Hearing Research 319 (2015) 1e11

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Hearing Research
journal homepage: www.elsevier.com/locate/heares

Review

Tinnitus and neural plasticity (Tonndorf lecture at XIth International

Tinnitus Seminar, Berlin, 2014)
Jos J. Eggermont a, b, *
a
b

Department of Psychology, University of Calgary, Calgary, Alberta, Canada

Department of Physiology and Pharmacology, University of Calgary, Calgary, Alberta, Canada

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 8 August 2014
Received in revised form
23 September 2014
Accepted 2 October 2014
Available online 12 October 2014

Ten years ago, animal models of noise-induced hearing loss predicted three cortical neural correlates of
tinnitus resulting from noise-induced hearing loss: increased spontaneous ring rates, increased neural
synchrony, and reorganization of tonotopic maps. Salicylate also induces tinnitus, however, the cortical
correlates were reduced spontaneous ring rates, unchanged neural synchrony but some change to the
tonotopic map. In both conditions increased central gain, potentially a correlate of hyperacusis, was
found. Behavioral animal models suggested that tinnitus occurred, albeit not in all cases. The study of the
neural substrates of tinnitus in humans is currently strongly based on network connectivity using either
spontaneous EEG or MEG. Brain imaging combined with powerful analyses is now able to provide in
excellent detail the lay out of tonotopic maps, and has shown that in people with tinnitus (and clinical
normal hearing up to 8 kHz) no changes in tonotopic maps need to occur, dispensing therefore of one of
the postulated neural correlates. Patients with hyperacusis and tinnitus showed increased gain, as
measured using fMRI, from brainstem to cortex, whereas patients with tinnitus without hyperacusis only
showed this in auditory cortex. This suggested that top down mechanisms are also needed. The open
problems can be formulated by the following questions. 1) Are the neural substrates of tinnitus etiology
dependent? 2) Can animal results based on single unit and local eld potentials be validated in humans?
3) Can sufcient vs. necessary neural substrates for tinnitus be established. 4) What is the role of
attention and stress in engraining tinnitus in memory?
2014 Elsevier B.V. All rights reserved.

1. Introduction

1.1. Neural plasticity in sensory cortex

I was an invited speaker at the 2nd International Tinnitus

Seminar, held June 10e11, 1983, in New York City, where Juergen
Tonndorf was the guest of honor. The content of our talks
(Eggermont, 1984; Tonndorf, 1984) was very similar, both dealing
with the potential pathophysiology of tinnitus. It was clear that we
both banked heavily on a peripheral origin of tinnitus. These days
most bets are on a central origin of tinnitus, but as we will see the
role of the auditory periphery not only becomes clearer but also is
likely the dominant cause of transient and early onset tinnitus.

Tinnitus is often seen as a result of maladaptive plasticity in the

auditory nervous system. Which neural plasticity mechanisms may
play a role in generating tinnitus? There are ve types of neocortical neural plasticity that can in turn be grouped as rapid or slow
acting (Feldman, 2009). Rapid plasticity is of the Hebbian type and
requires correlation between the rings of two neurons, most often
the input and output neuron. The slow plasticity is typically called
homeostatic, and keeps the cumulative Hebbian changes in check,
so that the balance of excitation and inhibition is maintained
(Turrigiano, 1999).
The three rapid types of plasticity in sensory neocortex are 1)
activity- and correlation-dependent potentiation including spiketime dependent plasticity (STDP); 2) training- or attentiondependent potentiation in adults; and 3) response depression to
deprived inputs. The slow forms are 4) response potentiation of
spared inputs, and 5) gain changes following substantial overuse or
deprivation (Feldman, 2009). STDP has also been implicated in the

* Department of Psychology, University of Calgary, 2500 University Drive N.W.,

Calgary, Alberta, Canada T2N 1N4. Tel.: 1 403 220 5214; fax: 1 403 282 8249.
E-mail address: eggermon@ucalgary.ca.
http://dx.doi.org/10.1016/j.heares.2014.10.002
0378-5955/ 2014 Elsevier B.V. All rights reserved.

J.J. Eggermont / Hearing Research 319 (2015) 1e11

interaction between sound and somatosensory stimuli in the dorsal

cochlear nucleus and might underlie long-lasting bimodal plasticity, and potentially plays a role in the generation of tinnitus
(Dehmel et al., 2012; Koehler and Shore, 2013; Tzounopoulos et al.,
2004, 2007).
The mechanisms underlying homeostatic plasticity and
maintaining a stable function in the face of activity-dependent
changes are rst of all found in changing the gain of inhibitory and excitatory synapses to cortical pyramidal cells. In case of
sensory deprivation this would result in strengthening of excitatory synapses and weakening of inhibitory synapses. A second
mechanism, which may be additional to the rst and in case of
sensory deprivation consists of increasing the number of Na
channels and decreasing the K channels in the cell membrane.
The result is a lowering of the threshold of ring (Turrigiano,
2011) and potentially increased spontaneous ring of the
neuron.
Slow gain changes have been demonstrated in the human
auditory system following either 2 weeks of sound deprivation by
wearing earplugs for all but one-hour/day, or listening to 60 dB
SPL broadband noise for 2 weeks through ear buds (Formby et al.,
2003). Before the exposure, the participants classied the loudness of a range of tones (500 and 2000 Hz) from very soft to
uncomfortably loud on a 7-point scale. After the 2-week deprivation period the participants classied them again and now
required the tone SPLs previously rated in the range of comfortable to uncomfortable to be reduced by 6e8 dB for the same
loudness rating. There was no loudness classication change for
softer sounds. This suggests that as a result of the deprivation the
auditory gain was increased. Following the continuous exposure to
noise, the SPLs had to be increased by about 6e8 dB for the same
rating as before the overuse exposure, suggesting a decrease in
auditory gain. This illustrates the type 5 cortical plasticity
described above.

2. Acute effects of noise trauma

I have experienced many times that very loud sound produces
instantaneous but generally short-lasting tinnitus. To investigate
the effects of exposure to very-loud sound in primary auditory
cortex of ketamine-anesthetized adult cats, we aimed at recording
from the same neurons before and for some duration after the noise
~ a et al., 2003) used two
trauma. For that purpose we (Noren
microelectrode arrays, each with 8 electrodes arranged in a 4  2
pattern with electrode distances of 0.5 mm in and between rows.
After nding the optimal locations of the two arrays so that they
would cover the part of primary auditory cortex (AI) with characteristic frequencies (CFs) between ~3 and 30 kHz, we rst recorded
frequency-tuning curves (FTC), post-stimulus time histograms
(PSTHs), and spontaneous ring, each over 15 min. Then, with the
electrode arrays in place, we exposed the cat for 1 h to a 5 kHz tone
at 120 dB SPL and again started recording spontaneous ring, FTCs
and PSTHs immediately after the exposure, i.e., within the rst
15e30 min. This procedure was then repeated several times until
4e6 h after the exposure depending on the stability of the
recording. Six hours after the exposure we also measured the ABR
thresholds, and they were on average 40 dB elevated compared to
controls for the frequency range of 6e32 kHz (Fig. 1B).
2.1. Frequency tuning curves and post stimulus time histograms
Let us rst look at what happens to the FTCs. As an illustration
(Fig. 1A) we show the changes occurring for a unit with a very
narrow FTC, with characteristic frequency (CF) 10 kHz and a
threshold of 5 dB SPL (below the range shown in the top panel). The
frequency-response area shown here also represents the driven
ring rate; the outer boundary reects 25% of the peak ring rate
and is considered the FTC, the light shaded boundary is at 50% and
the black boundary at 75% of the peak-ring rate. The vertical gray

Fig. 1. Acute effects of noise trauma on frequency tuning. A, the time progress of recovery from noise-trauma illustrated by a single unit FTC recorded prior and at several time post
~ a et al. (2003) and Noren
~ a and Eggermont, 2003).
exposure. B, average ABR threshold loss about 6 h after the 1 h exposure to a 5 kHz tone at 120 dB SPL. Based on data from Noren

J.J. Eggermont / Hearing Research 319 (2015) 1e11

line indicates the trauma tone frequency (TTF). In the rst 15 min
following the trauma, second panel from the top, we note that the
neuron does no longer respond to frequencies in its pre-trauma
7e14 kHz response range, but shows activity in a region well
below this range. The threshold is now around 50 dB SPL. The next
recording, third panel from the top, was taken around 1 h 40 min
post-trauma and shows an FTC with a CF at 5 kHz and a threshold at
40 dB SPL. Fig. 1A shows the FTC at 3 h 40 min post-trauma with a
CF now at about 6 kHz and a threshold around 25 dB SPL. Note that
there still is no response (except for 60e65 dB SPL) for frequencies
in the pre-trauma response area. These changes are very rapid, and
reect unmasking of previous inhibited excitatory inputs from the
thalamus. After the neuron ceased ring to the 7e14 kHz sounds,
this lateral inhibition effect to lower (and potentially higher) frequencies disappeared.
The measurement procedure of the FTC also allowed the construction of PSTHs. We show here (Fig. 2), the PSTHs recorded > 2 h
after the trauma compared to those before the trauma for three
frequency regions; below the TTF (Be group, top 3 panels), 0e1
octave above the TTF (Ab1 group, middle row of 3 panels), and >1
octave above the TTF (Ab2 group, bottom 3 panels). We also
distinguish between low level sound (40 dB SPL; left 3 panels),
moderate level sound (45e60 dB SPL, middle column of panels) and
high level sounds (65 dB, right 3 panels). We notice that for sound
60 dB SPL most panels show a decrease in the PSTH. However,
only for frequencies below the TTF and for sound levels 65 dB SPL,
we observe a strong increase of the PSTH. This reects the spared
inputs, which show a gain increase. This could reect homeostatic
plasticity, or alternatively, a reduction in lateral inhibition.

2.2. Spontaneous neural activity

We evaluated the spontaneous ring rate (SFR), and the crosscorrelation function between the spontaneous rings of two
~a
simultaneously recorded spike trains over a 15-min period (Noren
and Eggermont, 2003). It should be noted that we have never seen
increased spontaneous burst ring in auditory cortex either
following noise trauma or salicylate administration as reported
after salicylate administration in the inferior colliculus (IC) of the
rat (Chen and Jastreboff, 1995; Manabe et al., 1997). However, as an
acute effect of noise trauma we did see a transient suppression of
burst ring for units with CFs in the range of 0e1 octave above the
TTF. In Fig. 3 we use the following additional abbreviations; After1,
0e15 min following the trauma, After2, >2 h after the trauma.
Given two spike trains a and b, with ring rates FRa and FRb, the
geometric mean ring rate M(FR) is dened as (FRa*FRb)0.5. Fig. 3A
shows the changes in M(FR) in the rst 15 min after the trauma
(black bars) and >2 h after the trauma (open bars). We note that in
the rst 15 min after the trauma the M(FR)s have not changed
signicantly, whereas > 2 h after the trauma they have increased 2
fold except for units with CFs in the 0-1 octave region above the TTF.
Neural synchrony in the nervous system can be quantied by a
cross-correlation function. This is a statistic representing the
average value of the product of two random processes, which, in
our case, are spike trains. If we make the assumption that it is
simply the occurrence, rather than the shape of an action potential,
which conveys information, then the correlation function reduces
to a simple probability Rxv(z) of observing a spike in one train y at
time t z, given that there was a spike in a second train x at time t.

Fig. 2. Acute effects of noise trauma on post stimulus time histograms. Averaged PSTHs for tone pips (duration 15 ms) with frequency below the TTF (Be; A, D, and G), for frequencies 0e1 octave above the TTF (Ab1; B, E, and F), and for tones with frequency > 1 octave above the TTF (Ab2; C, F, and I) for 3 intensity groups (indicated at top of each
column). PSTHs were each obtained at the best frequency. Note in D and E that the slightly elevated discharge induced by tone pipe is shorter in the post-trauma than in the pre~ a et al. (2003).
trauma condition, whereas pre- and post-trauma maxima of averaged PSTHs were not different. Clear response enhancement is shown in panel G. From Noren

J.J. Eggermont / Hearing Research 319 (2015) 1e11

Komiya, 2000; Seki and Eggermont, 2002), and signicant increases in SFR and r. The main characteristic of the reorganized
topographic maps is that the area previously representing frequencies in the hearing loss range (e.g., 8e40 kHz) is now tuned to
frequencies around the edge frequency of the undamaged region
with normal thresholds.
3.1. Tonotopic maps

Fig. 3. Acute effects of the acoustic trauma on the peak cross-correlation coefcient r.
(A) Change in M(FR) averaged (geometric mean) into six CF combinations. (B) Change
in r averaged (geometric mean) into six frequency bands, immediately (After1) and a
few hours (After2) after the acoustic trauma (S.E.M., *P < 0.0083). Immediately after
the acoustic trauma (black bars), one notes that r is signicantly increased in the Ab2~ a, A.J. and Eggermont, J.J. (2003)
Ab2 group whereas M(FR) is not. Reprinted from Noren
Changes in spontaneous neural activity immediately after an acoustic trauma: implications for neural correlates of tinnitus. Hear Res, 183, 137e153, with permission from
Elsevier.

This equation forms the basis for estimating the cross-correlation

function between two spike trains using histogram techniques to
obtain the cross-correlation histogram, or 'cross-correlogram' for
short. The presence of a signicantly large peak or trough in the
correlogram of the spontaneous rings is an indication of neural
interaction. This peak value, expressed as a correlation coefcient is
designated by r.
Quite in contrast to the changes in spontaneous ring rates, the
peak cross-correlation coefcients (r) as described above and
dened in Eggermont (1992) were already signicantly increased in
the rst 15 min after the trauma, namely for unit pairs with pretrauma CFs > 2 octave above the TTF (Fig. 3B). More than 2 h after
the trauma, the r values were further increased and now were also
signicant for pairs with one unit's CF < TTF and the other >2 octave
above TTF. Note that correlation between spike trains from units
with CFs <1 octave above the TTF were not changed from pre-trauma
values. The slow increase in M(FR) and the fast increase in r suggests
quite different plasticity mechanisms; potentially slow homeostatic
ones for spontaneous ring rates, and rapid Hebbian ones for crosscorrelation coefcients. It also suggests that increased SFR in primary auditory cortex is not a neural substrate for the short-lasting
tinnitus experienced immediately after the noise trauma, but
increased neural synchrony, as quantied by r, may be.
3. Chronic effects of noise trauma
Chronic effects of noise trauma in cat primary auditory cortex
include reorganization of the tonotopic map (Eggermont and

Fig. 4A illustrates a tonotopic map in a control animal. Briey,

we measure the frequency-tuning curves and indicate its CF for
each recording site on the cortical surface, and use a color scheme
as indicated below to indicate the CF. In this case and more
generally, there is no smooth transition of CFs from low to high
from the posterior ectosylvian sulcus (PES) to the anterior one
(AES), albeit that on average the CFs increase toward anterior locations. In some cases neighboring electrodes could have CFs
differing by 2 octaves. The measurement of such discontinuities is
one of the advantages of micro-electrode arrays above repeated
recordings with a single electrode. With an electrode array, one
knows accurately the distance between the electrodes and all recordings are from the same depth below the cortical surface. From
this we suggest that tonotopy in cat primary auditory cortex is only
approximate. We generally combine several individual cat tonotopic maps into one map (Fig. 4B); here this is done by lining the
recording sites up relative to the position of the tip of the PES
(indicated by a red dot in A) and the line connecting with the tip of
the AES, the posterioreanterior axis. This is not without pitfalls, as
the location of auditory cortex in the cat does not follow anatomical
markers. Still, the combined map in the right hand panel shows
clearly the tonotopic gradient from middle left to top right. It also
indicates a change in frequency gradient in the right-most part
where recording sites are in the anterior auditory eld (AAF). Later
on we will show more-detailed maps from individual cats. The
tonotopic maps are constructed by plotting the CFs of the
frequency-tuning curves on the recording positions on the cortical
surface. After cortical map rorganization the CFs of the tuning
curves recorded at positions in the hearing loss area are changed
towards those for the edge frequencies and with their normal
thresholds. It should be noted that in cats there is no reorganization
of the cortical tonotopic map for hearing losses 25 dB (Rajan,
1998; Seki and Eggermont, 2002). One expects this to hold as
well for humans (Langers et al., 2012).
At 3e16 weeks after inducing a permanent hearing loss, by a 2 h
exposure to a 5 kHz tone at 126 dB SPL, the tonotopic map in AI has
changed dramatically (Fig. 5A), no CFs > 15 kHz are present in the
example shown, and a large region of AI is now tuned to 10e15 kHz.
In fact in this example the highest CF was 12 kHz (Eggermont and
Komiya, 2000).
3.2. Spontaneous activity
Fig. 5B shows the SFRs in a group of control and exposed cats;
the signs indicate the SFRs in controls and the lled red squares
those in exposed cats. Note the logarithmic scales. SFRs in controls
are between 0.2 and 8 sp/s, on average 1.4 sp/s and independent of
CF (see locally-weighted regression line). In the exposed cats, the
SFR in the reorganized region with CFs between 7 and 12 kHz is
signicantly increased largely by increases for low SFR pre-trauma
units.
The neural synchrony changes in chronic noise trauma depended strongly on the hearing loss in the reorganized region (Fig. 6).
For hearing losses <20 dB no changes occurred, for higher losses the
increases were signicant and correlated with the amount of
hearing loss.

J.J. Eggermont / Hearing Research 319 (2015) 1e11

Fig. 4. Tonotopic map in AI of an individual cat and pooled across cats. A, electrode positions on a photograph of cat primary auditory cortex. CFs are color coded as indicated below
the panel. B, Compound CF maps in AI in control cats. The center of each polygon, constructed using the tessellation method, corresponds to the coordinates of a recording site in
auditory cortex along the anteroposterior axis (abscises) and the ventrodorsal axis (ordinates). The tip of the posterior ecto-Sylvian sulcus was taken as the (0,0) coordinate. The CF
is represented by color as indicated by the color bar. From From Valentine PA, Teskey GC and Eggermont JJ. (2004) Kindling changes burst ring, neural synchrony and tonotopic
~ a and Eggermont (2005). (For interpretation of the
organization of cat primary auditory cortex. Cerebral Cortex 14: 827-839 by permission of Oxford University Press, and Noren
references to colour in this gure legend, the reader is referred to the web version of this article).

4. Centralization of tinnitus
Is tinnitus generated in the peripheral auditory system or in the
central nervous system? The fact that tinnitus is a conscious
percept requires that the tinnitus-inducing changes in the auditory
system nd their way into the consciousness network. This
network starts in the auditory parabelt areas and their connections
with the ventral medial prefrontal cortex (vmPFC; Del Cul et al.,
2009), so activity in auditory cortex beyond AI is paramount for
the tinnitus percept (Laureys et al., 2000; Plewnia et al., 2007).
These regions also include the frontal eye elds, the left inferior
frontal cortex, and the insula which are part of the attention
network which gas been shown to affect tinnitus perception
(Husain and Schmidt, 2014).
Two studies by Mulders and Robertson (2009, 2011) addressed a
potential step into this centralization process. In the rst study,
guinea pigs were exposed for 1 h to a 10 kHz tone presented at
124 dB SPL; within 4e12 h after the trauma there was a small increase in the SFR in the central nucleus of the inferior colliculus
(ICC), at 2 weeks after the trauma there was a massive increase in

SFR for CFs above 10 kHz. However, following cochlear ablation,

cooling or perfusion with kainic acid, all of which abolish (spontaneous) ring in auditory nerve bers, the SFR in the ICC dropped
to pre-trauma values. Even following 6 weeks post-trauma,
cochlear ablation still resulted in central SFR values that were
decreased to pre-trauma values. This suggested that the increased
SFR in the ICC resulted from an amplication of the SFR of it afferents as a consequence of an increased central gain. In the followup study they performed cochlear ablation at 8 and 12 weeks post
trauma, and in these cases the SFR was reduced by only a small
amount and remained approximately at the 2-week post-trauma
values. This points to a very late centralization of the noisetrauma induced hyperactivity in the ICC of the guinea pig, sometime between 6 and 8 weeks post trauma.
5. Effects of salicylate on auditory cortex
Behavioral measures conrmed the presence of tinnitus
induced by salicylate in rats (Heffner and Heffner, 2012; Yang et al.,
2007). Salicylate injection has been used in a large number of

Fig. 5. Chronic effects of noise trauma on the tonotopic map and spontaneous ring rates. A, Tonotopic map recorded 3 weeks following noise trauma induced by exposure for 2 h to
a 5 kHz tone at 126 dB SPL. B, Spontaneous ring rates in control () and noise exposed (-) cats. The ellipse indicates the reorganized frequency region. Note the logarithmic scales.
The gray arrow indicated the trauma tone frequency. Data from Eggermont and Komiya (2000).

J.J. Eggermont / Hearing Research 319 (2015) 1e11

Fig. 6. Dependence of peak cross-correlation coefcient R (S.E.M.) on average hearing

loss. Data from.Seki and Eggermont (2003).

studies. The ease of application by injection and predictable result

also allows the study of the same neurons before, during, and after
the injection. In addition to causing a temporary hearing loss, salicylate induces direct central effects in the auditory system
(Kenmochi and Eggermont, 1997). Ochi and Eggermont (1996)
administered a dose of 200 mg/kg in ketamine-anesthetized cats
that resulted in a peripheral hearing loss of about 20 dB but did not
change the overall SFR in primary auditory cortex (AI) neurons that
were continuously recorded before, during and up to 6 h after the
administration. In contrast, there was a signicant increase in the
second cortical area (AII; Eggermont and Kenmochi, 1998) and a
pronounced decrease in anterior auditory eld (AAF). Zhang et al.
(2011) using chronically implanted electrodes in AI of awake cats,
investigated stimulus-evoked and spontaneous ring rate changes
after systemic injection of 200 mg/kg salicylate. Sound-evoked
ring rates were signicantly increased from 1 h after salicylate
administration, and the increase of driven ring rates lasted longer
than 3 days, with a peak at 12 h post administration. This signicant
enhancement of neural responses was observed over the entire
tested frequency range (0.1e16 kHz), with a relative peak in the
3.2e9.6 kHz frequency region. Salicylate administration, however,
decreased the mean SFR in AI units, and the decrease of SFR was
larger in the units with a high initial spontaneous rate. No indications of changes in burst ring were found after salicylate
application.
Sun et al. (2009) chronically monitored the local eld potentials
(LFPs) and SFRs from multiunit clusters in the auditory cortex of
awake rats before and after treatment with 150 mg/kg of salicylate.
The amplitude of the LFP elicited with 60 dB SPL tone bursts
increased signicantly 2 h after salicylate treatment, particularly at
16e20 kHz, i.e., frequencies associated with the behaviorally estimated tinnitus pitch. LFP amplitudes had largely recovered 1e2
days post-salicylate when behavioral results indicated that tinnitus
had ceased. The mean SFR recorded from a nine-unit cluster preand post-salicylate decreased from 22 spikes/s before treatment to
14 spikes/s 2 h post-salicylate and recovered 1 day post-treatment,
in line with results in cats (Zhang et al., 2011). The alterations of LFP
amplitude likely reect salicylate-induced gain changes in the
~ a et al., 2010). This again suggests that
auditory system (Noren
salicylate-induced tinnitus is associated with sound evoked hyperactivity in auditory cortex and reduced SFRs. Despite these
reduced SFRs in auditory cortex, the same dose produced besides
the behavioral indices of tinnitus, a signicant increase in metabolic activity in rat auditory cortex and inferior colliculus as
measured using microPET (Paul et al., 2009) and thus potentially
reects increased inhibitory synaptic activity.

Behavioral studies suggested that the pitch of salicylate-induced

tinnitus in the rat is in the 16e20 kHz range. To further evaluate
this, Stolzberg et al. (2011) made frequency-tuning curve measurements at the levels of cochlea and cortex in ketamine/xylazine
anesthetized rats. Both compound action potentials and distortion
product otoacoustic emission measurements revealed a salicylateinduced cochlear decit in which the amplitude reduction was least
at 16 kHz and signicantly greater at high and low frequencies. In a
separate group of rats, frequency-tuning curves in primary auditory
cortex neurons were tracked using multi-electrode arrays before
and after systemic salicylate treatment. This revealed a population
of neurons that shifted their frequency of maximum sensitivity (i.e.
characteristic frequency, CF) towards the tinnitus frequency region
of the tonotopic axis (~16 kHz). This suggested that salicylateinduced tinnitus may result from an expanded cortical representation stemming from an altered prole of input from the cochlea.
Moreover, the pliability of cortical frequency receptive elds during
salicylate-induced tinnitus could be due to salicylate's direct action
on intracortical inhibitory networks.
These data suggest that the primary auditory cortex is involved
in the hyperacusis-like effects of salicylate, the absence of changes
in, or reduction of, SFR in AI and the increase in SFR in AII, combined
with increases in SFR for the external nucleus of the inferior colliculus (Chen and Jastreboff, 1995; Manabe et al., 1997), suggests a
primary involvement of the extralemniscal pathway for salicylate
induced tinnitus.
Comparing noise trauma and salicylate effects on auditory cortex answers the rst question posed in the abstract: The neural
substrates of tinnitus etiology are clearly etiology dependent.
6. Proposed bottom-up neural correlates of tinnitus
The experiments reviewed above suggested that transient
tinnitus immediately after the noise exposure might be due to the
increased neural synchrony in auditory cortex. Chronic tinnitus
following noise trauma may in addition have as its substrates
increased SFR and reorganization of the cortical tonotopic map.
Such centrally increased SFR may initially result from an amplication of peripheral SFR, in the ventral (Vogler et al., 2011) or dorsal
cochlear nucleus (Kaltenbach et al., 2000). The central amplication reects homeostatic plasticity (Schaette and Kempter, 2006)
that tries to stabilize function in the face of activity-dependent
changes, but as a maladaptive consequence also increases the
spontaneous ring rates.
6.1. Increases in SFR and neural synchrony in auditory cortex are
not sufcient for inducing tinnitus
6.1.1. Long-term exposure to non-traumatic sound
Some answers on the role of SFR and neural synchrony were
extracted from a study that exposed cats to putatively non~ a et al., 2006).
traumatic sound over a long period of time (Noren
We choose a random-frequency tone pip stimulus with 16 frequencies per octave, between 4 and 20 kHz. Tone pips at each
frequency were randomly generated in time using a Poisson distribution. Each frequency's distribution was independently generated and thus in the overall stimulus tone pips occurred at
completely random intervals with frequent overlap. We called this
an enhanced acoustic environment (EAE) (Fig. 7). We presented this
stimulus continuouslydinitially for at least 4 months at 80 dB SPL,
and later on we showed that results were similar for exposure to
this EAE for 6 weeks at 68 dB SPL and also for 4e20 kHz steeplyltered noise at this level and duration (Pienkowski et al., 2011).
The effects caused by the 80 dB SPL stimulus bafed us (Fig. 8);
~ a et al., 2006) found that neurons in AI had become
we (Noren

J.J. Eggermont / Hearing Research 319 (2015) 1e11

spared frequencies (Rajan, 1998; Calford, 2002). Behavioral studies

using conditioned responses (Yang et al., 2007, 2011) have provided
evidence that abnormal cortical activity is correlated with tinnitus.

Fig. 7. Waveform and spectrogram of the EAE for a 2-s-long sequence. The EAE was
composed of tone pips randomly selected from 32 frequencies between 5 kHz and
20 kHz, separated by 1/16th octave and of equal SPL. The overall SPL of the EAE was
~80 dB. Tone pips at any given frequency were presented at an average rate of about
3 Hz, which gives an aggregate rate of 96 Hz when all stimuli are considered.
~ a et al. (2006).
From.Noren

largely insensitive to stimulus frequencies in the range of 4e20 kHz

despite the fact that the ABR thresholds (for tone pips from 3 to
32 kHz) were completely normal. We found a strong response
enhancement for frequencies above 20 kHz, and below 4 kHz
(especially below 1.25 kHz) accompanied by a threshold decrease of
up to 20 dB. One has to realize that the control data in the upper
panel are the average across 15 normal hearing cats, with a dearth
of units with CFs below 5 kHz. This was a consequence of not always being able to sample from lower CF units located in the PES
with the electrode arrays we used at that time. But since they were
also used for the EAE cats, we can interpret the reduced thresholds
as resulting from reduced lateral inhibition from the overused and
suppressed EAE-frequency range, and increased gain change for the

Fig. 8. Effects of >4 months exposure to 80 dB SPL sound with a frequency range of
4e20 kHz. Averaged post-stimulus time histograms across all control and EAE cats. (a,
b) Averaged PSTHs (2-ms time bins) as a function of SPL, over a 100-ms time window,
in control and EAE cats. Vertical dashed lines indicate 10-ms intervals. Horizontal
dashed lines indicate frequency range of the EAE. Colored bars, mean ring rate. In
control cats, the mean response suggested that the highest sensitivity (lowest
thresholds) was to frequencies around 10 kHz and that the largest responses were to
frequencies between 2.5 kHz and 10 kHz. In EAE cats, the most sensitive frequencies
were those below 1.25 kHz and above 20 kHz. Note that neural responses in EAE cats
~a
were much more spread out over time compared to those in control cats. From Noren
et al. (2006). (For interpretation of the references to colour in this gure legend, the
reader is referred to the web version of this article).

6.1.2. Spontaneous neural activity

~ a et al., 2006) also observed that the SFRs were now
We (Noren
signicantly increased compared to controls for AI regions with CFs
below and above the 4e20 kHz region (Fig. 9, top). Similarly, we
found that the neural synchronydas measured from the peak
cross-correlation coefcientsdwas strongly increased for neighboring electrodes,  0.5 mm distance, and also had a much larger
spatial extension. This was particularly clear for unit pairs originating from the frequency region below that of the EAE, i.e., below
the 10% point of the distance between the PES and AES (Fig. 9,
bottom), which showed strongly enhanced synchrony up to
3e4 mm electrode distances. This probably signies the stronger
connections over large distances (that is, into the reorganized region) made by horizontal bers. In these cats, the range of strong
correlations is much larger, especially in the e50% to 50% region,
which reects the entire area with characteristic frequencies
<5 kHz but also a substantial part of the 5e20 kHz area. In addition,
the area with characteristic frequencies above 20 kHz (70e125%)
also showed strongly increased neural synchrony. This suggests
that increases in neural synchrony are sensitive indicators of
changes in auditory cortex, and in this study were strongly correlated with tonotopic map changes.
6.2. Exposure at environmental noise levels
At lower EAE levels (~68 dB SPL) and shorter exposure durations
(~6 weeks) there were again no ABR threshold changes. We
sampled more densely in these studies, now using two 16electrode arrays (8  2 pattern, electrode distance 0.25 mm in
the row and 0.5 mm between rows), and also recorded outside
primary auditory cortex (Pienkowski and Eggermont, 2009). Fig. 10
shows an example of the tonotopic maps obtained in individual
animals, on the left the recording sites of auditory cortex in a
control cat. For the exposed cat, the EAE was steeply-ltered
4e20 kHz noise (Pienkowski and Eggermont, 2012). Filled circles
indicate positions where we could reliably estimate the CFs, open
circles recording positions were we could not do so because of very
low ring rates. The AI region is indicated by the surrounding
boundary line and based on changes in frequency gradient at the
boundaries, and tone-pip latencies. Below the map we show the
distribution of CFs and the neural thresholds of the cortical
recording sites. Compared to our recordings presented earlier (cf.
Fig. 8), the sampling was denser in the lower frequency regions as
reected in the lower-envelope of the primary auditory neuron
thresholds. In the central panel on top the tonotopic map for the
control cat is shown, and represented with the center of gravity
(1SD) for octave-wide CF ranges. Here we used the distance from
the AI-AAF boundary as the spatial coordinate. In the right-hand
panel we show the recordings from an EAE-exposed animal,
again the AI is outlined by the boundary curve. As is most clear from
the distribution of CFs below this map there is a paucity of neurons
with CFs corresponding to the EAE frequencies, and an increase in
units with CFs above and below that range (note that the vertical
scale of the histogram is different from that for the controls on the
left). The threshold distribution shows a gap for the EAE frequencies. Both the CF-distribution and the thresholds recover
completely after 8e12 weeks post-exposure (Pienkowski and
Eggermont, 2009). The tonotopic map middle-lower panel shows
a different gradient compared to the control, largely due to a posterior shift in the center of gravity for high-CF neurons and an
anterior shift in the center of gravity for low-CF neurons. It is noted

J.J. Eggermont / Hearing Research 319 (2015) 1e11

Fig. 9. Effect of long-term non-traumatic sound exposure on spontaneous ring rates and neural synchrony. Top. Recording sites in control cats and EAE cats with mean SFR for
recordings at sites located <10% of the PES-AES distance, 10e70% of the PES-AES distance, and >70% of the PES-AES distance. *P < 0.05, **P < 0.01. Bottom. Neural synchrony maps in
primary auditory cortex. (A, B) Synchrony, dened here as the peak strength of the corrected cross-correlogram, as a function of the position of the recording electrode along the
posteroeanterior axis (abscissa) and the distance between the two electrodes involved in the calculation of synchrony (ordinate), in (A) control and (B) EAE cats. For each electrode
pair, positions along the posterioreanterior axis are plotted. Colored bar indicates the peak cross-correlation coefcients. In control cats, the strongest synchrony was found between neighboring electrodes in the array and most correlations occurred locally. Note the increased synchrony in EAE cats compared to control cats, especially for larger distances
~ a et al. (2006). (For interpretation of the references to colour in this gure legend, the reader is referred to the web version of this article).
between electrodes. From Noren

Fig. 10. Effects of 6 weeks exposure with a 4e20 kHz EAE presented at ~70 dB SPL. Multi-unit (MU) spike recordings from the auditory cortex of a representative unexposed control
cat (A) and a cat exposed for 6 wk to a 4e20 kHz steeply-ltered band of uniform white noise at ~70 dB SPL (B). In the top left and top right, color-coded (see center insert) MU CFs
are shown superposed on a photo of the cortical surface. Open circles indicate electrode penetrations, which yielded a poor response with ambiguous CF. AI is outlined and lightly
shaded to distinguish it from surrounding auditory elds (anterior auditory eld, posterior auditory eld, AII, DP; see text for full names). Scale bars (bottom-right corner of
photo) 2 mm pes, posterior ectosylvian sulcus; aes, anterior ectosylvian sulcus; D, dorsal; P, posterior. CF-distance plots for MUs sampled in AI are shown beside each twodimensional map (as indicated with arrows); these are projections of the two-dimensional map in AI onto the axis of the predominant tonotopic gradient. Black circles give
the mean positions of the AI units in each of the seven color-coded, octave-wide bins (error bars 1 SD). Belo the two-dimensional maps, we show histogram distributions of AI unit
CFs (left), and scatter plots of AI unit response thresholds vs. the CF (right). From Pienkowski and Eggermont (2012). (For interpretation of the references to colour in this gure
legend, the reader is referred to the web version of this article).

J.J. Eggermont / Hearing Research 319 (2015) 1e11

that the tonotopic map did not recover after 12 weeks post exposure in quiet, in fact the maps became progressively more
reorganized.
For these low-level EAE exposed animals, the SFR increased
signicantly at the edges of the EAE frequency range (Munguia
et al., 2013), as did the peak ring rates as a function of tone pip
level. Thus, we have an increased central gain outside the EAE region, accompanied by increased SFRs. In addition, the neural synchrony increased for short inter-electrode distances and mostly so
for electrode pairs outside the EAE region. In contrast to the slow
recovery of the SFRs to pre-exposure values, the synchrony changes
did not recover after 12 weeks post-trauma (Pienkowski and
Eggermont, 2009) suggesting that neural synchrony changes are
related to tonotopic map changes (Eggermont, 2007).
Thus, homeostatic plasticity resulting in increased SFR and
Hebbian plasticity resulting in neural synchrony increase also occur
after environmental noise level exposure, likely the result of
frequency-specic gain changes. This could represent a neural
substrate of tinnitus without hearing loss. However, it could also
indicate that increased SFR and neural synchrony is not sufcient to
induce tinnitus, as it has not been demonstrated that such longlasting low-level exposures lead to tinnitus.

7. Findings in humans with tinnitus

Studies in tinnitus patients are based on either functional
magnetic resonance imaging (fMRI) and thus reect stimulusinduced changes that represent the presence or absence of hyperacusis or the effects on attention to the tinnitus. Such measurements also allow the construction of tonotopic maps. Spontaneous
activity has been recorded using positron emission tomography
(PET). Connectivity changes between various brain areas compared
to controls have been obtained using spontaneous electroencephalography (EEG), magnetoencephalograpy (MEG) and fMRI. Here,
we will compare some of the proposed neural substrates of tinnitus
in animal auditory cortex with ndings in humans. This will suggest that animal model data cover only a few aspects of the ndings
in humans, the data suggest that there is evidence for increased
spontaneous activity, potential reorganized tonotopic maps provide there is a sufcient hearing loss, and effects of central gain
changes. This partly validates ndings based on single unit and
local eld potentials in animal models of tinnitus to those for
tinnitus in humans.

7.1. Tonotopic map changes

There have been estimates of tonotopic maps in human core
auditory cortex, based on equivalent dipole localization of MEG and
EEG data, that have suggested differences in chronic tinnitus patients from controls (Mhlnickel et al., 1998; Wienbruch et al.,
2006). However, the relatively poor spatial resolution of these
techniques left some doubts. Recently, with dramatically improved
analysis techniques for blood oxygen level dependent (BOLD) responses in fMRI, Langers et al. (2012) found that tonotopic map
changes in auditory core cortex in tinnitus patients were not
different from those in hearing loss matched controls. Thus, tonotopic map changes are not necessary for tinnitus to occur. A caveat
here is that in the patients and controls the average thresholds up
to 8 kHz were below 20 dB, i.e., clinically normal and it has been
shown in animal experiments that map reorganization does not
occur when hearing loss is < 25 dB (Rajan, 1998; Seki and
Eggermont, 2002).

7.2. The role of hyperacusis

In an elegant study, Gu et al. (2010) tested the effect of hyperacusis in tinnitus patients on stimulus-induced BOLD responses
from the auditory midbrain, thalamus and core cortex. Patients
with tinnitus only, tinnitus and hyperacusis, and controls were
carefully matched in audiograms that were clinically normal. It
appeared that the stimulus evoked activity in inferior colliculus,
thalamus and core cortex was elevated compared to controlsdindicating an increased central gaindin patients with
tinnitus and hyperacusis. However, in patients with only tinnitus,
the BOLD responses were only elevated in auditory cortex. This
increase in BOLD response was attributed to attention, which has
barely an effect on midbrain and thalamus, but does enhance responses in auditory cortex (Roberts et al., 2013). These ndings
underlie the role of hyperacusis, i.e., increased central gain, at the
subcortical levels as illustrated above in the centralization of
tinnitus section.
7.3. Modiers of neural plasticity in tinnitus patients
The observation that spontaneous fMRI activity is not random
noise, but has a specic organization in the resting human brain
(Fox and Raichle, 2007) has boosted a new approach to tinnitus
research. This so-called resting-state functional connectivity reects correlations in slow (~0.1 Hz) spontaneous uctuations in the
BOLD signal. A potentially related electrophysiological correlate of
spontaneous BOLD uctuations is the slow (~0.1 Hz) voltage uctuation that has been observed with EEG recording (Steriade et al.,
ki, 2006) that
1993). Brain rhythms with higher frequencies (Buzsa
can be more easily recorded by EEG and MEG are phase-locked to
these very low-frequency oscillations (Young and Eggermont,
2009). If spontaneous neural activity reects ordered brain states
it should show highly specic patterns, and these should reect the
functional architecture of these networks.
Tinnitus may be related to changes in the resting-state neural
networks of the brain. Maudoux et al. (2012a,b) tested 13 chronic
tinnitus patients and 15 age-matched healthy controls with a 3T
MRI scanner during resting condition (i.e., eyes closed, no task
performance). Connectivity was investigated using independent
component analysis. Tinnitus and control groups showed different
graph-connectivity patterns. In the control group, the connectivity
graph could be divided into two distinct negatively correlated
networks. The rst one encompassed the auditory cortices and the
insula. The second one comprised frontoparietal and anterior
cingulate cortices, brainstem, amygdala, basal ganglia/nucleus
accumbens and parahippocampal regions. In the tinnitus group,
only the auditory cortex-insula network was present. Direct group
comparison showed in the tinnitus group an increased functional
connectivity between auditory cortical areas and the left parahippocampal region, being part of the second network in controls.
Connectivity in extra-auditory regions such as brainstem, basal
ganglia/nucleus accumbens, cerebellum, parahippocampal, right
prefrontal, parietal, and sensorimotor areas was increased in
tinnitus subjects. Thus, there was a modication of cortical and
subcortical functional network connectivity in tinnitus patients
that serves attention, memory, and emotion.
These ndings implicate nonauditory regions in tinnitus physiopathology and suggest that various regions of the brain seem
involved in the persistent awareness of the phenomenon as well as
in the development of the associated distress leading to disabling
chronic tinnitus. This increase in functional connectivity between
auditory and parahippocampal regions in tinnitus agrees with
ndings of Vanneste et al. (2011) based on resting-state EEG measurements. Comparing resting-state electrical brain activity of

10

J.J. Eggermont / Hearing Research 319 (2015) 1e11

tinnitus patients and controls, they reported an increased activity

in the gamma-frequency band in the parahippocampal area. They
also found an increase in connectivity between parahippocampal
regions and auditory cortical areas in tinnitus patients compared to
control subjects. Highly and low distressed tinnitus patients
differed in terms of activation of the left middle frontal gyrus,
supporting the idea of a fronto-parietal-cingulate network, which
seems to be more active in highly distressed tinnitus patients
(Golm et al., 2013). Since Golm et al. compared highly and low
distressed tinnitus patients, matched for tinnitus loudness, this
emphasized the role of the prefrontal cortex in the emotional
processing of tinnitus. The middle frontal gyrus had been linked to
the perception of tinnitus (Weisz et al., 2005) and recently also to
tinnitus distress (De Ridder et al., 2011). Two decades ago, Jastreboff
(1990) had already suggested that the prefrontal cortex was a region for integrating sensory and emotional characteristics of
tinnitus.
Tinnitus, just as pain, is a conscious percept, which requires
attention to be perceived, does not wake you up, and can often be
inaudible when attention is directed to other aspects of conscious
processing. The starting point for understanding what makes
tinnitus audible and often annoying is identifying the neural correlates of awareness. Laureys and Schiff (2012) have reviewed
imaging studies showing that patients in a persistent vegetative
state show a reduced blood ow in the anterior and posterior
cingulate, in the precuneus, and in fronto-parietal-temporal areas.
In these patients sound activates the primary auditory cortex on
both sides, but no activity is observed in the inferoparietal cortex,
in the hippocampus or in the anterior cingulate cortex (ACC). These
areas are coactivated with primary auditory cortex in normal
controls, suggesting that activity in primary auditory cortex is
insufcient to produce a conscious percept of sound. This is also
illustrated in the differences in brain activation for near threshold
sounds, which are sometimes perceived and sometimes not. When
such sounds are perceived the dorsal ACC and the anterior insula
are activated, and when they are not consciously perceived there is
only activation in auditory cortex (Seeley et al., 2007). This may
also apply to tinnitus.
In patients with tinnitus, PET imaging has shown that frontal
and parietal areas are coactivated with auditory cortex (Lockwood
et al., 2001). Reorganization of tonotopic maps in auditory cortex
(Eggermont and Roberts, 2004) correlate most of the time with
phantom sound percepts but is insufcient to make tinnitus distressing. This also requires activation of the ACC (Vanneste et al.,
2010). Imaging studies of psychological stress further suggest that
bothersome tinnitus is correlated with a functional coupling of
amygdala, dorsal ACC, insula, and locus coeruleus that occurs after
stress. Such stress can lead to sustained salience of the stressor and
an aversive memory thereof (Roozendaal et al., 2009). De Ridder
et al. (2011) suggested that a decient thalamic gating function
(Rauschecker et al., 2010) can emerge as a consequence of an
aversive tinnitus memory together with chronic stress and represents an additional factor contributing to the perpetuation of the
phantom percept. They suggested that both tinnitus and phantom
pain are perceptual states of continuous learning, wheredin the
absence of an external inputdthe phantom percept is reinforced
and the connection with aversive emotional associations is
continuously updated. In a recent meta analysis of neural network
changes in tinnitus patients, Husain and Schmidt (2014) reported
changes in the default network, in the connectivity between
auditory cortex and the limbic system that mediates stress, in the
connection of the auditory system via the limbic system and
attention network, and also in connections between visual cortex
and the auditory cortex, and between visual cortex and the attention network (Roberts et al., 2013).

8. Concluding remarks
This survey suggests that bottom-up changes in SFR and spontaneous neural synchrony are necessary but not sufcient for
tinnitus perception. Although not described above, salicylate
(another tinnitus-inducing agent) application results in decreased
central ring rates including in primary auditory cortex, however
with increased central gain in these structures. Increased SFR was
found in secondary auditory cortex that can be reached by the
extra-lemniscal system with bypassing the primary auditory cortex
(Eggermont and Kenmochi, 1998). So increased SFR in primary
auditory cortex may not be necessary for tinnitus to occur. Attention networks may engrain the tinnitus percept in memory and
affect auditory cortex functions. Limbic system activity and stress
may further solidify tinnitus. It still remains a mystery why only
~30% of people with hearing loss have (complain about) tinnitus. So
the search is still on for the sufcient conditions leading to tinnitus.
Suggestions that damage to different types of ribbon synapses is
important (Rttiger et al., 2013), or that gating functions of the
striatum may reect genetic predispositions (Rauschecker et al.,
2010) lead to an innite regress as it is not clear why these things
occur. For instance, tinnitus has low heritability as shown in a
recent extensive analysis (Kvestad et al., 2010) so genetic predispositions are unlikely.
Acknowledgments
This research was supported by Alberta Innovates-Health Solutions, the Natural Sciences and Engineering Research Council of
Canada, and the Campbell McLaurin Chair for Hearing Deciencies.
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Abbreviations
AAF: anterior auditory eld
ACC: anterior cingulate cortex
AES: anterior ectosylvian sulcus
AI: primary auditory cortex
BOLD: blood oxygen level dependent
CF: characteristic frequency
EAE: enhanced acoustic environment
EEG: electroencephalography
fMRI: functional magnetic resonance imaging
FTC: frequency-tuning curve
IC: inferior colliculus
ICC: central nucleus of the IC
MEG: magnetoencephalography
M(FR): geometric mean ring rate
PES: posterior ectosylvian sulcus
PET: positron emission tomography
PSTH: post-stimulus-time histogram
SFR: spontaneous ring rate
SPL: sound pressure level
STDP: spike-time dependent plasticity
TTF: trauma-tone frequency
vmPFC: ventral medial prefrontal cortex