rate (16‑32 Hz).[50] Compatible with this
idea, a case study exploring protocols of acoustic stimulation
reported how a 6‑kHz tone amplitude‑modulated at a rate of
40 Hz was judged to provide tinnitus suppression.[47] More
recently, Reavis et al.,[51] examined the short‑term suppressive
effects of external sounds (17 modulated sounds at different
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Hoare, et al.: Sound‑based tinnitus treatment
modulation rates and carrier frequencies, and un‑modulated
sounds at different carrier frequencies) matched to the tinnitus
loudness. They found that the greatest immediate suppression
was induced by 40‑Hz amplitude‑modulated tones with carrier
frequencies near the tinnitus pitch. These stimulus conditions
generated up to 100% suppression during a 3 min stimulation
period, with residual inhibition lasting up to 90 s after the
stimulus ended. The long‑term and specific neurophysiological
effects of “S tones”, on auditory cortical activity, however, are
yet to be demonstrated.
Neuromonics®
This tinnitus treatment makes claims to address the
underlying neurological causes of tinnitus to deliver clinically
proven long‑term relief naturally, without medication or
surgery (http://www.neuromonics.com/). As with some of
the other sound‑based devices it is delivered as part of a
broader tinnitus treatment program, involving a counseling
element that incorporates principles of cognitive behavioral
therapy.[52] The sound‑based component of the treatment
provides a means to “more readily promote desensitization
to patients’ tinnitus perception” using sound stimuli more
acceptable to patients than broadband masking noises.[53] A
small, lightweight Oasis™ device with headphones delivers
music that is spectrally modified according to an individual’s
hearing thresholds, embedded within a broadband noise. At
the first phase of treatment, the device is worn for at least 2 h
per day, which can be during activities like reading, preparing
meals or at the office.
independent review of three controlled clinical trials that
had been conducted by investigators having financial links
with the Neuromonics company.[53,57,58] Again, they were
critical of the lack of methodological rigor which, together
with the potential for commercial bias, restricts any possible
conclusions of effectiveness relative to other treatments.
The manufacturers of the Neuromonics device do not make
detailed claims for the specific mechanism of action for the
sound delivery system, although generally, it is proposed
that the “specialized acoustic stimulus targets the effects of
auditory deprivation, while it’s relaxing music is intended to
reduce involvement of the limbic and autonomous nervous
system in the perception of tinnitus.”[54] To the best of our
knowledge, the specific neurophysiological effects have yet
to be investigated.
Widex®Zen
Zen is a music program that is available in some Widex®
hearing
aids
(http://www.widex.co.uk/en/products/
thewidexsound/zen/). Zen plays random, wind‑chime‑like
(fractal) tones with harmonic, but not predictable,
relationships that can be used for relaxation[59] or for making
tinnitus less noticeable.[60] There is a range of different
Zen programs and each sound type can be adjusted to
individual preference in terms of pitch, tempo and volume.
The device is recommended to form part of a more holistic
audiological management program incorporating education
and counseling.[60,61]
Evaluation of its efficacy and neurophysiological
mechanism of action
Evaluation of its efficacy and neurophysiological
mechanism of action
Clinical observations of patient benefit are generally
encouraging. For example, in the House Clinic (Los Angeles,
USA), 14 patients had completed the treatment by the end
of the study period and reported a mean reduction in tinnitus
distress (Tinnitus Reaction Questionnaire, TRQ) score from
46 to 17 (62% average reduction).[54] However, the authors
do note that 15 patients returned their device, indicating
rather poor overall compliance. In the only randomized trial
of the device so far, Davis et al.,[52] examined the efficacy
of the Neuromonics treatment compared to counseling with
the provision of a noise generator or counseling alone. The
authors’ metric of patient benefit was a clinically significant
change in tinnitus distress at 6 months (40% reduction in
overall TRQ) score. This criterion was achieved for 86% of
patients receiving the “full Neuromonics© package,” 47%
of patients receiving the noise generator and counseling,
and just 23% of those who received counseling alone.
Despite these positive reports, in our systematic review of
randomized clinical trials (RCTs) for tinnitus[55] we assessed
that the study quality in Davis et al.,[52] to be low. Study
design and procedures for blinding researchers and patients
were weak, and there was a risk of bias through inadequate
randomization. Henry and Istvan[56] have also published an
The intervention is based on the hypothesis that bothersome
tinnitus involves limbic system activity where tinnitus
is associated with a stress response, and that music has
de‑stressing properties.[59] A survey of Widex® Zen use
found that the Zen “Aqua” program was generally preferred
by patients, possibly because it has a restricted range of
low‑pitched sounds compared to the other Zen programs
involving moderate to higher pitched sounds.[59] Kuk et al.,[59]
investigated efficacy in a self‑selecting sample of 26 patients.
The protocol of treatment reported in this study required the
patient to listen to the stimuli for a 15‑30 min period each
day in a quiet and relaxing situation. All 26 patients showed
a reduction in tinnitus distress (TRQ score) at their final
assessment and for 18 patients (69%), the change was greater
than 20 points. Visual inspection of the data plot suggests
that only 7 participants (~27%) had a clinically significant
reduction in TRQ (i.e., 40%) at follow‑up. Sweetow and
Sabes concluded from a further small cohort study (N = 14)
patient benefits were generally greater when amplification
was combined with fractal tones, compared to amplification
alone.[61] However, improvements over 6 months were
modest at best. Only four patients showed a reduction of at
least 40% on their TRQ scores, while one patient reported
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that their tinnitus got worse by more than 40% on the TRQ.
Future opportunities for evaluation might also benefit from
considering neurophysiological measures of limbic system
activity to quantify the effect of listening to the fractal tones
on the underlying stress response.
Auditory perceptual training
At present, this is an experimental intervention using
personalized sounds to reduce the perceived tinnitus
distress, using either single‑frequency tones or auditory
sound objects. A common approach has been to train people
with tinnitus on a frequency‑discrimination task (FDT)
using either fixed‑frequency differences[62‑64] or an adaptive
procedure.[35,65‑67] In a typical approach, patients might be
presented with trials of sound pairs or triplets and required
to make a decision as to which interval has the higher pitch
(two‑alternative forced‑choice paradigm) or, which is the
odd‑one out (three‑alternative forced‑choice paradigm). This
type of paradigm forms the basis of psychophysical measures
of perceptual thresholds and the rules of the procedure can
be selected to track performance at a particular point on the
psychometric curve (such as 71% or 79% accuracy).[68]
Evaluation of its efficacy and neurophysiological
mechanism of action
The putative mechanism of action exploited by FDT concerns
what is known about auditory cortical reorganization in the
treatment of tinnitus, predominantly from animal studies.
The concept draws on those observations which indirectly
link tinnitus, hearing loss, and auditory perceptual learning,
to altered patterns of neural activity within the central
auditory system. If tinnitus is the unfortunate perceptual
consequence of neural plasticity, then interventions that
can drive changes in frequency representation at the level
of the cortex, and potentially disrupt the tinnitus‑generating
network, offer therapeutic possibilities. The reference tone for
the discrimination task is typically tailored to the individual
pattern of hearing loss or dominant tinnitus pitch, so to provide
maximal sound enrichment to this region of frequency tuning
within the central auditory system. At present, these links
are rather speculative. For example, no human studies of
tinnitus have yet provided substantial physiological evidence
in support of evoked or induced changes in tinnitus‑related
activity as a result of auditory training. An equally plausible
(cognitive) alternative is that effects on attention may be the
determining factor of benefit when it comes to FDT.
A recent systematic review considered 10 studies that have
so far been conducted to evaluate the efficacy of auditory
perceptual training.[69] Nine out of the 10 studies reported
some significant change in either qualitative or quantitative
outcomes measures after auditory training. However, all
studies were quality rated as providing low or moderate
levels of evidence for the estimated effects they reported.
113
Our systematic review highlighted a pressing need for
randomized controlled studies that will generate high‑quality
unbiased and generalizable evidence for whether or not
auditory perceptual training has a clinically relevant effect
on tinnitus.
We recently reported two randomized controlled trials
of FDT involving 70 people with chronic subjective
tinnitus.[70] The first study assessed the effect of FDT using
(A) a single frequency in the region of normal hearing,
(B) a single frequency in the region of hearing loss, or
(C) a high‑pass (missing fundamental) harmonic‑complex
tone that provided high‑frequency stimulation but evoked
a low pitch percept. Hence, we compared training at
hearing loss frequencies (conditions B and C) with a
previously untested “active control,” condition (A). In
Study 1, all the participants were trained for 30 min per
day on 5 days each week for 4 weeks. In study 2, all the
participants were trained on condition A for either 15 min
per day for 4 weeks, or 1 h per day for 2 weeks. We adopted
self‑report (Tinnitus Handicap Questionnaire, THQ) and
psychoacoustic outcome measures of tinnitus, we provided
full familiarization of those measurement procedures before
the baseline assessment, and we obtained data at 1 month
follow‑up. Overall there was a reduction in tinnitus distress
(THQ scores) that was significant within the training period
and again at 1‑month follow‑up [Figure 3]. However, against
the general hypothesis, our results indicated that benefit
was not specifically associated with training that provided
enrichment at hearing‑loss frequencies, because benefits
were also present for the “control” group in condition
(A). Although there was a noticeable increase in dominant
tinnitus pitch in participants who trained in condition (A),
overall there was no significant change in tinnitus loudness,
Figure 3: Improvements on Tinnitus Handicap Questionnaire
(THQ) score after frequency discrimination training. Data are the
mean THQ scores (±95% confidence intervals) for 70 individuals
who completed a course of 10 h training over a 4‑week period.
Compared to baseline, mean THQ score was significantly reduced
after 2‑weeks training and at a 4‑week follow‑up assessment (*,
P < 0.05)
Noise & Health, March-April 2013, Volume 15
Hoare, et al.: Sound‑based tinnitus treatment
dominant pitch or bandwidth after training. Further work
is needed to assess the reliability of these findings and
to investigate whether any changes might be in terms of
generic cognitive effects such as changes in the focus of
selective attention.
Points to consider in the design of device evaluation
trials
Standards for conducting clinical trials include the
Consolidated Standards of Reporting Trials (CONSORT)
and the CONSORT supplement for non‑pharmacological
interventions.[71] This standard provides rigorous review
criteria for RCTs and hence the appropriate transparency to
evaluate the merits of these clinical approaches. Although the
guidelines provided by the CONSORT criteria are principally
aimed at study review, they do describe many of the key
components that a high‑quality clinical trial should either
document or incorporate into their study design. Indeed,
our recent trial of FDT was designed specifically with these
standards in mind.[50]
Although focused on auditory perceptual training, some of
the recommendations in our previous review[55] are equally
valid for any studies that set out to evaluate the efficacy of
a technological sound‑based device to be used as part of a
tinnitus treatment program. Specific recommendations for
future trials were, (i) use a combination of quantitative (e.g.,
neuroimaging) and qualitative (e.g., validated questionnaire)
outcome measures, (ii) choose a qualitative outcome measure
that is sensitive to change (i.e., preferably not the Tinnitus
Handicap Inventory), (iii) be able to have confidence in the
stability of the pre‑treatment baseline for outcome measures,
(iv) choose an active control, i.e., compare to more than “no
intervention,” and (v) demonstrate longer‑term patient benefits.
Many of the clinical interventions reviewed here comprise
treatment regimes, which include sound stimulation in the
context of a structured assessment and counseling package
that is individualized to each patient profile. It has been argued
that sound therapies actually result in little or no benefit over
and above that offered by the psychological component of
tinnitus therapy.[72] Indeed psychological therapies, including
cognitive behavior therapy, are well known to be effective
at relieving tinnitus distress.[55] Two questions for further
consideration are highly relevant to the UK perspective, if
not elsewhere too. First, are audiologists (working in the
National Health Service (NHS)) and hearing‑aid dispensers
(on the high street) sufficiently skilled and supported to
administer psychological or counseling interventions?[73]
Second, is the additional cost and resource implication of a
multi‑component treatment package really worth it? These
are provocative, but valid, questions given the “culture shift”
towards availability and marketing of new technological
sound‑based interventions. We would therefore welcome
high‑quality evidence of efficacy and cost benefits provided
by large‑scale randomized controlled clinical trials.
Noise & Health, March-April 2013, Volume 15
Conclusions and future directions
In this paper, we have briefly introduced the reader to the
putative physiological mechanisms of tinnitus within the
central auditory system (hyperexcitability, reorganization
of frequency tuning, spontaneous hyperactivity, and
modulation by emotional processing). Although many of
the recent technological innovations for individualized
sound‑based interventions make reference to central auditory
mechanisms as a key, underlying principle for their efficacy,
there is insufficient rigorous neurophysiological evidence
as yet to strongly support those claims. We would therefore
advocate the use of both qualitative and quantitative outcome
measures, including neuroimaging where feasible, as preand post‑intervention assessments. Ultimately, the most
comprehensive perspective on treatment efficacy and its
neural mechanism of action will be informed by such trial
designs.
Acknowledgments
DJH, MS, and DAH are funded by the National Institute for Health
Research (NIHR) Biomedical Research Unit Program. however, the
views expressed are those of the authors and not necessarily those
of the NHS, the NIHR or the Department of Health. PA is funded by
the UK Medical Research Council.
Address for correspondence:
Dr. Derek Hoare,
NIHR Nottingham Hearing Biomedical Research Unit,
Ropewalk House, 113 The Ropewalk, Nottingham, UK,
NG1 5DU.
E‑mail: derek.hoare@nottingham.ac.uk
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How to cite this article: Hoare DJ, Adjamian P, Sereda M, Hall DA.
Recent technological advances in sound-based approaches to tinnitus
treatment: A review of efficacy considered against putative physiological
mechanisms. Noise Health 2013;15:107-16.
Source of Support: Nil, Conflict of Interest: DJH and DAH
are principal investigators on the clinical trial of Acoustic CR
Neuromodulation referred to in this manuscript..
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