Hearing Research
journal homepage: www.elsevier.com/locate/heares
Review
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
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
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.
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
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.
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
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).
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
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).
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).
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.
10
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.
References
ki, G., 2006. Rhythms of the Brain. Oxford University Press, Oxford.
Buzsa
Calford, M.B., 2002. Dynamic representational plasticity in sensory cortex. Neuroscience 111, 709e738.
Chen, G.D., Jastreboff, P.J., 1995. Salicylate-induced abnormal activity in the inferior
colliculus of rats. Hear. Res. 82, 158e178.
Dehmel, S., Pradhan, S., Koehler, S., Bledsoe, S., Shore, S., 2012. Noise overexposure
alters long-term somatosensory-auditory processing in the dorsal cochlear
nucleusepossible basis for tinnitus-related hyperactivity? J. Neurosci. 32,
1660e1671.
Del Cul, A., Dehaene, S., Reyes, P., Bravo, E., Slachevsky, A., 2009. Causal role of prefrontal cortex in the threshold for access to consciousness. Brain 132, 2531e2540.
De Ridder, D., Elgoyhen, A.B., Romo, R., Langguth, B., 2011. Phantom percepts:
tinnitus and pain as persisting aversive memory networks. Proc. Natl. Acad. Sci.
U. S. A. 108, 8075e8080.
Eggermont, J.J., 1984. Tinnitus: some thoughts about its origin. J. Laryngol Otol.
(Suppl. 9), 31e37.
Eggermont, J.J., 1992. Neural interaction in cat primary auditory cortex. Dependence
on recording depth, electrode separation and age. J. Neurophysiol. 68, 1216e1228.
Eggermont, J.J., 2007. Correlated neural activity as the driving force for functional
changes in auditory cortex. Hear. Res. 229, 69e80.
Eggermont, J.J., Kenmochi, M., 1998. Salicylate and quinine selectively increase
spontaneous ring rates in secondary auditory cortex. Hear. Res. 117, 149e160.
Eggermont, J.J., Komiya, H., 2000. Moderate noise trauma in juvenile cats results in
profound cortical topographic map changes in adulthood. Hear. Res. 142, 89e101.
Eggermont, J.J., Roberts, L.E., 2004. The neuroscience of tinnitus. Trends Neurosci.
27, 676e682.
Feldman, D.E., 2009. Synaptic mechanisms of plasticity in neocortex. Annu. Rev.
Neurosci. 32, 33e55.
Formby, C., Sherlock, L.P., Gold, S.L., 2003. Adaptive plasticity of loudness induced by
chronic attenuation and enhancement of the acoustic background. J. Acoust.
Soc. Am. 114, 55e58.
Fox, M.D., Raichle, M.E., 2007. Spontaneous uctuations in brain activity observed
with functional magnetic resonance imaging. Nat. Rev. Neurosci. 8, 700e711.
ner-Herwich, B., 2013. Neural correGolm, D., Schmidt-Somoa, C., Dechent, P., Kro
lates of tinnitus related distress: an fMRI-study. Hear Res. 295, 87e99.
Gu, J.W., Halpin, C.F., Nam, E.C., Levine, R.A., Melcher, J.R., 2010. Tinnitus, diminished
sound-level tolerance, and elevated auditory activity in humans with clinically
normal hearing sensitivity. J. Neurophysiol. 104, 3361e3370.
Heffner, H.E., Heffner, R.S., 2012. Behavioral tests for tinnitus in animals. In:
Eggermont, J.J., Zeng, F.-G., Ray, R.R., Popper, A.N. (Eds.), Springer Handbook of
Auditory Research, Tinnitus, vol. 47. Springer ScienceBusiness Media New
York, pp. 21e58.
11
reduced cochlear output and the failure to adapt the central auditory response
causes tinnitus in noise exposed rats. PLoS ONE 8 (3), e57247.
Schaette, R., Kempter, R., 2006. Development of tinnitus-related neuronal hyperactivity through homeostatic plasticity after hearing loss: a computational
model. Eur. J. Neurosci. 23, 3124e3138.
Seeley, W.W., Menon, V., Schatzberg, A.F., et al., 2007. Dissociable intrinsic connectivity net- works for salience processing and executive control. J. Neurosci.
27, 2349e2356.
Seki, S., Eggermont, J.J., 2002. Changes in cat primary auditory cortex after minorto-moderate pure-tone induced hearing loss. Hear. Res. 173, 172e186.
Seki, S., Eggermont, J.J., 2003. Changes in spontaneous ring rate and neural synchrony in cat primary auditory cortex after localized tone-induced hearing loss.
Hear Res. 180, 28e38.
Dossi, R., Nun
~ ez, A.,1993. The slow (<1 Hz) oscillation in
Steriade, M., Contreras, D., Curro
reticular thalamic and thalamocortical neurons: scenario of sleep rhythm generation in interacting thalamic and neocortical networks. J. Neurosci. 13, 3284e3299.
Stolzberg, D., Chen, G.-D., Allman, B.L., Salvi, R.J., 2011. Salicylate-induced peripheral
auditory changes and tonotopic reorganization of auditory cortex. Neuroscience
180, 157e164.
Sun, W., Lu, J., Stolzberg, D., Gray, L., Deng, A., Lobarinas, E., Salvi, R.J., 2009. Salicylate
increases the gain of the central auditory system. Neuroscience 159, 325e334.
Tonndorf, J., 1984. Auditory coding mechanisms. J. Laryngol. Otol., Suppl. 9 128e131.
Turrigiano, G., 1999. Homeostatic plasticity in neuronal networks: the more things
change, the more they stay the same. Trends Neurosci. 22, 221e227.
Turrigiano, G., 2011. Too many cooks? Intrinsic and synaptic homeostatic mechanisms in cortical circuit renement. Annu. Rev. Neurosci. 34, 89e103.
Tzounopoulos, T., Kim, Y., Oertel, D., Trussell, L.O., 2004. Cell-specic, spike timingdependent plasticities in the dorsal cochlear nucleus. Nat. Neurosci. 7, 719e725.
Tzounopoulos, T., Rubio, M.E., Keen, J.E., Trussell, L.O., 2007. Coactivation of pre and
postsynaptic signaling mechanisms determines cell-specic spike-timing
dependent plasticity. Neuron 54, 291e301.
Valentine, P.A., Teskey, G.C., Eggermont, J.J., 2004. Kindling changes burst ring,
neural synchrony and tonotopic organization of cat primary auditory cortex.
Cereb. Cortex 14, 827e839.
Vanneste, S., Plazier, M., van der Loo, E., van de Heyning, P., Congedo, M., De Ridder, D.,
2010. The neural correlates of tinnitus-related distress. Neuroimage 52, 470e480.
Vanneste, S., van de Heyning, P., De Ridder, D., 2011. The neural network of phantom
sound changes over time: a comparison between recent-onset and chronic
tinnitus patients. Eur. J. Neurosci. 34, 718e731.
Vogler, D.P., Robertson, D., Mulders, W.H.A.M., 2011. Hyperactivity in the ventral
cochlear nucleus after cochlear trauma. J. Neurosci. 31, 6639e6645.
Weisz, N., Moratti, S., Meinzer, M., Dohrmann, K., Elbert, T., 2005. Tinnitus
perception and distress is related to abnormal spontaneous brain activity as
measured by magnetoen- cephalography. PLoS Med. 2, 546e553.
Wienbruch, C., Paul, I., Weisz, N., Elbert, T., Roberts, L.E., 2006. Frequency organization of the 40-Hz auditory steady-state response in normal hearing and in
tinnitus. Neuroimage 33, 180e194.
Yang, S., Weiner, B.D., Zhang, L.S., Cho, S.-J., Bao, S., 2011. Homeostatic plasticity
drives tinnitus perception in an animal model. PNAS 108, 14974e14979.
Yang, G., Lobarinas, E., Zhang, L., Turner, J., Stolzberg, D., Salvi, R., Sun, W., 2007.
Salicylate induced tinnitus: behavioral measures and neural activity in auditory
cortex of awake rats. Hear. Res. 226, 244e253.
Young, C.K., Eggermont, J.J., 2009. Coupling of mesoscopic brain oscillations: recent
advances in analytical and theoretical perspectives. Prog. Neurobiol. 89, 61e78.
Zhang, X., Yang, P., Cao, Y., Qin, L., Sato, Y., 2011. Salicylate induced neural changes in
the primary auditory cortex of awake cats. Neuroscience 172, 232e245.
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