Reversible Long-Term changes in Auditory Processing in

Reversible Long-Term Changes in Auditory Processing
in Mature Auditory Cortex in the Absence of Hearing
Loss Induced by Passive, Moderate-Level Sound
Exposure
Martin Pienkowski1,2 and Jos J. Eggermont1,2,3
guards against permanent threshold shifts, despite the fact that
TTS may be induced. Ward et al. (1976) suggested considerably
lower criteria for TTS avoidance, termed “effective quiet” levels. Examples are 76 dB (A) for an 8 hr exposure to broadband
noise, down to 65 dB (A) for octave-wide noise centered at 4
kHz, the frequency to which humans are normally most sensitive.
Early animal experiments have shown that at these more moderate sound levels even months of continuous exposure have no
apparent effect on behavioral thresholds, cochlear potentials, or
hair cell morphology (Kemp 1935). More recently, Canlon and
Fransson (1995), performing sound conditioning experiments,
exposed guinea pigs to a continuous tone of 1 kHz at 81 dB SPL
for 24 days. Auditory brainstem response (ABR) thresholds at
1 and 2 kHz were obtained before exposure and at days 1, 5, 10,
and 15 during sound conditioning as well as on the final 24th
day and were not changed by the exposure. Surface preparations of the organ of Corti at 14 or 30 days postexposure did not
reveal any significant hair cell loss.
Until recently, there was a widespread belief that prolonged
exposure to moderate-level sounds also has no effect on the
mature central auditory system, unless the sounds are associated with a behavioral drive and are thus attended to (e.g., see
reviews by Dahmen & King 2007; Keuroghlian & Knudsen 2007;
Polley et al. 2008; Sanes & Bao 2009). However, we showed
that a several-week to several-month passive exposure of adult
cats to moderate-level (70 dB SPL), band-limited noise and
tone pip ensembles can lead to a profound and frequencyspecific “suppression” of neural activity in both primary (AI)
and secondary (AII) auditory cortices, in the absence of hearing
loss (Noreña et al. 2006; Pienkowski & Eggermont 2009, 2010a,
2010b; Pienkowski et al. 2011). The suppression is persistent
and can progress, after several months of exposure, to a reorganization of the AI tonotopic map that is not unlike the reorganization observed after a hearing loss restricted to a part of the
frequency range (Robertson & Irvine 1989; Irvine et al. 2000).
It is also reminiscent of the “functional blindness” described in
visual cortex in severe cases of lazy eye, or amblyopia (Hofer
et al. 2006; He et al. 2007; Hooks & Chen 2007; Levi & Li
2009; Bavelier et al. 2010): in both cases, the sensory periphery functions normally, but there is a suppression of input to
the cortex. In the visual system, neural activity from the poorly
focused (lazy) eye is suppressed; in the auditory system, neural
activity in the exposure frequency range is suppressed.
We have recently reviewed some of our work on passive,
moderate-level sound exposure in the wider context of sensory
brain plasticity (Pienkowski & Eggermont 2011). In this article, we focus specifically on audiological issues, discussing the
It has become increasingly clear that even occasional exposure to loud
sounds in occupational or recreational settings can cause irreversible
damage to the hair cells of the cochlea and the auditory nerve fibers,
even if the resulting partial loss of hearing sensitivity, usually accompanied by tinnitus, disappears within hours or days of the exposure.
Such exposure may explain at least some cases of poor speech intelligibility in noise in the face of a normal or near-normal audiogram.
Recent findings from our laboratory suggest that long-term changes to
auditory brain function—potentially leading to problems with speech
intelligibility—can be effected by persistent, passive exposure to more
moderate levels of noise (in the 70 dB SPL range) in the apparent
absence of damage to the auditory periphery (as reflected in normal
distortion product otoacoustic emissions and auditory brainstem
responses). Specifically, passive exposure of adult cats to moderate
levels of band-pass-filtered noise, or to band-limited ensembles of
dense, random tone pips, can lead to a profound decrease of neural
activity in the auditory cortex roughly in the exposure frequency range,
and to an increase of activity outside that range. This can progress
to an apparent reorganization of the cortical tonotopic map, which is
reminiscent of the reorganization resulting from hearing loss restricted
to a part of the hearing frequency range, although again, no hearing
loss was apparent after our moderate-level sound exposure. Here, we
review this work focusing specifically on the potential hearing problems that may arise despite a normally functioning auditory periphery.
(Ear & Hearing 2012;33;305–314)
INTRODUCTION
Exposure to loud sound can irreversibly damage or destroy
peripheral auditory structures, including the inner hair cells (IHCs)
and outer hair cells (OHCs) of the cochlea and the spiral ganglion
cells (SGCs) of the auditory nerve (Borg et al. 1995; Henderson et
al. 2006; Ohlemiller 2008). This can lead to permanent decreases
in hearing sensitivity and frequency selectivity, and to poor speech
intelligibility in noise, as well as tinnitus (Moore 1996; Houtgast &
Festen 2008; Roberts et al. 2010). Even exposures leading “only”
to temporary threshold shifts (TTSs) can produce permanent
damage, such as the destruction of IHC ribbon synapses and the
resulting gradual degeneration of the denervated SGCs (Kujawa
& Liberman 2006, 2009). It is possible that noise-induced SGC
degeneration could explain at least some cases characterized by
poor speech reception in noise but with relatively normal audiograms and cochlear function (Nábĕlek 1988; Gordon-Salant 2005;
Frisina 2009; Lagacé et al. 2010).
At present, an 8 hr daily exposure of 85 dB (A) is considered acceptable (NIOSH 1998; OSHA 2002) because it safeDepartments of 1Physiology and Pharmacology; 2Psychology; and 3Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
0196/0202/12/3303-0305/0 • Ear & Hearing • Copyright © 2012 by Lippincott Williams & Wilkins • Printed in the U.S.A.
305
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possibility that long-term occupational or recreational sound
exposure at levels presently considered acceptable triggers
auditory cortical plasticity and causes problems with hearing
despite normal cochlear and even lower brainstem function.
PASSIVE EXPOSURE TO MODERATELEVEL, BAND-LIMITED NOISE OR TONE
ENSEMBLES TRIGGERS AUDITORY
CORTICAL PLASTICITY IN ADULT CATS
In this section, we briefly summarize our recent findings of
auditory cortical plasticity after the passive exposure of adult cats
to moderate-level sounds (as published in Noreña et al. 2006;
Pienkowski & Eggermont 2009, 2010a, 2010b; Pienkowski
et al. 2011). Our exposure stimuli consisted of sharply bandlimited noise or tonal ensembles. Various exposure bandwidths (BWs) and center frequencies were used (e.g., 4 to
20 kHz, 2 to 4 kHz, and third-octave bands centered at 4 and
16 kHz). The average sound level was in the 65 to 70 dB range.
Adult (3-mo-old) cats were exposed for several days to several months, either continuously (24 hr/day) or intermittently
(12 hr exposure followed by 12 hr of quiet), while housed
together with their littermates in a free-range room (1.7  3.4 
3.0 m) that was tiled and acoustically reflexive. The background
noise level (when no cats were present) was 42 dB SPL at
1 kHz, sloping down at initially 18 dB/octave to reach a plateau of 18 dB SPL at 6 kHz. There were no visible peaks in this
background spectrum (Noreña et al. 2008). The kittens were in
this room from 6 wk of age without any exposure. The kittens
were provided by the same supplier that provided our control
cats, which were also acquired at 6 wk of age. Thus, the acoustic environment for control and exposed cats was the same up
to the beginning of exposure. By 75 days of age, cat auditory
cortical response properties (e.g., tonotopy, frequency selectivity, latency, threshold, and firing rate) were mature or close to
maturity (Eggermont 1996b; Bonham et al. 2004), suggesting
Fig. 1. Mean auditory brainstem response (ABR) audiograms (error bars 
1 SE) from a group of unexposed control cats (black circles; solid lines) and
a group of cats exposed to moderate-level noise or tone ensembles (open
circles; dashed lines). After correcting for multiple comparisons, the mean
ABR audiograms for the control and exposed cats are not significantly different at any frequency, except 32 kHz (p  0.003; analysis of variance,
Bonferroni test), where exposed cats appear slightly more sensitive. This
is similar to the improved compound action potential thresholds observed
after sound conditioning (Kujawa & Liberman 1999).
that most, if not all, central developmental changes occurred
before the start of our exposure.
Exposed cat ABR thresholds and amplitudes were rarely outside of control norms, even immediately after a 5 mo exposure
at 80 dB SPL (Noreña et al. 2006). Figure 1 shows averaged cat
wave 4 ABR thresholds (error bars  1 SE) for a group of 24
unexposed controls (black circles; solid lines) and a (different)
group of 35 cats exposed to 70 dB SPL for 5 to 13 wk (open
circles; dashed lines). Because the exposure produced no loss of
sensitivity at the lateral lemniscus/inferior colliculus, the sites
of the generators of cat ABR wave 4, there could be no loss at
more peripheral stations. Also, although the average responses
of auditory cortical neurons were very much affected by the
exposure, as described later in the article, the lowest recorded
cortical thresholds at a given frequency were similar for control
and exposed cats, further supporting the observation that the
exposure had little or no effect on hearing sensitivity.
Extracellular multi-unit (MU) spike and local field potential
(LFP) activity were recorded from auditory cortex of control
and exposed cats under ketamine anesthesia. Recording was
performed with a pair of 16 microelectrode arrays (arranged in a
2  8 configuration, as illustrated in Fig. 2), predominantly from
pyramidal cells in deep cortical layer III or layer IV, the thalamic
input layers (Wallace et al. 1991; Ehret & Romand 1997). Auditory cortex was densely and uniformly sampled with the arrays
in all cats (e.g., Fig. 2). Figure 2 compares the tonotopic organization of primary auditory cortex (AI) (outlined and shaded for
emphasis) in a representative adult control (cat 444) and a cat
exposed continuously for 6 wk to a sharply filtered, 4 to 20 kHz
band of uniform white noise at 70 dB SPL (cat 435). Control
AI shows a clear tonotopic organization (Merzenich et al. 1975;
Reale & Imig 1980). The adjacent anterior auditory field and
posterior auditory fields show a much more crude tonotopy, and
the ventrally positioned secondary auditory cortex (AII) lacks
any apparent frequency map. This layout of auditory cortical
fields seems similar to that observed in humans (Formisano
et al. 2003; Langers et al. 2007; Humphries et al. 2010).
Between the two-dimensional maps of Figure 2 we show the
classic characteristic frequency (CF)–distance plots for AI,
which are simply one-dimensional projections of the AI map
onto the axis of the predominant tonotopic gradient. Last, below
the two-dimensional maps, we show histogram distributions of
AI MU characteristic frequencies (left), and scatter plots of AI
MU response thresholds versus the CF (right).
There is some variation in the shape and size of AI, but
that is common even between normal-hearing controls. What
is unusual after sound exposure is the underrepresentation in
both AI and AII of units with CFs in the exposure frequency
range, especially between 4 and 10 kHz, and an overrepresentation of units with CFs above (20 kHz) and below (1.2 kHz)
the exposure range. Note that units with the highest and lowest CFs cover a much larger than normal area of AI (compare
error bars on CF-distance plots), and that the thresholds of these
units are on average better than normal. This indicates that true
receptive field and tonotopic map reorganization has occurred,
as opposed to just a suppression of neural responses to frequencies in the exposure range. Again, the effect is reminiscent of
that observed after restricted hearing loss (Robertson & Irvine
1989; Rajan et al. 1993; Irvine et al. 2000; Noreña & Eggermont
2005), although the ABRs of exposed cat 435 were normal.
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Fig. 2. 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 4 to 20 kHzfiltered 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 fields (anterior auditory field, posterior auditory field, 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 two-dimensional 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). Data replotted
from data in Pienkowski et al. (2011).
The effects of sound exposure on neuronal frequency tuning in
auditory cortex can be summarized in the population frequencyresponse curve (FRC). Such population FRCs, averaged across a
number of cats, are presented in Figure 3 for both MU spike-based
(Fig. 3A) and LFP-based (Fig. 3B) data obtained from densely
sampled AI (sample sizes are specified in the figure). LFPs
mainly reflect synchronous postsynaptic potentials (Mitzdorf
1985), which are summed over a much larger brain volume than
the (high-pass filtered) spike activity recorded extracellularly on
the same electrode (Eggermont et al. 2011). Both spike and LFP
activity in AI were similarly affected by moderate-level sound
exposure, as described later in the article. The first column of
Fig. 3. First column: multi-unit (MU) spike (A) and local field potential (LFP)-based (B) population tuning curves obtained from a uniform sampling of AI in a
group of normal-hearing, unexposed control cats. Each individual frequency-response curve (FRC) was taken at the best response SPL (typically 55–65 dB SPL)
and normalized on its peak value before averaging. FRC thickness illustrates the Bonferroni-corrected 95% confidence interval about the mean. Subsequent
columns: population-averaged FRCs from groups of cats obtained immediately after long-term (5 wk), passive exposure to various sound stimuli, as specified
in the column headings. Dotted lines mark the bandwidths of the exposure stimuli. FRCs from the exposed cats are shown in gray, and are compared with the
control curve, reproduced in black; where the difference between the two curves is larger than half the sum of their 95% confidence levels (i.e., where there
is no overlap between curves), that difference is (conservatively) significant at p  0.05. Data replotted from Pienkowski and Eggermont, 2009 (columns 1 and
2), Pienkowski and Eggermont, 2010a (column 3), Pienkowski et al., 2011 (column 4), and Pienkowski and Eggermont, 2010b (columns 5 and 6).
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Figure 3 presents population-averaged FRCs obtained from a
group of unexposed controls. Individual FRCs were taken at the
stimulus level evoking the strongest response, typically 55 to 65
dB SPL, and normalized on this maximum value before averaging. The normalization facilitates comparisons between cats,
which show some variation in average response strength even
between controls, but does not change any of the reported findings regarding the effects of sound exposure. The thickness of the
tuning curve illustrates the Bonferroni-corrected 95% confidence
interval about the mean. In subsequent columns of Figure 3, we
show corresponding FRCs averaged from AI of groups of cats
exposed to continuous or intermittent sound for 5 to 13 wk. The
exposure stimuli are specified in the column headings and their
BWs are indicated with dotted lines. FRCs from the exposed cats
are shown in gray, and are compared with the control curve, copied in black. Where the difference between the two means is larger
than half the sum of their 95% confidence levels (i.e., where there
is no overlap between curves), that difference is (conservatively)
significant at p  0.05 (Gardner & Altman 1986). In Figure 3, all
responses were obtained within a day of the cessation of exposure;
the onset of, and the recovery from the effects of exposure will be
considered further in the subsequent sections.
Persistent, continuous exposure of adult cats to a random ensemble of tone pips bandlimited between 4 and 20 kHz, at an average
level of 68 dB SPL, led to a profound suppression of AI population activity in response to sounds in the exposure frequency range
(Fig. 3, second column; data from Pienkowski & Eggermont 2009).
Note that in the spike data, the strongest suppression occurred at
the inner edges of the exposure band, with a local minimum in suppression at 10 kHz, about an octave from either edge. The effect
was similar but significantly weaker after an intermittent exposure
(12 hr on/12 hr off) of the same type, duration, and intensity (Fig.
3, third column; data from Pienkowski & Eggermont 2010a). Profound suppression was also observed after continuous exposure to
4 to 20 kHz band-limited noise (Fig. 3, fourth column; data from
Pienkowski et al. 2011), although suppression was strongest from
4 to 10 kHz, and progressively weaker up to 20 kHz. Note that the
noise produced a highly significant increase in response strength
above and below the exposure range, evidence of a more extensive
reorganization of the AI tonotopic map (as opposed to just response
suppression) than produced by the 4 to 20 kHz tone pip ensemble,
a finding corroborated by the inspection of maps from individual
cats (Fig. 2B). Note, however, that a longer (5 mo) exposure to
the 4 to 20 kHz pips also produced a more extensive reorganization
in AI (Noreña et al. 2006; maps shown in Pienkowski & Eggermont 2009). With narrower tonal exposure BWs (an octave-band
spanning 2 to 4 kHz, or a pair of third-octave bands centered at 4
and 16 kHz), the suppression could extend about an octave beyond
the exposure frequency range (Fig. 3, fifth and sixth columns; data
from Pienkowski & Eggermont 2010b).
To study the time course of cortical response suppression, we
exposed a group of four cats to the 4 and 16 kHz third-octave bands
and recorded after 2, 7, 14, and 28 days of exposure (one cat per
time point). Averaged MU spike-based FRCs obtained from AI are
presented in Figure 4, in the same format as Figure 3 (exposed cat
FRCs in gray, control in black). After 2 days of exposure, strong
suppression was already evident, though only in the vicinity of
4 kHz; responses to lower frequencies were normal and those at
higher frequencies were enhanced. The resonance frequency of
the cat’s external ear is 3 kHz (Musicant et al. 1990), making
our free-field stimulation at 4 kHz effectively louder than that at
16 kHz by 10 dB, and likely explaining the faster onset of suppression at 4 kHz. By the end of the first week of exposure,
suppression was about equally strong at 4 and 16 kHz, with little
suppression between these two valleys, at 8 kHz. Between 1 and
4 wk of exposure, the range of suppression gradually expanded
to cover the entire 4 to 16 kHz band, with the 4 week data closely
resembling those after 7 to 13 wk (compare with the right-most
column of Fig. 3), except that in the 4 week cat, strongest enhancement was observed at low frequencies, whereas in the 7 to 13 wk
group, strongest enhancement was at high frequencies.
It is interesting that after the 7 to 13 wk exposure to the 4 and
16 kHz third-octave random tone pips, suppression in AII, which
is not tonotopically organized, remained more frequency-specific
than suppression in AI. Figure 5 shows MU spike-based (A) and
LFP-based (B) population-averaged FRCs from AII of exposed
cats (gray), compared with FRCs from AII of control cats (black)
(data from Pienkowski & Eggermont 2010b). Population tuning
in exposed cat AII shows clear notches at 4 and 16 kHz, closely
matching the magnitude of suppression in exposed cat AI (see
right-most column of Fig. 3). However, between the two notches,
responses in exposed AII are not significantly different from
control for spike-based data (Fig. 5A), and only slightly different
for LFP-based data (Fig. 5B). We will return to this difference
when we discuss the putative mechanisms of exposure-induced
auditory cortical plasticity in the following section.
Reversal of exposure-induced changes progressed slowly during a period of quiet recovery in a room shared with littermates.
Fig. 4. Population-averaged multi-unit (MU) spike-based frequency-response curves (FRCs) obtained from AI of cats exposed to a pair of third-octave bands
of tone pips centered at 4 and 16 kHz (dotted lines), with the duration of exposure increasing from left to right as specified in the column headings. Again,
exposed cat FRCs (gray) are compared with control cats (black), with curve thickness representing the Bonferroni-corrected 95% confidence interval for the
mean. Data replotted from Pienkowski et al. (2011).
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309
Fig. 5. Population-averaged multi-unit (MU) spike (A)
and local field potential (LFP)-based (B) frequency-response curves (FRCs) obtained from AII of cats exposed
to a pair of third-octave bands of tone pips centered at
4 and 16 kHz (dotted lines). FRCs from exposed AII are
shown in gray, and compared with control AII (black).
Curve thickness gives the Bonferroni-corrected 95%
confidence interval for the mean. Data replotted from
Pienkowski and Eggermont (2010b).
Figure 6 shows MU spike-based (A) and LFP-based (B) FRCs
from AI of cats exposed to the 4 to 20 kHz pips ensemble at
68 dB SPL for 6 wk. Black curves represent data from controls and gray curves represent data obtained within 1 day of
the cessation of exposure, as shown in the second column of
­Figure 3. Blue curves present measurements after 1 to 3 wk of recovery from exposure (two cats), and red curves after 8 to 12 wk of
recovery (five cats; data from Pienkowski & Eggermont 2009).
Some recovery toward normal population frequency tuning can
be seen within a few weeks of the end of exposure, but even
after 8 to 12 wk, recovery is not quite complete. Furthermore,
although the CF distribution of the AI neural population could
return to near-normal after 8 to 12 wk of recovery, neurons in the
region of AI tuned to the 4 to 20 kHz frequencies were no longer
tonotopically organized (Pienkowski & Eggermont 2009). We
also noted that the recovery of frequency tuning took longer
when the initial exposure-induced suppression was more pronounced, as was the case with the 2 to 4 kHz pips (Fig. 3, fifth
column; data on recovery in Pienkowski & Eggermont 2010b).
We also note that the quiet acoustic environment during cat
maturation and the age of the cats at exposure onset preclude
that our findings reflect a developmental phenomenon. It is also
stressed that the postexposure recovery of normal population frequency tuning is nearly complete after 3 mo in a quiet environment
(after a 6 wk exposure), but that the tonotopicity in the exposure
frequency region remains disordered. Additional passive presentation of tonal stimuli in the frequency range of this disordered
region only induces further response suppression (Pienkowski and
Eggermont, unpublished results). However, subsequent exposure
to sound in association with behaviorally meaningful tasks might
facilitate recovery from the effects of passive exposure, as suggested by developmental studies (Zhou & Merzenich 2007).
In conditioning experiments, several weeks of sound
exposure reduces the amount of hearing loss produced by a
subsequent (Canlon et al. 1988; Campo et al. 1991) or previous noise trauma (Noreña & Eggermont 2005). Several mechanisms have been invoked, ranging from upregulation of tyrosine
hydroxilase in lateral efferent terminals on auditory nerve fiber
dendrites (Niu & Canlon 2002) as well as activation of dopaminergic efferent pathways, which increase tonic inhibition of auditory nerve fibers and protect against glutamate excitotoxicity (Niu
et al. 2007). Other possibilities include activation of the hypothalamic-pituitary-adrenal axis, which upregulates cochlear
glycocorticoid reception (Tahera et al. 2007), and increasing the
resistance to free-radical damage (Harris et al. 2006). In C57B
mice that show early progressive hearing loss, sound exposure reduces the speed of this process (Willott & Turner 1999;
Willott & Bross 2004). In light of our findings of the effects of
various types of acoustic environments on auditory cortical processing one wonders what other changes these conditioning or
protective exposures can introduce. They will also likely affect
central processing as suggested by the findings of Pienkowski
and Eggermont (2009), which showed effects of exposure on
cortical spontaneous firing rates and neural synchrony, and the
potential to induce hyperacusis.
PUTATIVE MECHANISMS OF
EXPOSURE-INDUCED PLASTICITY
There are several potential mechanisms for the long-term
suppression of auditory cortical activity, which, at least initially,
seems restricted to the frequency band of the exposure stimulus
(Fig. 4, third column). One possibility is that the sustained
increase in the firing of auditory nerve fibers tuned to the
exposure range could trigger a homeostatic reduction in the
gains of afferent synapses in the auditory pathway (Turrigiano
1999; Turrigiano & Nelson 2004; Robinson & McAlpine 2009),
perhaps at the thalamocortical synapse. For example, if the
Fig. 6. Population-averaged multi-unit (MU) spike (A)
and local field potential (LFP)-based (B) frequencyresponse curves (FRCs) from AI of control cats (black),
and immediately after exposure to the 4 to 20 kHz
tone pip ensemble (dotted lines) for 6 to 8 wk (gray),
as shown in the second column of Figure 3. FRCs presented in blue color were obtained after 1 to 3 wk of
recovery from exposure, and those in red after 8 to 12
wk of recovery. Curve thickness gives the Bonferronicorrected 95% confidence interval for the mean. Data
replotted from Pienkowski and Eggermont (2009).
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auditory cortex became three times more active than usual as a
result of sound exposure, thalamocortical gains would be reduced
to one-third of normal. When the stimulus was turned off, test
sounds in the exposure frequency range would evoke only a third
of the activity seen in unexposed controls. Another possibility,
not mutually exclusive with the gain control hypothesis, is
that suppression results from a top–down-driven habituation
to the random, noninformative exposure sound (Castellucci
et al. 1978; Condon & Weinberger 1991; Rankin et al. 2009).
Several observations, however, do not appear consistent with
a pure habituation mechanism. Habituation has a fast onset
(minutes), whereas the suppression reported here seems to
take several weeks to fully develop (Fig. 4). Habituation can
arise after relatively few presentations of a repetitive stimulus,
whereas it seems that more persistent passive stimulation is
required to effect plasticity in adult auditory cortex. Zhang
et al. (2002) found that 20 days of continuously presented pulses
of broadband noise had no apparent effect on AI of rats that
were at least 30 days old at the start of exposure. In younger
rats, the same exposure led to abnormally broad frequency
tuning curves and a degraded tonotopic map when measured in
adulthood. The noise pulses were 50 msec long and presented
at the rate of 6/sec with a 1 sec silent period between each
six-pulse burst (i.e., the rats were effectively exposed to noise
only 15% of the time). The apparent need for more persistent
stimulation to effect change in adult auditory cortex was
supported by the decrease in the amount of suppression when
we reduced exposure from 24 to 12 hr/day (Fig. 3, second and
third columns).
It seems that the initial reduction of neural activity in the
region of AI tuned to the exposure stimulus also reduces
the lateral inhibition to adjacent AI regions, thereby increasing activity in those regions (Fig. 7). This increased activity
at frequencies above and below the exposure band could in
turn increase the lateral inhibition to neighboring regions (Fig.
7), potentially explaining the local minimum in suppression at
10 kHz for the 4 to 20 kHz tonal exposure (Fig. 3, second column), as well as the broadening of suppression beyond the
exposure range for narrowband stimuli (Fig. 3, fifth and sixth
columns; Fig. 4). The approximately octave-wide spread or
enhancement of suppression from the exposure band edge is
consistent with anatomical and physiological studies of lateral
(inhibitory) connections in AI (Wallace et al. 1991; Sutter &
Loftus 2003). In AII on the other hand, suppression remained
Fig. 7. A, Effects of sound exposure on auditory cortical activity. Initially, the band-limited exposure stimulus (black bar) causes a frequency-specific reduction
of cortical activity (B), by homeostatic gain control or
habituation, as discussed in the text. Decreased activity in the exposure frequency range reduces inhibition
to neighboring cortical regions, increasing activity in
those regions (C). This in turn increases inhibition to
the exposure region, further reducing activity particularly at the inner edges of the region (D).
largely restricted to the exposure range (Fig. 5), which is likely
a consequence of the lack of tonotopy in AII, resulting in a
smaller ranging and less synergistic lateral inhibitory effect.
Our recordings were performed under ketamine anesthesia.
Ketamine is a cataleptic anesthetic agent that produces anesthesia combined with excitatory effects on the EEG (Winters et al.
1972), mediated by activation of the mesencephalic reticular formation (Kayama 1983). This results in enhanced responsiveness
of cells in the auditory cortex to sound (Newman & Symmes
1974). Ketamine is also known as an N-Methyl-d-aspartate
Ca2+ noncompetitive channel blocker and as such may affect the
excitatory output of glutaminergic, most likely pyramidal cells
in the cortex. This in turn could affect the activity of gammaaminobutyric acid (GABAergic) cells and so influence tuning
and other response properties of the pyramidal cells (Olney
et al. 1991). However, animals under light ketamine anesthesia
show single neuron firing rates that are very similar to those
in awake animals. Tuning curve BWs under ketamine anesthesia are also very similar to those in awake animals (Eggermont
1996a; Bendor & Wang 2008).
POTENTIAL EFFECTS OF MODERATELEVEL SOUND EXPOSURE ON HEARING
AND IMPLICATIONS FOR AUDIOLOGY
What are the potential perceptual consequences of exposureinduced cortical response suppression and AI tonotopic map
reorganization? If loudness is monotonically related to the
response strength of a population of auditory neurons (Moore
et al. 1997), even at the cortical level (Phillips et al. 1994;
Hart et al. 2003), we would expect our cats to have a shallower
loudness function in the exposure frequency range, and a
steeper loudness function above or below that range. In other
words, they would have their internal volume control turned
down inside the exposure band, and turned up outside.
This expectation is largely consistent with the findings of
Formby et al. (2003). They asked normal-hearing human volunteers to wear either earplugs or a set of open-canal, in-theear speakers producing a low-level noise between 1 and 8 kHz
with a peak level of 50 dB SPL at 6 kHz. Each treatment
was worn continuously (at least 23 hr/day) for 2 wk, and subjects performed loudness judgments on 500 and 2000 Hz tones
before and after treatment. In Figure 8, it can be seen that noiseexposed subjects (circles) needed up to an additional 4 to 8 dB
PIENKOWSKI AND EGGERMONT / Ear & Hearing, Vol. 33, No. 3, 305–314
311
Fig. 8. Effects of 2 wk of moderate-level noise exposure (top panels) and earplug wearing (bottom panels)
on the loudness categorization of 500 Hz (left) and
2000 Hz tones (right) by human subjects, as described
in the text. Reprinted with permission from J Acoust
Soc Am. 2003;114:55–58.
of sound intensity to match their baseline loudness judgments.
Conversely, subjects who wore earplugs (squares) needed up
to 5 to 9 dB less sound intensity compared with their baseline.
Note that absolute thresholds were not affected, even temporarily, by either treatment. From our perspective (and that
of Formby et al.), the only surprising result was that the
noise-exposed subjects showed no difference in post-treatment
loudness judgments between 500 and 2000 Hz, despite the
fact that these tones were, respectively, an octave below and
an octave above the lower edge frequency of the noise. Additional evidence for loudness rescaling after sound exposure
was obtained by Noreña and Chery-Croze (2007). They found
that hearing-impaired subjects with hyperacusis (i.e., abormally
high loudness sensitivity) could be helped by several weeks
of just a few hours daily exposure to a moderate-level tone
ensemble shaped to the frequency range of the hearing loss,
which presumably reduced the slope of the abnormally steep
loudness function.
Would the auditory cortical plasticity induced by our noise
and tone ensembles develop in humans exposed to moderately
loud environments in the real world? Although our 4 to 20 kHz
noise and tone stimuli have near-identical long-term power spectra, they sound different, as the tone ensemble has a much more
variable short-term frequency spectrum and a low-pass modulation spectrum. Continuous exposure to either stimulus produced
a similar suppression of neural activity in AI (Fig. 3, second
and fourth columns), suggesting that mixes of tonal and noise
sounds (i.e., a more realistic, real-world noise) could have similar effects. There are several caveats, however. All of our stimuli
were sharply bandlimited, whereas the power spectra of natural
sounds would fall off more gradually; thus, the edge effect that
was proposed to enhance suppression (Fig. 7) should be smaller
for more realistic sounds. Another potential factor was that
our exposures were less structured (more random) than typical sources of real-world noise, and may thus have been easier
to “habituate to” (Kjellberg 1990). Perhaps the most important
factor was the duration of the exposure. Again, a decrease in the
suppression effect was found when the exposure was reduced
from 24 to 12 hr/day (Fig. 3, second and third columns); a further decrease might be expected from 12 to 8 hr or less. This
may, however, be more than offset by an intermittent, real-world
exposure that occurs over years or decades, rather than weeks or
months as in our laboratory. If so, would the time course of the
reversal of plasticity also be more protracted than that observed
in our studies? Would full reversal even be possible, given that
longer-term exposure leads to a more complete reorganization
of the tonotopic map in AI (Noreña et al. 2006)? The extent
to which the results presented in this article generalize to realworld noise is a subject of ongoing investigation.
Assuming that the loudness rescaling described earlier did in
fact “stick” in people exposed for a sufficiently longtime to moderate-level, real-world noise, what might be the consequences
for auditory perception? A number of studies have focused on
the effects of moderate exposure on general well-being (stress)
and the performance of job-related tasks (Wilkins & Acton
1982; Kjellberg 1990; Kristal-Boneh et al. 1995; Melamed &
Bruhis 1996; Chen et al. 1997; Van Gerven et al. 2009). Fewer
studies have investigated the effects on hearing. Kujala et al.
(2004) compared a small (N  10) group of young adult subjects
(mean age  28 yr) with a history of moderate noise exposure
(working in shipyards and preschools) with a group of age- and
hearing-matched controls. Although audiograms were not presented, they were reported to be in the normative range for all
participants, and were not significantly different between the
two groups. Using both behavioral testing and scalp recordings
of evoked potentials from the auditory cortex, Kujala et al demonstrated a significantly poorer discrimination of the syllables
/ka/ and /pa/ in exposed subjects. With regard to the long-latency
auditory potentials evoked by these syllables, they showed no
differences between the subject groups in either the amplitudes
or the latencies of the P1, N1, and P2 components, suggesting that the cortical representation of the syllables was normal
in the exposed group. However, exposed subjects exhibited
a reduced mismatch negativity response during a standard/
deviant syllable paradigm, corroborating the behavioral finding
of impaired syllable discrimination. It may be that the changes
in the cortical population response observed in our studies
(Fig. 3) represent the neurophysiological underpinnings of
poorer syllable discrimination in the subjects of Kujala et al.
This would suggest that frequency-specific changes in loudness,
resulting from putative cortical gain changes, can lead to problems in discriminating speech sounds.
Another issue is whether moderate-level sound exposure can
lead to tinnitus. Tinnitus has been associated with, among other
things, an increase in neural spontaneous firing, an increase
in the synchrony of neural firing, and cortical tonotopic map
reorganization, all of which can result from a traumatic noise
exposure (e.g., Noreña & Eggermont 2003, 2005, 2006; Seki &
Eggermont 2003; Kotak et al. 2005; Yang et al. 2007; Roberts et
al. 2010; Engineer et al. 2011). Topographic map reorganization
312 PIENKOWSKI AND EGGERMONT / Ear & Hearing, Vol. 33, No. 3, 305–314
and increased spontaneous firing in somatosensory cortex is likewise correlated with phantom pain after limb amputation (Flor
et al. 1995; Grüsser et al. 2001). Our exposed cats presented all
three putative neural correlates of tinnitus, but without hearing
loss. Map reorganization after moderate-level exposure has been
discussed earlier (Fig. 2B). Relative to controls, our exposed cats
also showed increased spontaneous firing in AI regions outside
the exposure frequency range, and decreased spontaneous firing
within the exposure range (Noreña et al. 2006; Pienkowski &
Eggermont 2010b). Furthermore, the synchrony of spontaneous
firing was increased relative to controls, especially between pairs
of units with at least one unit located in an AI region outside
the exposure frequency range (Noreña et al. 2006; Pienkowski
& Eggermont 2009). We have not yet tested our exposed cats
behaviorally for tinnitus, but it would be interesting if tinnitus
could be experienced with normal cochlear function. To date,
chronic tinnitus has been demonstrated in the absence of permanent threshold shift in chinchillas after a 1 hr exposure to a 4
kHz tone at 85 dB SPL, which nevertheless produced small but
significant OHC lesions (Bauer et al. 2008), and in mice after a
45 min exposure at 16 kHz and 116 dB SPL (Middleton et al.
2011), which likely led to some SGC degeneration, as reported
by Kujawa and Liberman (2009).
Although chronic tinnitus can be experienced by people with
normal audiograms (Savastano 2008), it has been suggested that
such people may in fact have cochlear “dead regions” (Weisz
et al. 2006), regions of profound IHC or auditory-nerve fiber
loss that may not be detected by pure-tone audiometry (Moore
2004). Alternatively, they may have moderate OHC damage that
also escapes audiometric detection but is reflected, for example,
in abnormally small otoacoustic emissions (Job et al. 2007).
Davis and El Refaie (2000) reported a tinnitus prevalence of
7.5% in people with little exposure to noise, compared with
20.7% in people with high lifetime exposure (see also Davis
1989). However, these groups were not matched for hearing
loss. In a more controlled study, Rubak et al. (2008) reported
that tinnitus was not associated with the level or the duration of
noise exposure in people with normal hearing, but was associated with the exposure parameters in cases of hearing loss. Thus,
it remains unclear whether or not moderate noise exposures that
do not lead to hearing loss constitute a risk for tinnitus.
CONCLUSION
Many people with normal or near-normal audiograms,
especially among the elderly, have problems with speech
intelligibility in noisy environments (Gordon-Salant et al.
2010). We have suggested that at least some of these cases
may be linked to noise exposure. The noise may be traumatic,
leading to damage to cochlear structures and SGCs without
necessarily producing permanent absolute threshold shifts, at
least not until later in life. The noise may also be nontraumatic
yet lead to persistent changes in auditory cortical function even
when the cochlea and lower brainstem remain structurally and
functionally sound. Both types of exposure fall under the radar
of present occupational noise standards, which aim only to
prevent permanent increases in pure-tone thresholds.
Another area of potential concern is sound exposure during
early infancy. Perhaps most vulnerable are premature infants
spending time in neonatal intensive care units. As might be
expected given prevailing neonatal intensive care unit sound lev-
els (Williams et al. 2007), large-sample studies using the (Gorga
et al. 2000) and ABR (Sininger et al. 2000) found little evidence
of increased risk of peripheral hearing loss. Nevertheless, the
developing brain is in general considerably more plastic than the
adult brain. Thus, plasticity of the developing auditory brain (or
disruption of the normal developmental trajectory) can be triggered with a relatively shorter sound exposure period, and with
more lasting effects, as demonstrated in animal studies (Stanton
& Harrison 1996; Zhang et al. 2001, 2002; Chang & Merzenich
2003; Han et al. 2007; de Villers-Sidani et al. 2008). It is vital
to note that plasticity induced by moderate-level noise in infants
could delay or impair language development (Brown 2009),
although more work is needed to substantiate this risk.
ACKNOWLEDGMENTS
This work was supported by the Alberta Heritage Foundation for Medical
Research, by the Natural Sciences and Engineering Research Council, and
by the Campbell McLaurin Chair of Hearing Deficiencies.
Address for correspondence: Jos J. Eggermont, PhD, Department of
Psychology, University of Calgary, 2500 University Drive NW, Calgary,
Alberta, Canada T2N 1N4. E-mail: [email protected].
Received May 13, 2011; accepted November 13, 2011.
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