Martin Pienkowski 1,2 and Jos J. Eggermont 1,2,3

Transcription

1 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 Pienkowski 1,2 and Jos J. Eggermont 1,2,3 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; ) Departments of 1 Physiology and Pharmacology; 2 Psychology; and 3 Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada. 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 safeguards 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 0196/0202/12/ /0 Ear & Hearing Copyright 2012 by Lippincott Williams & Wilkins Printed in the U.S.A. 305

2 306 PIENKOWSKI AND EGGERMONT / Ear & Hearing, Vol. 33, No. 3, 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 MODERATE- LEVEL, 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 ( 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.

3 PIENKOWSKI AND EGGERMONT / Ear & Hearing, Vol. 33, No. 3, 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 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 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).

4 308 PIENKOWSKI AND EGGERMONT / Ear & Hearing, Vol. 33, No. 3, 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).

5 PIENKOWSKI AND EGGERMONT / Ear & Hearing, Vol. 33, No. 3, 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).

6 310 PIENKOWSKI AND EGGERMONT / Ear & Hearing, Vol. 33, No. 3, 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 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 Ca 2+ 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 MODERATE- LEVEL 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 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).

7 PIENKOWSKI AND EGGERMONT / Ear & Hearing, Vol. 33, No. 3, 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: 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

8 312 PIENKOWSKI AND EGGERMONT / Ear & Hearing, Vol. 33, No. 3, 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 levels (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. 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