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Tinnitus, colloquially known as ringing in the ears, refers
to the perception of sound in the absence of a corre-
sponding external auditory stimulus. This phantom
sensation reduces quality of life for millions worldwide
and, at present, has no medical cure. Although tinnitus
is most common after the age of 60years—8–20% of
elderly individuals are affected—chronic tinnitus can
occur at any age1. Approximately 1–2% of the general
population in Western industrialized countries experi-
ence unremitting tinnitus to the extent that they seek
assistance from health professionals, including family
physicians, otolaryngologists, audiologists, psychiatrists
and neurologists1,2. Tinnitus as a result of exposure to
loud noises is a major service-related disability for sol-
diers returning from war zones3. In 2011, the United
States Government disbursed more than one billion US
dollars in disability payments to members of the military
suffering from tinnitus.
In this Review, we focus on currently known factors
that trigger tinnitus, the psychoacoustic properties of
tinnitus, and the neural mechanisms underlying gen-
eration of tinnitus and the associated symptomatology.
We also discuss treatment approaches which, though not
fully effective in eliminating the tinnitus, have prom-
ise for reducing its impact on quality of life for many
affected individuals.
Triggers and associated conditions
Numerous precipitating factors have been associated
with tinnitus. The most common condition that predis-
poses to tinnitus is hearing loss (as assessed by clinical
audiogram), which is present in up to 90% of individuals
with tinnitus4–6. The most common reasons for hearing
loss are recreational or occupational noise exposure,
and ageing. Other factors that can predispose to tinni-
tus include head and neck injuries, use of ototoxic drugs,
infections, and a range of medical conditions that can
affect hearing.
Depending on the bandwidth of the perceived sound,
tinnitus is typically described as a steady tonal or hiss-
ing percept, but some people with tinnitus report more
complex sounds such as insect sounds, chimes, running
water, or multiple sounds, though some of this vari-
ability could relate to the descriptors that the patients
choose to describe their percept rather than to variability
in the percept itself7. Tinnitus varies in terms of time
course (continuous or intermittent), spatial attributes
(whether experienced in one or both ears or perceived
to be ‘inside’ the head), degree of intrusiveness, and
with respect to whether hyperacusis (increased sensi-
tivity to ordinary environmental sounds) is also pres-
ent. Anxiety, sleeplessness, and depression are common
comorbidities, particularly soon after tinnitus onset.
1Department of
Otolaryngology, Molecular
and Integrative Physiology,
Biomedical Engineering,
University of Michigan,
1150 W Medical Center Drive,
Michigan 48104, USA.
2Department of Psychology,
Neuroscience, and Behavior,
McMaster University, 1280
Main Street West, Hamilton,
Ontario L8S 4K1, Canada.
3Department of Psychiatry
and Psychotherapy and
Interdisciplinary Tinnitus
Clinic, University of
Regensburg, Universitätsstr.
84, D-93053 Regensburg,
Germany.
Correspondence to S.E.S.
sushore@umich.edu
doi:10.1038/nrneurol.2016.12
Published online 12 Feb 2016
Maladaptive plasticity in tinnitus—
triggers, mechanisms and treatment
Susan E. Shore1, Larry E. Roberts2 and Berthold Langguth3
Abstract | Tinnitus is a phantom auditory sensation that reduces quality of life for millions of
people worldwide, and for which there is no medical cure. Most cases of tinnitus are associated
with hearing loss caused by ageing or noise exposure. Exposure to loud recreational sound is
common among the young, and this group are at increasing risk of developing tinnitus. Head or
neck injuries can also trigger the development of tinnitus, as altered somatosensory input can
affect auditory pathways and lead to tinnitus or modulate its intensity. Emotional and attentional
state could be involved in the development and maintenance of tinnitus via top-down
mechanisms. Thus, military personnel in combat are particularly at risk owing to combined risk
factors (hearing loss, somatosensory system disturbances and emotional stress). Animal model
studies have identified tinnitus-associated neural changes that commence at the cochlear
nucleus and extend to the auditory cortex and other brain regions. Maladaptive neural plasticity
seems to underlie these changes: it results in increased spontaneous firing rates and synchrony
among neurons in central auditory structures, possibly generating the phantom percept. This
Review highlights the links between animal and human studies, and discusses several therapeutic
approaches that have been developed to target the neuroplastic changes underlying tinnitus.
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Auditory nerve
The nerve that innervates
cochlear hair cells and has
acentral projection to the
cochlear nucleus.
Suprathreshold hearing
Hearing at levels above the
measuring threshold.
Hidden hearing loss
Hearing loss that is not
detectible by conventional
auditory threshold testing and
which reflects deficits in
suprathreshold hearing.
Auditory brainstem
response
Volume-conducted far field
potentials reflecting
synchronous activation of
brainstem structures beginning
with the cochlear nucleus and
ending at the inferior colliculus.
dB hearing level
Decibels hearing level; dB
relative to the quietest sound
at a given frequency that a
young individual with normal
hearing is able to hear.
The high variability in characteristics of tinnitus has
sparked investigation into the possibility that subtypes
exist. Each subtype could be associated with a specific
aetiol ogy and pathophysiology8, notwithstanding the
fact that, as tinnitus is an auditory percept, some com-
monalities must exist in its underlying neural mecha-
nisms. Identification of subtypes could be worthwhile
insofar as clinical management can be optimized for
typical cases or unusual aetiologies, allowing effective
treatment in rare cases9–11.
In the past decade, animal model studies have indi-
cated that most cases of chronic tinnitus do not arise
from increased activity in the cochlear nerve driven by
the damaged cochlea, but develop as a consequence of
changes in central auditory pathways and other brain
regions when the brain loses its input from the ear.
Clinical observations support this conclusion: tinni-
tus is a predictable outcome when the auditory nerve
is sectioned during surgery for the removal of acous-
tic neuromas, and when tinnitus exists before surgery,
nerve section typically does not eliminate it12. Although
exceptions to these principles have been reported,
poss ibly owing to pathological alterations in the olivo-
cochlear efferent system or other factors13,14, sectioning
of the auditory nerve is not a recommended procedure
for the treatment of tinnitus; on the contrary, when
hearing function is augmented by cochlear implants in
individuals with sensorineural hearing loss, the tinnitus
associated with the hearing loss is often reduced and
sometimes even eliminated15.
Although deafferentation of auditory pathways
seems to be a critical trigger for tinnitus, the relation-
ship between tinnitus and hearing loss is not straight-
forward: ~10–15% of people with tinnitus have normal
clinical audiograms up to 8 kHz16,17, and many indivi-
duals who have age-related high-frequency hearing
loss do not have tinnitus18. What these cases tell us
about tinnitus is currently under debate. Recent animal
model studies suggest that noise exposure or ageing
could involve neuropathic changes in the cochlea that
do not increase hearing thresholds, but rather exhibit
themselves when suprathreshold hearing is tested19. The
cochlear transduction mechanism (inner and outer
hair cells on the basilar membrane of the inner ear and
their associated stereocilia) often recovers from dam-
age following noise exposure, but synapses connecting
auditory nerve fibres (ANFs) to the inner hair cells are
more vulnerable to damage by noise exposure20 and the
effects of ageing21. Particularly vulnerable are synapses
on ANFs that have high thresholds for depolarization
and are tuned to frequencies above the noise exposure
frequency22,23. This pattern ofsynaptic pathology is
relevant to tinnitus in the absenceof a threshold shift,
because its presence would not affect the detection of
low-level sounds (thus exempting the audiogram) but
would affect ANFs tuned to higher frequencies that
are normally perceived in tinnitus17. The presence of
hidden hearing loss in tinnitus is supported by evidence
that WaveI (which reflects auditory nerve response) of
the auditory brainstem response (ABR) to suprathreshold
sounds is reduced in patients with tinnitus but normal
audiograms17,24. By contrast, Wave V (which reflects
processing in the auditory midbrain) can be either
normal17 or enhanced24 in tinnitus, revealing increased
central gain. To what extent deafferentation, either hid-
den or detectable in the audio gram, is a critical trig-
gering factor in tinnitus, is yet to be determined, but
understanding the relationship of hearing loss to tinni-
tus can provide insight into the mechanisms underlying
thecondition.
Tinnitus and audiometric hearing loss
When individuals with hearing loss that is typically in
the high-frequency range (detected by the audiogram)
are asked to rate several sound frequencies for similar-
ity to their tinnitus, frequencies that are judged to be
similar typically commence near the edge of the normal
hearing range and increase in proportion to the extent
of the threshold shift, yielding a ‘tinnitus spectrum’ that
spans the hearing-impaired region25–27. Similarly, tin-
nitus can be transiently suppressed for 30–60seconds
after presentation of a band-limited masking noise, a
phenomenon known in the tinnitus literature as resi dual
inhibition29. This forward-masking effect is optimal
when the centre frequency of the band- limited mask-
ing noise is also in the hearing loss region18. However,
if hearing loss is deep18, maskers centred at lower fre-
quencies can be more effective28. These results apply
to cases of notched hearing loss that is visible on the
audiogram25,29 and probably also to hidden hearing loss
(in which tinnitus spectra shift inversely with respect to
audiometric thresholds, even when thresholds remain
<20 dB hearing level up to 8 kHz17). These psycho acoustic
properties of tinnitus are relevant to understanding the
neural mechanisms underlying tinnitus. They suggest
that aberrant neural activity taking place among neu-
rons tuned to the hearing-impaired frequencies gen-
erates tinnitus, and disrupting this aberrant activity
suppresses it. Questions remain, however, as to what
the aberrant neural activity consists of, and where in the
auditory projection pathway does it occur.
Animal models of tinnitus
Questions about the neural changes in tinnitus have
been addressed by animal studies that have examined
the neural effects of noise trauma (or other procedures,
such as salicylate injections, which are beyond the scope
of this Review and are reviewed elsewhere30), which are
known to impair the cochlear transduction mechanism.
Key points
• Tinnitus is prevalent in up to 15% of the world population
• Tinnitus is linked to hearing loss: loss of input from the cochlea to central auditory
pathways triggers plastic neural changes that result in increased spontaneous activity
and synchrony in affected regions
• Neurons in nonauditory regions are also affected by tinnitus
• Although tinnitus is often linked to noise exposure, tinnitus does not always occur
after noise damage in humans or animal models
• An understanding of the neural mechanisms of tinnitus is essential for developing
effective treatments
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Tonotopicity
Frequency-specific
organization at the
auditorysystem.
Experimental paradigms for noise-induced tinnitus
Noise exposure, depending on its intensity and dura-
tion, results in either a permanent threshold shift
(PTS) or a temporary threshold shift (TTS). The pres-
enceor absence of tinnitus in animals is determined
either by assessing whether conditioned responses to
sound stimuli change when the animals are placed in
a silent environment, or by measuring the extent to
which a silent period can modulate reflexive responses
to an unexpected suprathreshold sound (see REF.31 for
review). An example of the latter method—used by
many, but not all, of the studies reviewed below—is the
‘gap–prepulse inhibition of acoustic startle (GPIAS)’
procedure, developed by Turner and colleagues for use
with rats and mice32,33 and modified for use with guinea
pigs34,35. Inthis method, startle suppression by an acous-
tic prepulse verifies that functional hearing is present
after noise exposure, whereas the failure of a silent inter-
val to modulate the startle response indicates that the
silent interval has been filled by a tinnitus sound (FIG.1a).
Animals are segregated into ‘tinnitus’ and ‘no tinnitus’
groups on the basis of whether startle suppression by the
silent interval falls beneath a specified criterion (FIG.1b).
Many animal studies using GPIAS and other models of
tinnitus have used noise exposure levels that induce TTS
but not PTS, so that hearing threshold is preserved.
Although the validity of animal models of tinnitus
is not without challenge36–38, an increasing number of
studies are demonstrating the usefulness of these proce-
dures: after tinnitus-inducing noise exposure, animals
that express behavioural evidence of tinnitus show con-
sistent neurophysiological patterns that differ from ani-
mals that do not show such signs of tinnitus39–45. These
findings give greater assurance that the neural changes
being measured are inextricably linked with tinnitus,
and that such changes can be differentiated from those
that are attributed only to hearing loss or hyperacusis.
Using behavioural models, three types of neural changes
have been associated with tinnitus: increases in the
spontaneous activity of auditory neurons in subcortical
and cortical structures, increased burst firing in these
structures, and increased synchronous activity among
neurons affected by noise exposure41.
Neurophysiological alterations in tinnitus
Frequency-specific increases in spontaneous firing rates.
Altered neuronal activity is detected as a physiological
correlate of tinnitus in the first structure of the central
auditory pathway, the cochlear nucleus (FIG.2).Use of an
operant conditioning protocol first identified that ani-
mals with behavioural evidence of tinnitus exhibited
increased spontaneous firing rates (SFRs) in neurons
that have best frequencies (the frequencies to which the
neuron is most sensitive) close to the noise exposure
spectrum46. Subsequent studies using different oper-
ant techniques or GPIAS confirmed that pure tone or
band-limited noise exposure resulted in increased SFRs
in fusiform cells — the principal output neurons of the
dorsal cochlear nucleus (DCN) — with best frequen-
cies close to the noise exposure frequency and to the
behavourally determined tinnitus frequencies39,40,45.
Some of these studies used noise exposure levels that
produced only TTS, so that sound thresholds had recov-
ered by the time of tinnitus testing39,40, in line with the
studies showing tinnitus in humans with clinically nor-
mal audiograms17,47. Best-frequency-specific increases
in SFR in the DCN that are close to the noise-exposure
frequencies after TTS39,40 also suggest a loss of ANF input
to the cochlear nucleus from high-threshold ANFs, even
after audiometric thresholds have recovered20,23. Other
evidence indicates that increased SFRs can occur in the
ventral cochlear nucleus (VCN) after various types of
hearing impairment48–50, which suggests that the VCN
could also be a site of hyperactivity-initiation in the
brain. However, studies using a behavioural tinnitus
model to examine frequency-specific increases in SFR in
the VCN after noise exposure and tinnitus testing are yet
to be performed. Thus, at present, the DCN can be con-
sidered as the site at which diminished auditory nerve
input initiates increased spontaneous activity—the
first physiological hallmark of tinnitus—which is then
conveyed to higher brainstem and cortical regions51,52.
Several studies of the next auditory centre of the brain,
the inferior colliculus, have demonstrated increased SFRs
just below, within and just above the noise-damaged
region of the cochlea; these increased SFRs correlated
with the presence of tinnitus in some studies53,54, but not
in others55,56. The increased spontaneous activity in the
inferior colliculus seems to depend on transmission of
increased spontaneous firing from the DCN, because
DCN ablation before noise damage prevents increases
in SFRs in the inferior colliculus and the development
of tinnitus57. According to one study, DCN ablation after
noise damage immediately abolished increased SFRs in
the inferior colliculus58, though according to another
study59, tinnitus can persist after DCN ablation. Together,
these findings suggest that tinnitus could be generated
in the DCN, but structures further along the auditory
pathway, beyond the cochlear nucleus, are involved in
maintaining tinnitus. Nevertheless, it is unlikely that
the inferior colli culus maintains increased SFRs inde-
pendently, because the increased SFRs can be abolished by
cochlear ablation for up to 6weeks after noise exposure,
but not later60. By contrast, increased SFR in the DCN is
notaffected by subsequent elimination of either afferent
or efferent inputs at 4–6weeks after exposure61,62. In addi-
tion, thetime course and tonotopicity of increased SFR in
the inferior colliculus mimics that of the DCN63. We can
conclude from these studies that elevated spontaneous
activity in the DCN is probably transmitted to the inferior
colliculus, and subsequently to the thalamus, either from
the inferior colliculus or possibly independently from the
DCN through direct projections64–66.
Tinnitus-related hyperactivity is maintained in the
auditory thalamus: the neurons in the medial genicu-
late body (MGB) of rats show increased SFRs after noise
damage, which correlate with the degree of tinnitus
measured using GPIAS67. Neurons in the primary audi-
tory cortex, which were shown in early studies to have
increased spontaneous activity after noise damage4,68,
were confirmed to exhibit tinnitus-related increases in
SFR in later studies that used GPIAS69,70.
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Startle
pulse
Gap
No gap
Gap–normal
Gap–tinnitus
Startle
response
All observations
0
10
20
30
40
a b
Background noise (60
dB)
Startle pulse (115
dB)
Tinnitus
No tinnitus
Tinnitus
Normalized startle
distribution
50 50 10
Time (ms)
Normalized startle amplitude
0 0.5 1 21.5
Spike-timing-dependent
plasticity
Spike-timing-dependent
strengthening or weakening
ofsynaptic transmission
measured invitro.
Stimulus-timing-dependent
plasticity
The macroscopic equivalent
ofspike-timing-dependent
plasticity, measured invivo.
Hebbian plasticity
The strengthening of synaptic
transmission when presynaptic
activation precedes
postsynaptic activation.
Neural synchrony and burst-firing
In addition to increased SFR, two other markers have
been suggested as physiological correlates of tinnitus:
increased synchrony between neurons, and increased
bursting in a specific auditory structure. Increasedsyn-
chrony between neurons could create perceptual group-
ing of auditory objects71 and thus it is feasible that
increased synchrony in the absence of a physical audi-
tory stimulus could lead to the perception of a phantom
sound72. Indeed, a recent study reported increased SFRs,
bursting and neural synchrony in the fusiform cells of
the DCN, establishing the presence of all three correlates
in the earliest central auditory region that correlate with
tinnitus41. In the inferior colliculus, increased bursting
and synchrony across multi-unit clusters was observed
in chinchillas with tinnitus that was confirmed with an
operant conditioning model73. The bursting and synchro-
nous firing were not confined to the central nucleus of
the inferior colliculus, but were also evident in regions
surrounding the central nucleus, particularly the dorsal
cortex. In other research using GPIAS, tinnitus-related
maladaptive plastic changes of neural responses in the
medial geniculate body were observed in noise-exposed
adult rats with behavioural evidence of tinnitus. In addi-
tion to increased SFRs, the MGB units in animals with
tinnitus exhibited altered burst-firing properties, which
correlated with the severity of tinnitus67.
Changes in the MGB caused by tinnitus-inducing
procedures would be expected to influence the responses
of neurons in the primary auditory cortex. After noise
over-exposure that elevated ABR thresholds above the
exposure frequency, neurons in the region of the pri-
mary auditory cortex that corresponded to the range of
hearing loss shifted their preferred tuning to frequencies
near the audiometric edge, such that these frequen-
cies became over-represented in the cortical tonotopic
map74,75. Neurons in the primary auditory cortex also
showed increases in SFR, increased synchronization, and
increased burst firing75. Increased SFR and synchrony
were observed primarily in neurons tuned to frequencies
within the range of hearing loss, and increased synchrony
was confined to these neurons. Burst firing increased
immediately after noise trauma, but subsided to normal
over the measurement period of a few hours, whereas the
changes in SFR and synchrony persisted. Althoughthe
presence of tinnitus was not assessed in these experi-
ments, subsequent studies confirmed increased cortical
synchrony and SFR in animals with GPIAS-verified tin-
nitus, giving credence to the validity of hyperactivity and
synchrony as neural correlates oftinnitus76.
Mechanisms of increased SFR and synchrony
Neural plasticity beginning at brain stem
A plethora of studies have shown that cochlear dam-
age alters homeostatic and long-term plasticity in the
cochlear nucleus. Even a partial reduction of auditory
nerve inputs to the dorsal and ventral divisions of the
cochlear nucleus decreases release of the inhibitory
neuro transmitters glycine and γ-aminobutyric acid
(GABA), and alters their receptors44,77. Additionally, both
severeand partial cochlear damage78,79 increase excita-
tory neuro transmission and upregulate excitatory non-
auditory projections80. Decreased inhibition combined
with increased excitation could result in increased SFRs
of cochlear nucleus neurons. This aberrant activity could
be transmitted to the MGN either directly65,81, or through
the inferior colliculus. At the level of the MGB, however,
there is little evidence of tinnitus-related decreases in
GABAergic neurotransmission82. Rather, at this level, tin-
nitus measured with GPIAS was associated with increases
in tonic extrasynaptic GABAA receptor currents in action
potentials or evoked bursts, and with increased expres-
sion of GABAA receptor δ-subunits, which could result
in hyperpolarization and a shift from tonic to burst- firing
mode. This shift could alter the salience of tinnitus sig-
nals in the auditory cortex. These findings are consistent
with thalamocortical dysrhythmia, which results from
abnormal interactions between thalamus and cortex
caused by neuronal hyperpolarization and the initiation
of low-threshold calcium spike bursts83.
Spike-timing-dependent plasticity (STDP) invitro84, and
its macroscopic inviv o correlate, stimulus-timing- dependent
plasticity (StDP)85, play a major role in encoding of infor-
mation in the DCN. In the healthy auditory system, this
form of long-term plasticity presents as Hebbian plasticity
in the principal output neurons of the DCN invitro86.
StDP is governed not only by the temporal order of pre-
synaptic and postsynapticactivity, butalso via functional
Figure 1 | Assessment of tinnitus in animals with GPIAS. a | Gap–prepulse inhibition of
acoustic startle (GPIAS) assay for tinnitus. A startle stimulus is presented to the guinea pig in
a background noise. The height of the arrow indicates the amplitude of the startle response,
which is detected by a piezo electric plate under the animal. In animals without tinnitus, the
gap in the background noise suppresses the startle response (middle row). In animals with
tinnitus, the gap is filled by the tinnitus and the reduction in startle response is diminished.
b | Gaussian-mixture model analysis partitions the normalized startle values into two
distributions: ‘normal’ (no evidence of tinnitus) and ‘tinnitus’. Republished with permission
J.Neurosci. 33, 19647–19656
(2013); permission conveyed through Copyright Clearance Center, Inc.
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Primary auditory cortex
Anterior auditory field
Cingulate gyrus
Hippocampus
Amygdala
Thalamus
Inferior colliculus
Somatosensory
pathways
Posterior parietal
cortex
Cochlear nucleus
Frontal cortex
Extralemniscal inputs
Cochlea
Auditory pathways
Memory/emotion
Attention and
consciousness
Sensorimotor
Cerebellar
pathways
Secondary auditory cortex
modulation by N-methyl--aspartate (NMDA) and
acetylcholine87. In vivo, fusiform cells in the DCN and
neurons in the primary auditory cortex demonstrate
primarily Hebbian plasticity in normal-hearing ani-
mals85 (FIG.3). However, animals with tinnitus, assessed
by GPIAS, show primarily anti- Hebbian plasticity in
both regions. By contrast, neurons in animals that
do not develop tinnitus show increased long-term
depression40,70,88. Altered acetylcholine- mediated neu-
romodulation, NMDA receptor changes, increased
glutamatergic transmission and decreased glycinergic
and/or GABAergic transmission contribute to these
changes77,80,89,90,91 (FIG.4). Computational studies indicate
that STDP can alter synchronization, suggesting that
the tinnitus-associated StDP changes lead to the alter-
ations in neural synchrony that are observed in animals
withtinnitus41,92,93.
Factors contributing to resistance to tinnitus
Although most studies assessing the mechanisms of tinni-
tus have focused on animals or humans that develop tin-
nitus, equally important is to understand the resistance to
developing tinnitus that is seen in many indivi duals after
the same noise-exposure conditions. PTS studies that
compared animals with and without tinnitus after the
same noise exposure have shown important differences
between these groups that would not have been discerned
if animals had been divided into only noise-exposed and
control groups. An exemplary study demonstrated that
after a mild PTS, animals with GPIAS-assessed tinnitus
exhibited an increased ABR Wave V amplitude at supra-
threshold levels in contrast with a reduced Wave V ampli-
tude in the animals without tinnitus94. The animals with
tinnitus showed no significant change in cortical activity
measured with local field potentials invivo, but showed
a significant increase in Wave V ABR amplitude, repre-
senting synchronous activity of neurons in the inferior
colliculus. This finding is consistent with another study
demonstrating reduced levels of the activity-regulated
cytoskeleton-associated protein (Arc) in the auditory
cortex of animals that developed tinnitus, but not in
those that did not develop tinnitus, measured using an
operant conditioning paradigm95. Other studies demon-
strated differences in KCNQ2/3 and HCN channel activ-
ity between animals with and without tinnitus after PTS,
suggesting that the effect of noise trauma on intrinsic
membrane properties (that is, nonsynaptic factors) also
contributes to the development of tinnitus43,96 (FIG.3).
Studies using a TTS or the hidden hearing loss model
are particularly useful for dissecting mechanisms of
resistance to tinnitus, as central effects can be more
purely attributed to central homeostatic or timing-
dependent plasticity mechanisms in the absence ofdif-
ferences in audiometric hearing level. Two studies of
guinea pigs in which all animals exhibited only TTS after
noise exposure reported that the animals that did not
develop tinnitus (as assessed by GPIAS) showed more
long-term depression than long-term potentiation in the
DCN. By contrast, the animals that developed tinnitus
exhibited more long-term potentiation than long-term
depression39,40. Other studies using TTS models have
correlated the GPIAS-tinnitus index with other physio-
logical or molecular changes, and have shown that a high
tinnitus index correlates with an increased likelihood of
increased SFR, bursting and synchrony in the cochlear
nucleus and MGB67,86. In addition, neurons from animals
with tinnitus fired more spikes per burst relative to non-
tinnitus neurons, suggesting a tinnitus-related increase
in intrinsic membraneexcitability41,82.
Role of nonauditory structures
Somatosensory pathways
Animal studies have shown that integration of audi-
tory and somatosensory afferent projections occurs as
early in the auditory pathway as the cochlear nucleus,
where projections from the auditory nerve and tri-
geminal and dorsal column ganglia and brain stem
nuclei converge97,98. These projection neurons termi-
nate primarily on the cochlear nucleus granule cells,
whose parallel-fibre axons terminate on the apical den-
drites of DCN fusiform cells99–101. Auditory nerve fibres,
bringing input from the cochlea, terminate on the basal
dendrites of the fusiform cells. Fusiform cells are, there-
fore, ideally placed for multisensory integration via
stimulus-timing-dependent long-term plasticity85.
After cochlear damage reduces auditory nerve input
to the cochlear nucleus, somatosensory inputs to the
cochlear nucleus are upregulated over a few days78,80,102,
resulting in heightened fusiform cell responses to
somatosensory stimulation103. This effect is initiated
by increased glutamatergic neurotransmission from
somato sensory fibres after loss of input of auditory
nerves from the cochlea104. Interestingly, the upregula-
tion of glutamatergic inputs from the somatosensory sys-
tem occurs after a ‘threshold’ level of cochlear damage;
beyond this threshold, no further changes occur105.
Figure 2 | Simplified representation of auditory and nonauditory pathways in
tinnitus. The auditory pathway commences with the cochlear nucleus and projects
through the inferior colliculus to the thalamus and auditory cortex. Return projections
Output from auditory pathways distributes to several major nonauditory regions of the
brain, including areas involved in memory, emotions, attention, consciousness and
sensorimotor processing. In this summary diagram, connections among these regions
reciprocal, mediated directly by corticocortical projections or via the thalamus, as well
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c
−40 −30 −20 −10 0 10 20 30 40
−60
−40
−20
0
20
40
Bimodal interval (ms)
Change in SFR (%)
a
Sound
Stellate
cell
Fusiform
cell
Cartwheel
cell
Parallel fibre Granule
cell
Auditory
nerve fibre
Excitatory
Inhibitory
Inferior
colliculus
Sp5
Sp5 probe
DCN
probe
b
Recording
electrodes
Stimulation
electrode
Auditory
stimulus Sham
Exposed,
with tinnitus
Exposed,
no tinnitus
Sound Sp5 stimulation
Tinnitus-related changes in auditory–somatosensory
integration by the fusiform cells include increased long-
term potentiation40, prob ably mediated by the increased
nonauditory glutamatergic innervation after cochlear
damage78,79. Importantly, animals that did not develop
tinnitus displayed increased long-term depression at
fusiform synapses. The plasticity differences between
animals with and without tinnitus involve a complex
interplay between multiple mechanisms involved in
homeostatic and timing-dependent plasticity. Given the
profound alterations in processing involved in somato-
sensory integration in the cochlear nucleus, which are
mimicked in the auditory cortex106, it is not surprising
that a majority of people with tinnitus can manipulate
the loudness and pitch of their tinnitus by stimulating
or moving their face and neck107,108, regions providing
trigeminal and dorsal column inputs to the cochlear
nucleus101,109,110. Up to two thirds of humans with tinnitus
have this type of tinnitus, referred to as somatosensory
tinnitus or somatic tinnitus107,108.
Nonauditory brain networks
Animal studies95,111 and human neuroimaging
studies112–114 have confirmed tinnitus-related changes in
several nonauditory brain areas. Tinnitus is accompanied
by structural and functional alterations in the prefron-
tal cortex, parietal cortex, cingulate cortex, amygdala,
hippo campus, nucleus accumbens, insula, thalamus and
cere bellum112,115 (FIG.2). Though many of the changes seen
in these regions could relate to tinnitus, it is challenging
Figure 3 | Mechanisms of tinnitus initiation in the dorsal cochlear nucleus. a | Schematic of stimulation paradigm in the
fusiform cells as a result of granule-cell activation. b | Locations of the recording and stimulating electrodes for initiating
c |
Hebbian in sham-treated animals (where somatosensory preceding auditory stimulation produces facilitation at +20 ms and
depression at -10 ms) to anti-Hebbian rules in guinea pigs with tinnitus (facilitation now seen when auditory precedes
order of Sp5 and sound stimuli: the brown vertical line indicates the Sp5 stimulation, and the sinusoid represents the tone
J.Neurosci. 33, 19647–19656 (2013); permission conveyed through Copyright Clearance Center, Inc.
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Nature Reviews | Neurology
Noise exposure
↓
ANF
Intrinsic cellular change Synaptic change
Change in
NMDA-R
↑
Transmission
by Glu
↓
Transmission
by GABA
↓
Transmission
by Gly
↑
Synchrony Changes in spike-timing-
dependent plasticity
↑
Spontaneous
firing rates
Tinnitus
Changes in Kv
and HCN
Neurotransmitter actions
Triggering factors
Ion channel changes
Physiological
correlates of tinnitus
to distinguish between effects of tinnitus and those of
comorbidities of hearing loss, hyperacusis and distress
behaviour, which are common in patients with tinnitus.
One study116 attempted to resolve previous conflicting
reports of differences in grey matter volume in the sub-
callosal region of patients with tinnitus and controls by
measuring hearing thresholds up to 16 kHz, beyond the
clinical standard of 8 kHz117,118. No definitive group differ-
ences in grey matter volume or concentration were found;
however, grey matter concentration was negatively cor-
related with threshold increases at frequencies >8 kHz,
which was not measured by previous studies116. Afunc-
tional MRI (fMRI) study found that responses in the
auditory midbrain to suprathreshold sounds correlated
with abnormal sound level tolerance when the presence
of tinnitus was equal between groups, whereas tinnitus
itself (with abnormal sound level tolerance equal between
groups) was associated with increased activity only in
the primary auditory cortex119. Notwithstanding these
results, it remains to be determined whether the changes
in nonauditory brain areas reflect a predisposition to or
a consequence of tinnitus development and/or abnormal
sound level tolerance. In spite of these challenges, we
can conclude from neuroimaging studies that compared
indivi duals with and without tinnitus that tinnitus- related
changes in brain structure and function extend well
beyond classical auditory pathways, even if the precise
functional role of the different nonauditory structures in
tinnitus is not yet unambiguously elucidated.
Changes in functional connectivity between brain
regions have also been extensively investigated in tin-
nitus. Increased connectivity between the auditory cor-
tices and a frontoparietal attention network was found
by several EEG, magnetoencephalography (MEG), and
resting-state fMRI studies115,120–122. The results are con-
sistent with the hypothesis that conscious perception
of sound, including the phantom sound of tinnitus,
requires long-range connectivity between auditory
and attention-related areas123. Distress involved in tin-
nitus (measured by tinnitus severity questionnaires)
has been associated with enhanced activity and con-
nectivity between auditory and stress-related brain
areas124–126. Anotable brain area consistently high-
lighted in functional imaging studies of tinnitus is the
parahippo campal region120,122,127–130 (a structure known
to be involved in memory), which has increased con-
nectivity with the auditory cortex in patients with tin-
nitus that can be detected with resting-state EEG127,129
and fMRI120,131. This finding is consistent with the
hypothesis that auditory perception is based on predic-
tions about the external world that require information
about the organism’s history with sound4,122,132. Such a
prediction that is based on auditory memory that was
encoded before the hearing loss would not correspond
with input from the damaged cochlea, which could
then activate frontoparietal attentional mechanisms
to resolve these disparities. Other brain areas showing
increased activation in individuals with tinnitus are
the anterior cingulate cortex (ACC) and insula124,128.
Asthese two areas are key regions of the ‘salience
network’ (REF.133), increased activity in theACC and
insula may reflect the attribution of salience to the
tinnitus sound. On the basis of these findings, tinni-
tus has been proposed to involve abnormal activity in
multiple overlapping networks in the brain122. Some
of the heterogeneity seen in patients with tinnitus,
particularly with respect to comorbid distress behav-
iour, could reflect variation in the involvement of
specificnetworks.
Treatment of tinnitus
Cognitive–behavioural therapy
Several pharmacological and nonpharmacologi-
cal approaches for the treatment of tinnitus have
been tested, but according to a meta-analysis, none
showed convincing evidence for reducing the tinni-
tus percept. To date, the best-established treatment is
cognitive behavioural therapy (CBT). In a Cochrane
meta- analysis of eight trials involving a total of 468
individuals, CBT was found to improve quality of life
and reduce depression scores, even though it did not
reduce tinnitus loudness or eliminate the percept134.
Inclinical practice, CBT is often combined with sound
therapy (see below). A recent large randomized clinical
trial has shown that, compared with the usual treat-
ment of audiological assessment with rehabilitation and
counselling, a multidisciplinary stepped care approach
involving counselling, sound therapy and elements of
CBT results in a substantial benefit in terms of tinnitus
severity and health-related quality of life135.
Figure 4 | Mechanisms that contribute to increased StDP, SFR and synchrony
inthe DCN. Putative cellular and/or molecular mechanisms underlying changes in
neurotransmission mediated by glycine (Gly), and γ-aminobutyric acid (GABA).
changes involve N-methyl-
V
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Sound therapy
Several types of sound therapy have been devised with the
aim of masking tinnitus or suppressing it through puta-
tive neuroplasticity mechanisms. One approach provides
music that is modified to compensate for the individual’s
pattern of hearing loss; in another, music is ‘notched’ to
exclude energy close to the tinnitus frequency136,137. The
resulting edges in the frequency spectrum of the sound
stimulus are thought to distribute lateral inhibition into
the notched region, suppressing tinnitus-related neural
activity138. Acoustic co-ordinated reset neuromodulation
consists of auditory stimuli presented as short tones in a
random varying sequence above and below the tinnitus
frequency, with the goal of reducing tinnitus-related neu-
ronal hypersynchrony. A randomized placebo-controlled
pilot study in which this method was used in 63 patients
with tinnitus found significant reductions of tinnitus
loudness and perceived annoyance, as well as reduced
abnormal oscillatory activity measured by EEG139.
In contrast with the methods in which sound is pre-
sented passively, several forms of active auditory training
have been explored in an attempt to induce neuroplastic
changes. These studies have employed sounds of varying
spectral complexity with frequencies within or just below
that of the hearing loss or tinnitus frequencies140. On the
basis of results obtained in rats with GPIAS-measured
tinnitus, vagus nerve stimulation was paired with pres-
entation of sound in the range of functional hearing. This
intervention normalized tonotopic map organizationand
abolished behavioural evidence of tinnitus in rats69,
andproduced positive initial results in a human study
that involved 10 patients141. Another novel approach that
is currently being tested in humans applies paired audi-
tory and somatosensory stimulation at timing orders and
intervals chosen to suppress SFR and synchrony in audi-
tory pathways, exploiting the StDP demonstrated in DCN
in animal studies40. Although these innovative forms of
sound therapy have shown some positive results in pilot
studies, they are considered as experimental until results
are confirmed in large randomized controlled trials.
Reversing hearing loss
As hearing loss represents the most important trigger for
tinnitus, restoration of auditory input should reduce tin-
nitus. Accordingly, in the majority of patients with either
unilateral or bilateral profound sensorineural hearing
loss and tinnitus, cochlear implantation can suppress
tinnitus perception15. The efficacy of hearing aids for tin-
nitus reduction is less clear142, probably because hearing
aids cannot restore auditory nerve signals in the cases of
inner hair cell or ribbon synapse loss. Moreover, ampli-
fication of sound by hearing aids is limited in the higher
frequency range, in which most tinnitus patients have
hearing loss (and perceive their tinnitus). Accordingly,
recent studies have only shown a benefit in those patients
with a tinnitus pitch below 6 kHz143,144.
Pharmacological treatments
Several pharmacological agents have been investigated
for the treatment of tinnitus, but none has shown any
reduction of tinnitus beyond placebo effects145. Treatment
with antidepressants improved comorbid depressive
or anxiety disorders146, but did not reduce tinnitus147.
Ameta-analysis of anticonvulsant treatment with car-
bamazepine, gabapentin or lamotrigine did not reveal
additional benefits compared with placebo in controlled
studies148. Benzodiazepines have been reported to have
beneficial effects on tinnitus distress149, but long-term
data do not exist and routine use of benzodiazpines
cannot be recommented owing to the risk of develop-
ing dependency150,151. New approaches currently being
investigated include potassium channel modulators67,96
and intratympanic application of the NMDA receptor
antagonist esketamine152. As multiple signalling path-
ways could be involved in supporting brain network
activity in tinnitus, it has been suggested that pharmaco-
logical compounds or combinations of compounds that
act on multiple neurotransmitter systems could be more
effective at suppressing tinnitus than agents that target
specificreceptors145.
Neuromodulation
An expanding investigation of the neuronal mechanisms
of tinnitus is driving investigation of new techniques as
potential therapeutic approaches. Repetitive transcranial
magnetic stimulation (rTMS) uses the rhythmic appli-
cation of brief magnetic pulses that are delivered by a
coil placed on the scalp to modulate auditory cortical
activity. A recent meta-analysis demonstrates beneficial
effects of this approach, but the effect sizes are small and
the duration of treatment effects often remains limited153.
Better results were obtained with additional stimulation
of prefrontal brain areas154. It remains to be seen whether
further refinement of these approaches or other novel
treatment strategies will deliver superior improvements
in tinnitus behaviour and perception. Nevertheless, the
increasing number of innovative treatment approaches
based on recent advances in neuroscientific tinnitus
research is an encouraging development.
Integration of animal and human studies
Behavioural and functional imaging studies of human
patients with tinnitus have corroborated several of the
changes reported in animal studies, including increased
gain in central pathways17,155, reduced inhibition in the
auditory cortex156, and macroscopic tonotopic map reorg-
anization in the primary auditory cortex if audiometric
hearing loss is present157, though tinnitus patients with-
out audiometric hearing loss do not show macroscopic
cortical map reorganization158, suggesting the tonotopi-
cal reorganization could be more closely linked to hear-
ing loss than to tinnitus. However, depending on the
extent to which cortical neurons lose their input from
the ear, some degree of tuning shift would be expected
to accompany the tinnitus. Changes in sound-evoked
responses of primary auditory cortex neurons tuned
to frequency range of the tinnitus have been found to
track tinnitus suppression during residual inhibition in
patients with tinnitus159. This result is consistent with
studies in humans119 and animals70 that found tinnitus
to be associated with neural changes in this brain region.
Interestingly, sound-driven responses in the secondary
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(nonprimary) auditory cortex were larger in indivi-
duals with tinnitus than159 in controls, and did not track
residual inhibition. It was suggested that neural changes
occurring in nonprimary auditory cortex reflect dis-
inhibition of this region by attention, prediction failure,
or deafferentation. Persistent disinhibition of the audi-
tory cortex in tinnitus119 could explain why individuals
with tinnitus do not perform as well as controls on tasks
requiring top-down modulation of attention132.
A major contribution of research in humans has
been the identification of brain areas outside of auditory
pathways that are involved in tinnitus. Investigation of
nonauditory structures was motivated initially by sur-
prising results from functional imaging studies113,114 and
by prescient models of tinnitus that proposed an involve-
ment of limbic161,162 and somatosensory structures108.
More recently, MEG studies of brain network activity
in tinnitus have been guided by the concept of thalamo-
cortical dysrhythmia83, which proposes that tinnitus is
generated by changes in oscillatory brain activity that
occur in the thalamus and cortex when thalamic neu-
rons are hyperpolarized by deafferentation of auditory
pathways. As described earlier in this article, animals
with behavioural signs of tinnitus showed hyperpolar-
ization and a shift towards burst firing in MGB neurons82.
Early MEG research in humans, based on the concept of
thalamo cortical dysrhythmia, reported increased delta
and reduced alpha oscillations in the auditory cortex
of tinnitus subjects163–165. Human studies also identified
increased gamma oscillations163–165. Owing to the small
neural distances involved, gamma oscillations are likely
to reflect local communication within auditory struc-
tures, whereas slow-wave delta oscillations are likely
to represent longer-range communication between the
auditory cortex and nonauditory regions involved in
dispersed tinnitus network activity. One notable study
found that delta oscillations associated with increased
tinnitus perception extended beyond circumscribed
regions of auditory cortex to encompass large parts of
temporal, parietal and sensorimotor cortex, and lim-
bic regions166. Investigation of nonauditory regions in
animal studies is a new direction of research that could
provide insight into the role of nonauditory structures in
tinnitus. STDP is likely to be engaged by brain network
activity in nonauditory brain regions, although to date,
its role in tinnitus has been investigated only in auditory
and somatosensory pathways. Coupling between brain
regions expressed in electrical oscillatory activity has not
yet been investigated in animal models.
Conclusions
Research conducted in animal models suggests that tin-
nitus is generated by aberrant neural changes in central
auditory structures that occur when these structures
are deafferented by damage to the cochlea, as detected
with audiograms or more-sensitive measures. Neural
plasticity is involved in producing these changes, which
include increased spontaneous activity, bursting and
synchronous activity among neurons in subcortical
and cortical auditory regions, and strengthened inputs
from somatosensory to deafferented auditory structures.
Functional imaging of patients with tinnitus has shown
that neural changes are also observed in non auditory
brain regions involved in attention, emotion and mem-
ory. A continuing challenge for research in human and
animal models will be to distinguish between neural
changes that are essential for tinnitus perception and
those that are related to hearing loss, hyperacusis or
distress behaviour, which are often seen in patients
withtinnitus.
1. Axelsson,A. &Ringdahl,A. Tinnitus—a study of its
prevalence and characteristics. Br. J.Audiol. 23,
53–62 (1989).
2. Gallus,S. etal. Prevalence and determinants of
tinnitus in the Italian adult population.
Neuroepidemiology 45, 12–19 (2015).
3. Park,B. etal. Analysis of the prevalence of and
riskfactors for tinnitus in a young population.
Otol.Neurotol. 35, 1218–1222 (2014).
4. Roberts,L.E. etal. Ringing ears: the neuroscience
oftinnitus. J.Neurosci. 30, 14972–14979 (2010).
5. Reed,G.F. An audiometric study of two hundred
cases of subjective tinnitus. AMA Arch. Otolaryngol.
71, 84–94 (1960).
6. Vernon,J. Attemps to relieve tinnitus. J.Am. Audiol.
Soc. 2, 124–131 (1977).
7. Hallberg,L.R. &Erlandsson,S.I. Tinnitus
characteristics in tinnitus complainers and
noncomplainers. Br. J.Audiol. 27, 19–27 (1993).
8. Landgrebe,M. etal. The Tinnitus Research Initiative
(TRI) database: a new approach for delineation of
tinnitus subtypes and generation of predictors for
treatment outcome. BMC Med. Inform. Decis. Mak.
10, 42 (2010).
9. De Ridder,D., Elgoyhen,A.B., Romo,R.
&Langguth,B. Phantom percepts: tinnitus and pain
as persisting aversive memory networks. Proc. Natl
Acad. Sci. USA 108, 8075–8080 (2011).
10. Lockwood,A.H., Salvi,R.J. &Burkard,R.F.
Tinnitus.N.Engl. J.Med. 347, 904–910 (2002).
11. Mardini,M.K. Ear-clicking ‘tinnitus’ responding
tocarbamazepine. N.Engl. J.Med. 317, 1542
(1987).
12. House,J.W. &Brackmann,D.E. Tinnitus: surgical
treatment. Ciba Found. Symp. 85, 204–216 (1981).
13. Baguley,D.M., Axon,P., Winter,I.M. &Moffat,D.A.
The effect of vestibular nerve section upon tinnitus.
Clin. Otolaryngol. 27, 219–226 (2002).
14. Soleymani,T. etal. Surgical approaches to tinnitus
treatment: a review and novel approaches.
Surg.Neurol. Int. 2, 154 (2011).
15. Blasco,M.A. &Redleaf,M.I. Cochlear implantation
in unilateral sudden deafness improves tinnitus and
speech comprehension: meta-analysis and systematic
review. Otol. Neurotol. 35, 1426–1432 (2014).
16. Barnea,G., Attias,J., Gold,S. &Shahar,A. Tinnitus
with normal hearing sensitivity: extended high-
frequency audiometry and auditory-nerve brain-stem-
evoked responses. Audiology 29, 36–45 (1990).
17. Schaette,R. &McAlpine,D. Tinnitus with a normal
audiogram: physiological evidence for hidden hearing
loss and computational model. J.Neurosci. 31,
13452–13457 (2011).
18. Roberts,L.E., Moffat,G., Baumann,M., Ward,L.M.
&Bosnyak,D.J. Residual inhibition functions
overlaptinnitus spectra and the region of auditory
threshold shift. J.Assoc. Res. Otolaryngol. 9,
417–435 (2008).
19. Kujawa,S.G. &Liberman,M.C. Adding insult to
injury: cochlear nerve degeneration after ‘temporary’
noise-induced hearing loss. J.Neurosci. 29,
14077–14085 (2009).
20. Furman,A.C., Kujawa,S.G. &Liberman,M.C.
Noise-induced cochlear neuropathy is selective for
fibers with low spontaneous rates. J.Neurophysiol.
110 , 577–586 (2013).
21. Sergeyenko,Y., Lall,K., Liberman,M.C.
&Kujawa,S.G. Age-related cochlear synaptopathy:
anearly-onset contributor to auditory functional
decline. J.Neurosci. 33, 13686–13694 (2013).
22. Kujawa,S.G. &Liberman,M.C. Synaptopathy in
thenoise-exposed and aging cochlea: primary
neuraldegeneration in acquired sensorineural
hearingloss. Hear. Res. 330(Pt. B), 191–199
(2015).
23. Lin,H.W., Furman,A.C., Kujawa,S.G.
&Liberman,M.C. Primary neural degeneration in
theguinea pig cochlea after reversible noise-induced
threshold shift. J.Assoc. Res. Otolaryngol. 12,
605–616 (2011).
24. Gu,J.W., Herrmann,B.S., Levine,R.A.
&Melcher,J.R. Brainstem auditory evoked potentials
suggest a role for the ventral cochlear nucleus in
tinnitus. J.Assoc. Res. Otolaryngol. 13, 819–833
(2012).
25. Norena,A., Micheyl,C., Chery-Croze,S. &Collet,L.
Psychoacoustic characterization of the tinnitus
spectrum: implications for the underlying mechanisms
of tinnitus. Audiol. Neurootol. 7, 358–369
(2002).
26. Sereda,M. etal. Re-examining the relationship
between audiometric profile and tinnitus pitch.
Int.J.Audiol. 50, 303–312 (2011).
27. Zhou,X., Henin,S., Long,G.R. &Parra,L.C.
Impairedcochlear function correlates with the
presence of tinnitus and its estimated spectral profile.
Hear. Res. 277, 107–116 (2011).
28. Terry,A.M., Jones,D.M., Davis,P.R., &Slater,R.
Parametric studies of tinnitus masking and residual
inhibition. Br. J. Audiol. 17, 245–256 (1983).
29. Roberts,L.E. Residual inhibition. Prog. Brain Res.
166, 487–495 (2007).
30. Stolzberg,D., Salvi,R.J. &Allman,B.L.
Salicylatetoxicity model of tinnitus. Front. Syst.
Neurosci. 6, 28 (2012).
REVIEWS
NATURE REVIEWS
|
NEUROLOGY ADVANCE ONLINE PUBLICATION
|
9
© 2016 Macmillan Publishers Limited. All rights reserved
31. Heffner,H.E. &Heffner,R.S. in Tinnitus
(edsEggermont,J.J. etal.) Ch. 2 487–495
(Springer,2012).
32. Turner,J., Larsen,D., Hughes,L., Moechars,D.
&Shore,S. Time course of tinnitus development
following noise exposure in mice. J.Neurosci. Res. 90,
1480–1488 (2012).
33. Turner,J.G. etal. Gap detection deficits in rats
withtinnitus: a potential novel screening tool.
Behav.Neurosci. 120, 188–195 (2006).
34. Dehmel,S., Eisinger,D. &Shore,S.E. Gap prepulse
inhibition and auditory brainstem-evoked potentials
asobjective measures for tinnitus in guinea pigs.
Front.Syst. Neurosci. 6, 42 (2012).
35. Berger,J.I., Coomber,B., Shackleton,T.M.,
Palmer,A.R. &Wallace,M.N. A novel behavioural
approach to detecting tinnitus in the guinea pig.
J.Neurosci. Methods 213, 188–195 (2013).
36. Hayes,S.H., Radziwon,K.E., Stolzberg,D.J.
&Salvi,R.J. Behavioral models of tinnitus and
hyperacusis in animals. Front. Neurol. 5, 179 (2014).
37. von der Behrens,W. Animal models of subjective
tinnitus. Neural Plast. 2014, 741452 (2014).
38. Galazyuk,A. &Hebert,S. Gap-prepulse inhibition
ofthe acoustic startle reflex (GPIAS) for tinnitus
assessment: current status and future directions.
Front.Neurol. 6, 88 (2015).
39. Dehmel,S., Pradhan,S., Koehler,S., Bledsoe,S.
&Shore,S. Noise overexposure alters long-term
somatosensory-auditory processing in the dorsal
cochlear nucleus—possible basis for tinnitus-related
hyperactivity? J.Neurosci. 32, 1660–1671 (2012).
40. Koehler,S.D. &Shore,S.E. Stimulus timing-
dependent plasticity in dorsal cochlear nucleus is
altered in tinnitus. J.Neurosci. 33, 19647–19656
(2015).
41. Wu,C., Martel,D. &Shore,S. Increased synchrony
andbursting of dorsal cochlear nucleus fusiform cells
correlates with tinnitus. J.Neurosci. http://dx.doi.org/
10.1523/JNEUROSCI.3960-15.2016
42. Kalappa,B.I. etal. Potent KCNQ2/3-specific channel
activator suppresses invivo epileptic activity and
prevents the development of tinnitus. J.Neurosci. 35,
8829–8842 (2015).
43. Li,S., Kalappa,B.I. &Tzounopoulos,T. Noise-induced
plasticity of KCNQ2/3 and HCN channels underlies
vulnerability and resilience to tinnitus. eLIFE 4,
e07242 (2015).
44. Middleton,J.W. etal. Mice with behavioral evidence
of tinnitus exhibit dorsal cochlear nucleus
hyperactivity because of decreased GABAergic
inhibition. Proc. Natl Acad. Sci. USA 10 8,
7601–7606 (2011).
45. Brozoski,T.J., Bauer,C.A. &Caspary,D.M. Elevated
fusiform cell activity in the dorsal cochlear nucleus of
chinchillas with psychophysical evidence of tinnitus.
J.Neurosci. 22, 2383–2390 (2002).
46. Kaltenbach,J.A., Zacharek,M.A., Zhang,J.
&Frederick,S. Activity in the dorsal cochlear nucleus
of hamsters previously tested for tinnitus following
intense tone exposure. Neurosci. Lett. 355, 121–125
(2004).
47. Xiong,H. etal. Hidden hearing loss in tinnitus patients
with normal audiograms: implications for the origin of
tinnitus. Lin Chung Er Bi Yan Hou Tou Jing Wai Ke Za
Zhi 27, 362–365 (in Chinese) (2013).
48. Vogler,D.P., Robertson,D. &Mulders,W.H.
Hyperactivity following unilateral hearing loss in
characterized cells in the inferior colliculus.
Neuroscience 265C, 28–36 (2014).
49. Sumner,C.J., Tucci,D.L. &Shore,S.E. Responses of
ventral cochlear nucleus neurons to contralateral
sound after conductive hearing loss. J.Neurophysiol.
94, 4234–4243 (2005).
50. Bledsoe,S.C.Jr etal. Ventral cochlear nucleus
responses to contralateral sound are mediated by
commissural and olivocochlear pathways.
J.Neurophysiol. 102, 886–900 (2009).
51. Kaltenbach,J.A. Summary of evidence pointing to a
role of the dorsal cochlear nucleus in the etiology of
tinnitus. Acta Otolaryngol. Suppl. 556, 20–26 (2006).
52. Wu,C., Stefanescu,R.A., Martel,D.T. &Shore,S.E.
Tinnitus: maladaptive auditory-somatosensory
plasticity. Hear. Res. http://dx.doi.org/10.1016/
j.heares.2015.06.005 (2015).
53. Robertson,D., Bester,C., Vogler,D. &Mulders,W.H.
Spontaneous hyperactivity in the auditory midbrain:
relationship to afferent input. Hear. Res. 295,
124–129 (2013).
54. Mulders,W.H., Barry,K. M. &Robertson, D. Effects
of furosemide on cochlear neural activity central
hyperactivity and behavioural tinnitus after cochlear
trauma in guinea pig. PLoS ONE 9, e97948 (2014).
55. Ropp,T.J., Tiedemann,K.L., Young,E.D. &May,B.J.
Effects of unilateral acoustic trauma on tinnitus-related
spontaneous activity in the inferior colliculus. J.Assoc.
Res. Otolaryngol. 15, 1007–1022 (2014).
56. Coomber,B. etal. Neural changes accompanying
tinnitus following unilateral acoustic trauma in the
guinea pig. Eur. J.Neurosci. 40, 2427–2441 (2014).
57. Brozoski,T.J., Wisner,K.W., Sybert,L.T.
&Bauer,C.A. Bilateral dorsal cochlear nucleus lesions
prevent acoustic-trauma induced tinnitus in an animal
model. J.Assoc. Res. Otolaryngol. 13, 55–66 (2011).
58. Manzoor,N.F. etal. Noise-induced hyperactivity in the
inferior colliculus: its relationship with hyperactivity in
the dorsal cochlear nucleus. J.Neurophysiol. 108,
976–988 (2012).
59. Brozoski,T.J. &Bauer,C.A. The effect of dorsal
cochlear nucleus ablation on tinnitus in rats. Hear Res.
206, 227–236 (2005).
60. Mulders,W. H., Ding,D., Salvi,R. &Robertson, D.
Relationship between auditory thresholds central
spontaneous activity, and hair cell loss after acoustic
trauma. J.Comp. Neurol. 519, 2637–2647 (2011).
61. Zacharek,M.A., Kaltenbach,J.A., Mathog,T.A.
&Zhang,J. Effects of cochlear ablation on noise
induced hyperactivity in the hamster dorsal cochlear
nucleus: implications for the origin of noise induced
tinnitus. Hear. Res. 172, 137–143 (2002).
62. Zhang,J.S., Kaltenbach,J.A., Godfrey,D.A.
&Wang,J. Origin of hyperactivity in the hamster
dorsal cochlear nucleus following intense sound
exposure. J.Neurosci. Res. 84, 819–831 (2006).
63. Manzoor,N.F., Gao,Y., Licari,F. &Kaltenbach,J.A.
Comparison and contrast of noise-induced
hyperactivity in the dorsal cochlear nucleus and inferior
colliculus. Hear. Res. 295, 114–123 (2013).
64. Anderson,L.A., Malmierca,M.S. &Wallace,M. N.
&Palmer, A. R. Evidence for a direct, short latency
projection from the dorsal cochlear nucleus to the
auditory thalamus in the guinea pig. Eur. J.Neurosci.
24, 491–498 (2006).
65. Malmierca,M.S., Merchan,M.A., Henkel,C.K.
&Oliver,D.L. Direct projections from cochlear nuclear
complex to auditory thalamus in the rat. J.Neurosci.
22, 10891–10897 (2002).
66. Schofield,B.R., Mellott,J.G. &Motts,S.D.
Subcollicular projections to the auditory thalamus
andcollateral projections to the inferior colliculus.
Front. Neuroanat. 8, 70 (2014).
67. Kalappa,B.I., Brozoski,T.J., Turner,J.G.
&Caspary,D.M. Single unit hyperactivity and bursting
in the auditory thalamus of awake rats directly
correlates with behavioural evidence of tinnitus.
J.Physiol. 592, 5065–5078 (2014).
68. Eggermont,J.J. &Roberts,L.E. The neuroscience of
tinnitus. Trends Neurosci. 27, 676–682 (2004).
69. Engineer,N.D. etal. Reversing pathological neural
activity using targeted plasticity. Nature 470,
101–104 (2011).
70. Basura,G., Koehler,S. &Shore,S.E. Bimodal stimulus
timing-dependent plasticity in primary auditory cortex
is altered after noise exposure with and without
tinnitus. J.Neurophysiol. 114 , 3064–3075 (2015).
71. Ilin,V., Malyshev,A., Wolf,F. &Volgushev,M. Fast
computations in cortical ensembles require rapid
initiation of action potentials. J.Neurosci. 33,
2281–2292 (2013).
72. Kaltenbach,J.A. Tinnitus: models and mechanisms.
Hear. Res. 276, 52–60 (2011).
73. Bauer,C.A., Turner,J.G., Caspary,D.M., Myers,K.S.
&Brozoski,T.J. Tinnitus and inferior colliculus activity
in chinchillas related to three distinct patterns of
cochlear trauma. J.Neurosci. Res. 86, 2564–2578
(2008).
74. Robertson,D. &Irvine,D.R. Plasticity of frequency
organization in auditory cortex of guinea pigs with
partial unilateral deafness. J.Comp. Neurol. 282,
456–471 (1989).
75. Norena,A.J., Tomita,M. &Eggermont,J.J. Neural
changes in cat auditory cortex after a transient pure-
tone trauma. J.Neurophysiol. 90, 2387–2401 (2003).
76. Basura,G.J., Koehler,S.D. &Shore,S.E. Bimodal
stimulus timing dependent plasticity in primary
auditory cortex is altered after noise exposure with
and without tinnitus. J. Neurophysiol. 114 ,
3064–3075 (2015).
77. Wang,H. etal. Plasticity at glycinergic synapses in
dorsal cochlear nucleus of rats with behavioral
evidence of tinnitus. Neuroscience 164, 747–759
(2009).
78. Zeng,C., Nannapaneni,N., Zhou,J., Hughes,L.F.
&Shore,S. Cochlear damage changes the distribution
of vesicular glutamate transporters associated with
auditory and nonauditory inputs to the cochlear
nucleus. J.Neurosci. 29, 4210–4217 (2009).
79. Barker,M. etal. Acoustic overexposure increases the
expression of VGLUT-2 mediated projections from the
lateral vestibular nucleus to the dorsal cochlear
nucleus. PLoS ONE 7, e35955 (2012).
80. Zeng,C., Yang,Z., Shreve,L., Bledsoe,S. &Shore,S.
Somatosensory projections to cochlear nucleus are
upregulated after unilateral deafness. J.Neurosci. 32,
15791–15801 (2012).
81. Schofield,B.R., Motts,S.D., Mellott,J.G.
&Foster,N.L. Projections from the dorsal and
ventralcochlear nuclei to the medial geniculate body.
Front. Neuroanat. 8, 10 (2014).
82. Sametsky,E.A., Turner,J.G., Larsen,D., Ling,L.
&Caspary,D.M. Enhanced GABAA-mediated tonic
inhibition in auditory thalamus of rats with behavioral
evidence of tinnitus. J.Neurosci. 35, 9369–9380
(2015).
83. Llinas,R.R., Ribary,U., Jeanmonod,D., Kronberg,E.
&Mitra,P.P. Thalamocortical dysrhythmia: a
neurological and neuropsychiatric syndrome
characterized by magnetoencephalography. Proc. Natl
Acad. Sci. USA 96, 15222–15227 (1999).
84. Tzounopoulos,T., Kim,Y., Oertel,D. &Trussell, L. O.
Cell-specific, spike timing-dependent plasticities in the
dorsal cochlear nucleus. Nat. Neurosci. 7, 719–725
(2004).
85. Koehler,S.D. &Shore,S.E. Stimulus-timing
dependent multisensory plasticity in the guinea pig
dorsal cochlear nucleus. PLoS ONE 8, e59828 (2013).
86. Roberts,P.D. &Leen,T.K. Anti-hebbian spike-timing-
dependent plasticity and adaptive sensory processing.
Front. Comput. Neurosci. 4, 156 (2010).
87. Stefanescu,R.A. &Shore,S.E. NMDA receptors
mediate stimulus timing dependent plasticity and
neural synchrony in dorsal cochlear nucleus.
Front.Syst. Neurosci. 9, 75 (2015).
88. Wu,C., Martel,D. &Shore,S. Transcutaneous
induction of stimulus timing dependent plasticity in
dorsal cochlear nucleus. Front. Syst. Neurosci. 9, 116
(2015).
89. Kaltenbach,J.A. &Zhang,J. Intense sound-induced
plasticity in the dorsal cochlear nucleus of rats:
evidence for cholinergic receptor upregulation.
Hear.Res. 226, 232–243 (2007).
90. Jin,Y.M., Godfrey,D.A., Wang,J. &Kaltenbach,J.A.
Effects of intense tone exposure on choline
acetyltransferase activity in the hamster cochlear
nucleus. Hear. Res. 216–217, 168–175 (2006).
91. D’Amour,J., A. &Froemke,R.C. Inhibitory and
excitatory spike-timing-dependent plasticity in the
auditory cortex. Neuron 86, 514–528 (2015).
92. Tass,P.A. &Popovych,O.V. Unlearning tinnitus-
related cerebral synchrony with acoustic coordinated
reset stimulation: theoretical concept and modelling.
Biol. Cybern. 106, 27–36 (2012).
93. Talathi,S.S., Hwang,D.U. &Ditto,W.L. Spike timing
dependent plasticity promotes synchrony of inhibitory
networks in the presence of heterogeneity. J.Comput.
Neurosci. 25, 262–281 (2008).
94. Tziridis,K. etal. Noise trauma induced neural plasticity
throughout the auditory system of mongolian gerbils:
differences between tinnitus developing and non-
developing animals. Front. Neurol. 6, 22 (2015).
95. Singer,W. etal. Noise-induced inner hair cell
ribbonloss disturbs central arc mobilization: a novel
molecular paradigm for understanding tinnitus.
Mol.Neurobiol. 47, 261–279 (2013).
96. Li,S., Choi,V. &Tzounopoulos,T. Pathogenic plasticity
of KV7.2/3 channel activity is essential for the induction
of tinnitus. Proc. Natl Acad. Sci. USA 11 0 , 9980–9985
(2013).
97. Dehmel,S., Cui,Y.L. &Shore,S.E. Cross-modal
interactions of auditory and somatic inputs in the
brainstem and midbrain and their imbalance in tinnitus
and deafness. Am. J.Audiol. 17, S193–209 (2008).
98. Wu,C., Stefanescu,R.A., Martel,D.T. &Shore,S.E.
Listening to another sense: somatosensory integration
in the auditory system. Cell Tissue Res. 361, 233–250
(2014).
99. Haenggeli,C.A., Pongstaporn,T., Doucet,J.R.
&Ryugo,D.K. Projections from the spinal trigeminal
nucleus to the cochlear nucleus in the rat. J.Comp.
Neurol. 484, 191–205 (2005).
100. Wright,D.D. &Ryugo,D.K. Mossy fiber projections
from the cuneate nucleus to the cochlear nucleus in the
rat. J.Comp. Neurol. 365, 159–172 (1996).
REVIEWS
10
|
ADVANCE ONLINE PUBLICATION www.nature.com/nrneurol
© 2016 Macmillan Publishers Limited. All rights reserved
101. Zhan,X., Pongstaporn,T. &Ryugo,D.K. Projections
of the second cervical dorsal root ganglion to the
cochlear nucleus in rats. J.Comp. Neurol. 496,
335–348 (2006).
102. Zeng,C., Shroff,H. &Shore,S.E. Cuneate and spinal
trigeminal nucleus projections to the cochlear nucleus
are differentially associated with vesicular glutamate
transporter-2. Neuroscience 176, 142–151 (2011).
103. Shore,S.E., Koehler,S., Oldakowski,M., Hughes,L.F.
&Syed,S. Dorsal cochlear nucleus responses to
somatosensory stimulation are enhanced after noise-
induced hearing loss. Eur. J.Neurosci. 27, 155–168
(2008).
104. Zhou,J., Nannapaneni,N. &Shore,S. Vessicular
glutamate transporters 1 and 2 are differentially
associated with auditory nerve and spinal trigeminal
inputs to the cochlear nucleus. J.Comp. Neurol. 500,
777–787 (2007).
105. Heeringa,A., Stefanescu,R.A., Raphael,Y.
&Shore,S. Altered vesicular glutamate transporter
distributions in the mouse cochlear nucleus following
cochlear insult. Neuroscience 315, 114–124 (2016).
106. Basura,G.J., Koehler,S.D. &Shore,S.E.
Multi-sensory integration in brainstem and auditory
cortex. Brain Res. 1485, 95–107 (2012).
107. Sanchez,T.G. &Rocha,C.B. Diagnosis and
management of somatosensory tinnitus: review article.
Clinics (Sao Paulo) 66, 1089–1094 (2011).
108. Levine,R.A., Abel,M. &Cheng,H. CNS
somatosensory–auditory interactions elicit or
modulate tinnitus. Exp. Brain Res. 153, 643–648
(2003).
109. Zhou,J. &Shore,S. Projections from the trigeminal
nuclear complex to the cochlear nuclei: a retrograde
and anterograde tracing study in the guinea pig.
J.Neurosci. Res. 78, 901–907 (2004).
110 . Zhou,J. &Shore,S. Convergence of spinal trigeminal
and cochlear nucleus projections in the inferior
colliculus of the guinea pig. J.Comp. Neurol. 495,
100–112 (2006).
111. Wallhausser-Franke,E. etal. Expression of c-fos in
auditory and non-auditory brain regions of the gerbil
after manipulations that induce tinnitus. Exp. Brain
Res. 153, 649–654 (2003).
112 . Adjamian,P., Hall,D.A., Palmer,A.R., Allan,T.W.
&Langers,D.R. Neuroanatomical abnormalities
inchronic tinnitus in the human brain.
Neurosci.Biobehav. Rev. 45C, 119–133 (2014).
113 . Lockwood,A.H. etal. The functional neuroanatomy of
tinnitus: evidence for limbic system links and neural
plasticity. Neurology 50, 114–120 (1998).
114 . Pinchoff,R.J., Burkard,R.F., Salvi,R.J., Coad,M.L.
&Lockwood,A.H. Modulation of tinnitus by voluntary
jaw movements. Am. J.Otol. 19, 785–789 (1998).
115 . Vanneste,S. &De Ridder,D. The auditory and non-
auditory brain areas involved in tinnitus. An emergent
property of multiple parallel overlapping subnetworks.
Front. Syst. Neurosci. 6, 31 (2012).
116 . Melcher,J.R. &Knudson,I. M. &Levine, R. A.
Subcallosal brain structure: correlation with hearing
threshold at supra-clinical frequencies (>8 kHz), but
not with tinnitus. Hear. Res. 295, 79–86 (2013).
117 . Landgrebe,M. etal. Structural brain changes in
tinnitus: grey matter decrease in auditory and non-
auditory brain areas. NeuroImage 46, 213–218
(2009).
118 . Muhlau,M. etal. Structural brain changes in tinnitus.
Cereb. Cortex 16, 1283–1288 (2006).
119 . Gu,J.W., Halpin,C.F., Nam,E.C., Levine,R.A.
&Melcher, J. R. Tinnitus,diminished sound-level
tolerance, and elevated auditory activity in humans
with clinically normal hearing sensitivity.
J.Neurophysiol. 104, 3361–3370 (2010).
120. Maudoux,A. etal. Auditory resting-state network
connectivity in tinnitus: a functional MRI study.
PLoSONE 7, e36222 (2012).
121. Schlee,W. etal. Mapping cortical hubs in tinnitus.
BMC Biol. 7, 80 (2009).
122. De Ridder,D. etal. An integrative model of
auditoryphantom perception: tinnitus as a unified
percept ofinteracting separable subnetworks.
Neurosci.Biobehav. Rev. 44C, 16–32 (2014).
123. de Lafuente,V. &Romo,R. Neuronal correlates of
subjective sensory experience. Nat. Neurosci. 8,
1698–1703 (2005).
124. Golm,D., Schmidt-Samoa,C., Dechent,P.
&Kroner-Herwig,B. Neural correlates of tinnitus
related distress: an fMRI-study. Hear. Res. 295,
87–99 (2013).
125. Vanneste,S. etal. The neural correlates of tinnitus-
related distress. NeuroImage 52, 470–480 (2010).
126. Schecklmann,M. etal. Auditory cortex is implicated
intinnitus distress: a voxel-based morphometry study.
Brain Struct. Funct. 218, 1061–1070 (2013).
127. Vanneste,S., Plazier,M., van der Loo,E.,
Van de Heyning,P. &De Ridder,D. The difference
between uni- and bilateral auditory phantom percept.
Clin. Neurophysiol. 122, 578–587 (2011).
128. Carpenter-Thompson,J.R., Akrofi,K., Schmidt,S.A.,
Dolcos,F. &Husain,F.T. Alterations of the emotional
processing system may underlie preserved rapid
reaction time in tinnitus. Brain Res. 1567, 28–41
(2014).
129. Vanneste,S., Heyning,P.V. &Ridder,D.D.
Contralateral parahippocampal gamma-band activity
determines noise-like tinnitus laterality: a region of
interest analysis. Neuroscience 199, 481–490 (2011).
130. Schecklmann,M. etal. Neural correlates of tinnitus
duration and distress: a positron emission tomography
study. Hum. Brain Mapp. 34, 233–240 (2013).
131. Maudoux,A. etal. Connectivity graph analysis of the
auditory resting state network in tinnitus. Brain Res.
1485, 10–21 (2012).
132. Roberts,L.E., Husain,F.T. &Eggermont,J.J. Role of
attention in the generation and modulation of tinnitus.
Neurosci. Biobehav Rev. 37, 1754–1773 (2013).
133. Menon,V. &Uddin, Saliency,L. Q. Sailency, switching,
attention and control: a network model of insula
function. Brain Struct. Funct. 214, 655–667 (2010).
134. Martinez-Devesa,P., Perera,R., Theodoulou,M.
&Waddell,A. Cognitive behavioural therapy for
tinnitus. Cochrane Database Syst. Rev. CD005233
(2010).
135. Cima,R.F. etal. Specialised treatment based on
cognitive behaviour therapy versus usual care for
tinnitus: a randomised controlled trial. Lancet 379,
1951–1959 (2012).
136. Davis,P.B., Paki,B. &Hanley,P.J. Neuromonics
tinnitus treatment: third clinical trial. Ear. Hear. 28,
242–259 (2007).
137. Vanneste,S. etal. Does enriched acoustic environment
in humans abolish chronic tinnitus clinically and
electrophysiologically? A double blind placebo
controlled study. Hear. Res. 296, 141–148 (2013).
138. Okamoto,H., Stracke,H., Stoll,W. &Pantev,C.
Listening to tailor-made notched music reduces tinnitus
loudness and tinnitus-related auditory cortex activity.
Proc. Natl Acad. Sci. USA 107, 1207–1210 (2010).
139. Tass,P.A., Adamchic,I., Freund,H.J., von
Stackelberg,T. &Hauptmann,C. Counteracting
tinnitusby acoustic coordinated reset neuromodulation.
Restor. Neurol. Neurosci. 30, 137–159 (2012).
140. Hoare,D.J., Searchfield,G.D., El Refaie,A.
&Henry,J.A. Sound therapy for tinnitus management:
practicable options. J.Am. Acad. Audiol. 25, 62–75
(2014).
141. De Ridder,D., Vanneste,S., Engineer,N.D.
&Kilgard,M.P. Safety and efficacy of vagus nerve
stimulation paired with tones for the treatment of
tinnitus: a case series. Neuromodulation 17, 170–179
(2014).
142. Hoare,D.J., Edmondson-Jones,M., Sereda,M.,
Akeroyd,M.A. &Hall,D. Amplification with hearing
aids for patients with tinnitus and co-existing hearing
loss. Cochrane Database Syst. Rev. 1, C D010151
(2014).
143. Schaette,R., Konig,O., Hornig,D., Gross,M.
&Kempter,R. Acoustic stimulation treatments against
tinnitus could be most effective when tinnitus pitch is
within the stimulated frequency range. Hear. Res. 269,
95–101 (2010).
144. McNeill,C., Tavora-Vieira,D., Alnafjan,F.
&Searchfield,G. D. &Welch,D. Tinnitus pitch,
masking, and the effectiveness of hearing aids for
tinnitus therapy. Int. J.Audiol. 51, 914–919 (2012).
145. Langguth,B. &Elgoyhen,A.B. Current pharmacological
treatments for tinnitus. Expert Opin. Pharmacother.
13, 2495–2509 (2012).
146. Zoger,S., Svedlund,J. &Holgers, K. M. The effects of
sertraline on severe tinnitus suffering— a randomized,
double-blind, placebo-controlled study. J.Clin.
Psychopharmacol. 26, 32–39 (2006).
147. Baldo,P., Doree,C., Molin,P., McFerran,D. &Cecco,S.
Antidepressants for patients with tinnitus. Cochrane
Database Syst. Rev. 9, CD003853 (2012).
148. Hoekstra,C.E., Rynja,S.P., van Zanten,G.A.
&Rovers,M.M. Anticonvulsants for tinnitus.
Cochrane Database Syst. Rev. 6, CD007960 (2011).
149. Han,S.S. etal. Clonazepam quiets tinnitus:
arandomised crossover study with Ginkgo biloba.
J.Neurol. Neurosurg. Psychiatry 83, 821–827
(2012).
150. Tunkel,D.E. etal. Clinical practice guideline: tinnitus.
Otolaryngol. Head Neck Surg. 151, S1–S40 (2014).
151. Zenner,H.P. etal. On the interdisciplinary S3
guidelines for the treatment of chronic idiopathic
tinnitus. HNO 63, 419–427 (in German) (2015).
152. van de Heyning,P. etal. Efficacy and safety of AM-101
in the treatment of acute inner ear tinnitus—a
double-blind, randomized, placebo-controlled phaseII
study. Otol. Neurotol. 35, 589–597 (2014).
153. Soleimani,R., Jalali,M.M. &Hasandokht,T.
Therapeutic impact of repetitive transcranial magnetic
stimulation (rTMS) on tinnitus: a systematic review
and meta-analysis. Eur. Arch. Otorhinolaryngol. http://
dx.doi.org/10.1007/s00405-015-3642-5 (2015).
154. Lehner,A. etal. Multisite rTMS for the treatment of
chronic tinnitus: stimulation of the cortical tinnitus
network—a pilot study. Brain Topogr. 26, 501–510
(2013).
155. Hebert,S., Fournier,P. &Norena,A. The auditory
sensitivity is increased in tinnitus ears. J.Neurosci.
33, 2356–2364 (2013).
156. Diesch,E., Andermann,M., Flor,H. &Rupp, A.
Interaction among the components of multiple
auditory steady-state responses: enhancement in
tinnitus patients, inhibition in controls. Neuroscience
167, 540–553 (2010).
157. Wienbruch,C., Paul,I., Weisz,N., Elbert,T.
&Roberts,L.E. Frequency organization of the 40-Hz
auditory steady-state response in normal hearing and
in tinnitus. NeuroImage 33, 180–194 (2006).
158. Langers,D.R., de Kleine,E. &van Dijk,P. Tinnitus
does not require macroscopic tonotopic map
reorganization. Front. Syst. Neurosci. 6, 2 (2012).
159. Roberts,L.E., Bosnyak,D.J., Bruce,I.C.,
Gander,P.E. &Paul,B.T. Evidence for differential
modulation of primary and nonprimary auditory
cortex by forward masking in tinnitus. Hear. Res. 327,
9–27 (2015).
160. Paul,B.T., Bruce,I.C., Bosnyak,D.J., Thompson,D.C.
&Roberts,L.E. Modulation of electrocortical brain
activity by attention in individuals with and without
tinnitus. Neural Plast. 2014, 127824 (2014).
161. Jastreboff,P.J. Phantom auditory perception
(tinnitus): mechanisms of generation and perception.
Neurosci. Res. 8, 221–254 (1990).
162. Leaver,A.M. etal. Cortico-limbic morphology
separates tinnitus from tinnitus distress. Front. Syst.
Neurosci. 6, 21 (2012).
163. Weisz,N. etal. The neural code of auditory phantom
perception. J.Neurosci. 27, 1479–1484 (2007).
164. Weisz,N., Moratti,S., Meinzer,M., Dohrmann,K.
&Elbert,T. Tinnitus perception and distress is related
to abnormal spontaneous brain activity as measured
by magnetoencephalography. PLoS Med. 2, e153
(2005).
165. Adjamian,P., Sereda,M., Zobay,O., Hall,D.A.
&Palmer,A.R. Neuromagnetic indicators of tinnitus
and tinnitus masking in patients with and without
hearing loss. J.Assoc. Res. Otolaryngol. 13, 715–731
(2012).
166. Sedley,W. etal. Intracranial mapping of a cortical
tinnitus system using residual inhibition. Curr. Biol. 25,
1208–1214 (2015).
Acknowledgements
The authors have received funding from the Tinnitus Research
Initiative. S.E.S. has received funding from the NIH (grants
NIHR01-DC004825, NIH P30-DC05188). L.E.R. has
received funding from the Natural Sciences and Engineering
Research Council of Canada and the Canadian Institutes of
Health Research and the American Tinnitus Association. B.L.
has received funding from the European Commission (TINNET
COST Action BM 1306). We thank Calvin Wu and Amarins
Heeringa for excellent assistance with graphics.
Author contributions
All authors researched literature for the article, provided sub-
stantial contributions to discussion of content and wrote,
reviewed and edited the manuscript.
Competing interests statement
B.L. has received honoraria for speaking and consultancy
from ANM, AstraZeneca, Autifony, Gerson Lehrman Group,
Lundbeck, McKinsey, Merz, Magventure, Novartis, Neuromod
Devices, Pfizer and Servier, grants and research support from
AstraZeneca, Cerbomed, Deymed, Magventure, Sivantos and
Otonomy, and travel and accommodation payments from
Lilly, Servier and Pfizer. B.L. holds patents for the use of
neuro navigation for transcranial magnetic stimulation and for
the use of cyclobenzaprine for tinnitus treatment. The other
authors declare no competing interests.
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