Effects of aspirin on human psychophysical tuning curves in forward and simultaneous masking

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Hearing Research 99 (1996) 110-118

Effects of aspirin on human psychophysical tuning curves in forward and simultaneous masking Hazel A. Beveridge a, Robert P. Carlyon b,, a Laboratory of Experimental Psychology, University o[Sussex, Brighton BNI 9QG, East Sussex, UK b MRC Applied Psychology Unit, 15 Chaucer Road, Cambridge CB2 2EF, UK Received 29 October 1995; revised 17 May 1996; accepted 31 May 1996

Abstract

Psychophysical tuning curves (PTCs) at 4 kHz were measured in forward and simultaneous masking under two experimental conditions: 1 h after listeners had ingested three 320 mg capsules of aspirin every 6 h for 3 days (3.84 g/day), and after an identical schedule of placebo ingestion. Aspirin and placebo allocation was double-blind. In addition to raising thresholds at several audiometric frequencies, aspirin elevated the tips and reduced the slopes of the PTCs, indicating a reduction in frequency selectivity. The aspirin-induced reduction in PTC slopes did not differ significantly between forward and simultaneous masking, nor did the overall reduction differ significantly between the low- and high-frequency side. However, a separate analysis of the data obtained in simultaneous masking indicated that the broadening in tuning caused by aspirin was greatest on the high-frequency side of the PTC. Keywords: Aspirin; Salicylate; Frequency selectivity; Forward masking; Simultaneous masking; Psychophysical tuning curve; Suppression

1. I n t r o d u c t i o n

The ingestion of moderate doses of aspirin (acetylsalicylic acid, or 'salicylate') produces a mild, reversible hearing loss, known as aspirin-induced hearing loss (AIHL) (Falbe-Hansen, 1941; McFadden et al., 1984). The reversible nature of A I H L makes it an attractive tool for studying the effects of sensory hearing loss on suprathreshold auditory abilities, as it allows the experimenter to compare the performance of the same subject both in the presence and absence of a hearing loss. Perhaps even more important is the existence of converging evidence that salicylate affects the operation of the cochlear outer hair cells (OHCs). This raises the possibility that, by measuring the effect of aspirin on performance in a variety of psychophysical tasks, one can examine the role played by a relatively specific cochlear mechanism in human hearing. Physiological evidence that salicylate affects the operation of OHCs comes both from in vitro studies, which show a reduction in the motility of isolated OHCs (Shehata et al., 1991; Tunstall et al., 1994a,b; Russell and Schauz,

* Corresponding author. Fax: bob.carlyon @mrc-apu.cam.ac.uk

(44)

1223-359062;

E-mail:

1995), and from a number of in vivo experiments. One consequence of salicylate administration is an elevation in the sharp tips of auditory-nerve frequency threshold curves (FTCs) (Evans and Borerwe, 1982; Stypulkowski, 1990; Murugasu and Russell, 1995), accompanied by a relative sparing of the FTC tails: this effect is produced by other manipulations believed to affect OHC motility, including mechanical biasing of the basilar membrane (Klis et al., 1988), mild acoustic trauma (Cody and Johnstone, 1980), and efferent stimulation (Guinan and Gifford, 1988). In addition, there is evidence that salicylate reduces the manifestations of an active source of cochlear non-linearity, believed to be the OHCs, as reflected by both spontaneous and evoked oto-acoustic emissions (McFadden and Plattsmier, 1984; Long et al., 1986; Long and Tubis, 1988b,a; Wier et al., 1988; Stypulkowski, 1990; Brown et al., 1993). The experiments reported here had several aims. First, we wanted to replicate, using a different technique, an earlier finding (Carlyon and Butt, 1993) that moderate doses of aspirin reduce human frequency selectivity. Carlyon and Butt reported that auditory filter shapes, obtained in forward masking using notched-noise maskers, were broader after a course of aspirin than after a similar regime of placebo ingestion. Although their data demonstrate an

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H.A. Beveridge, R.P. Carlyon/ Hearing Research 99 (I 996) 110-118

effect of aspirin on frequency selectivity, there are a number of differences between the notched-noise method and that used to measure FTCs which hinder a comparison between the physiological and psychophysical results: these differences include the variation of signal rather than masker level to obtain thresholds, and the use of broadband rather than narrowband maskers. In the present study we measure psychophysical tuning curves (PTCs), which are the direct psychophysical analog of FTCs, and show that the effect of salicylate on the two measures is qualitatively similar. A second aim was to determine whether the effect of aspirin on PTCs differed between forward and simultaneous masking. Clearly, the practical implications of aspirin ingestion for the perception of, for example, speech, depend strongly on its effect on frequency selectivity both to simultaneous and non-simultaneous sounds. One reason why aspirin may not have the same effect in the two situations comes from the observation that PTCs are broader in simultaneous than in forward masking, and from the suggestion that this difference is due to simultaneous maskers remote from the signal suppressing the response to that signal, thereby reducing its detectability (Wightman et al'., 1977; Vogten, 1978; Delgutte, 1990). Because suppression has been attributed to the saturation of OHC receptor currents (Geisler et al., 1990), and because the effects of aspirin are also believed to be mediated by OHCs, it is possible that the reductions in the detectability of the signal produced either by a simultaneous masker or by the administration of aspirin are mediated by the same mechanism. The way in which these two manipulations may combine to affect frequency selectivity is considered further in Section 4, which describes in more detail the mechanisms by which salicylate and suppression modify the operation of OHCs.

2. M e t h o d

2.1. Listeners and drug schedule

Nine male volunteers, aged 20-32 years, took part in the experiment, which was approved by the University of Sussex School of Biological Sciences Ethics Committee. Volunteers were given a list of contra-indications to aspirin i which, if occurring in any individual, would preclude his participation in the study. Listeners' medical records were screened by their doctors. Each volunteer was also informed of possible side effects to aspirin ingestion, and had absolute thresholds within 15 dB of the 1969

J Contra-indications: asthma, hay fever, urticaria, gastro-intestinal disorders, tinnitus, gout, impaired liver function, vitamin K deficiency, haemophilia, nasal polyps, hearing disorders, use of diuretics or recent surgery.

I 11

ANSI standard at all audiometric frequencies. A consent form was signed by each listener when successful screening had been completed. Listeners participated in two training sessions, lasting 2 h each, followed by a final training session of 3.5-4 h in length, with rest periods being taken as needed. Once training had been completed, five of the listeners ingested three 320 mg capsules of aspirin every 6 h for 3 days. One hour after the final dose, an experimental session commenced which lasted between 3.5 and 4 h. At least 1 week later, they underwent a second schedule of capsule ingestion and testing which was identical to the first, with the exception that the capsules contained placebo instead of aspirin. The other four listeners ingested placebo prior to the first experimental session and aspirin prior to the second. The allocation of aspirin and placebo was doubleblind. Both aspirin and placebo were administered in the form of opaque gelatine capsules. Aspirin capsules contained a mixture of one broken, uncoated aspirin tablet and cornflour; each placebo capsule contained a mixture of one broken sucrose/lactose tablet and cornflour. No blood samples were taken, and we therefore had to rely on threshold elevations for evidence that listeners had ingested sufficient aspirin to affect the region of the cochlea most sensitive to the signal frequency. 2.2. Stimuli and procedure

Each experimental session commenced with an estimate of the listener's absolute thresholds at all audiometric frequencies. These estimates were obtained from a small number of trials and will not be presented here. Following this, the absolute threshold was obtained for a 10-ms, 4-kHz signal, having a 5-ms raised-cosine rise and fall and no steady-state portion. It was generated digitally (20-kHz sampling rate) before being lowpass-filtered (Kemo VBF25.01; attenuation rate 135 dB/octave), passed through a programmable attenuator (Wilsonics PATT), and fed to one input of a headphone amplifier. The 10-ms, 4-kHz tone was then set to a level 15 dB above its absolute threshold for that session, and was used as the signal in the measurement of PTCs. The masker used in the measurement of PTCs consisted of two bands of noise, which were attenuated separately before being summed, gated on and off together with 4.1-ms raised-cosine ramps, and fed to one input of the headphone amplifier. The masker duration (including the ramps) was 200 ms. In forward masking, the masker ended 1 ms (zero-voltage points) before the onset of the signal; in simultaneous masking, the masker's offset ramp started 2 ms after that of the signal. One of the noise bands was generated by analog-multiplying a sinusoid (Farnell DSG2) by a white-noise source which had been lowpass-filtered at 50 Hz (Kemo VBF25.03; attenuation rate 48 dB/octave). This resulted in a 100-Hz wide band of noise with steep

112

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spectral slopes, and with a center frequency (fm) in forward masking of 2400, 3200, 3800, 4000, 4200, 4300, and 4400 Hz. An additional center frequency of 4800 Hz was used for simultaneous masking. The level of the 100-Hzwide noise band was varied adaptively so as to just mask the signal, as described in Section 2.2 below. The second band of noise consisted of a white noise source which had been low-pass filtered ( K e m o VBF25.03; attenuation rate 48 d B / o c t a v e ) at 1500 Hz. It served as a 'cue' to the end of the masker in forward masking (Neff, 1985), and, for consistency, was also present in the simultaneous masking condition. Its spectrum level was varied together with that of the first band, but was always 20 dB lower. Stimuli were checked by examining the electrical input to the Sennheiser HD414 SL headset using a Hewlett-Packard 3561A spectrum analyser. The headset was calibrated using a B & K artificial ear type 4153 fitted with a B & K condenser microphone cartridge type 4134. All measurements were obtained using a 2-up, 1-down 2-interval forced-choice adaptive procedure with a step size of 2 dB (Levitt, 1971). Trial-by-trial feedback was given to the listener regarding the correct response. For absolute threshold measurements, the signal level was increased by 2 dB after every incorrect response and decreased by 2 dB after every two consecutive correct responses. The change from ascending to descending attenuation, or vice versa, defined a turnpoint, and each run terminated after 12 turnpoints. The absolute thresholds for each run were obtained from the average of the last eight turnpoints. A similar procedure was adopted for the measurement of PTCs, except that the signal level was held constant and the masker level was varied, being decreased by 2 dB after every incorrect response and increased by the same amount after two consecutive correct responses. All values reported here represent the mean of the estimates obtained from four runs. Listeners sat in an IAC single-walled sound-attenuating booth, located inside a large sound-attenuating room, and listened monaurally.

Table 1 The second and third columns show absolute thresholds (in dB SPL) for a 10-ms, 4-kHz signal in the aspirin and placebo conditions, respectively. The final column shows the difference between these two values for each listener. Data of the five listeners ( L I - L 5 ) who showed a shift of at least 4 dB are shown in bold type. Listener

Aspirin(dB)

Placebo(dB)

Difference

L1 L2 L3 L4 L5 L6 L7 L8 L9 Mean S.E.

28.0 22.2 21.6 23.2 23.0 262 206 32.4 18.0 23.9 1.4

16.2 13.4 14.6 17.4 18.9 232 203 33.2 19.1 19.6 2.0

11.8 8.8 6.9 5.8 4.1 30 03 -0.8 - 1.0 4.3 1.5

3.2. P T C characteristics PTCs obtained from the five listeners ( L 1 - L 5 ) who met the arbitrary absolute threshold shift criterion are shown in SIMULTANEOUS --aspirin

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3.1. Absolute threshold shifts The aspirin-induced absolute threshold shifts for the 10-ms, 4-kHz signal are shown in Table 1. As noted above, no blood samples were taken, and so we had to rely on threshold shifts at 4 kHz for evidence that listeners had taken enough aspirin to affect the region of the cochlea most sensitive to that frequency. The results of five listeners (labelled L 1 - L 5 ) who fulfilled an arbitrary criterion of a minimum 4 dB absolute threshold shift are shown in bold type. Most o f the remaining discussion and analysis will focus on the results obtained from these five listeners.

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H.A. Beveridge, R.P. Carlyon /Hearing Research 99 (1996) 110-118 Table 2 Absolute values of the PTC slopes ( d B / k H z ) obtained in the aspirin and placebo conditions, together with the difference in slope between the two conditions, for listeners L I - L 5 Listener Low-frequency side Aspirin

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37.1 39.1 37.4 34.2 48.3 39.2

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100.1 44.2 65.6 5O.6 112,9 74.7

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Figs. 1 and 2 for simultaneous and forward masking respectively. For all listeners, the tips of the PTCs in both forward and simultaneous masking are elevated by the administration of aspirin, with the average size of this elevation being about 7 dB. This is not surprising, given that in the aspirin condition the signal SPL was set on average 7.5 dB higher than with placebo, as a result of the 7.5-dB difference in mean absolute threshold between the two conditions. More relevant are the effects of aspirin on the shapes of the PTCs. Although Figs. 1 and 2 reveal some differences across listeners, there is a general trend for the slopes of the PTCs to be shallower in the aspirin than in the placebo condition. Values of these slopes, derived from leastsquares linear fits 2 to each side of the PTC (including the 4000-Hz point), are shown for forward and simultaneous masking in Table 2. The table shows that aspirin reduced the slopes of both sides of the PTCs in both forward and simultaneous masking and for all listeners, the only exception being the forward-masked high-frequency slopes of listener L2. The general trend was confirmed by a 3-way A N O V A (drug × forward vs. simultaneous masking X low vs. high side of PTC), which showed that the slopes were significantly shallower with aspirin than with placebo (Fl, 4

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= 31.07, P < 0.01), indicating an aspirin-induced reduction in frequency selectivity. This effect remained significant when the data from all nine listeners were included in the analysis ( F t . 9 = 10.93, P = 0.01). The effect of aspirin on the PTCs of listeners L1-L5 did not differ between forward and simultaneous masking (interaction: FI, 4 = 0.21, P = 0.67), or between the low and high side of the PTC (interaction: /'1,4 = 1.72, P = 0.26). However, a separate analysis of their simultaneous masking data did reveal that the aspirin-induced reduction in slope was greatest on the high-frequency side of the PTC (FI. 4 = 10.41, P =

0.03). 2 Stelmachowicz et al. (1985) and Nelson and Fortune (1991b); Nelson and Fortune (1991a) have previously used least-squares criteria to fit three linear segments to tuning curves. As the low-frequency sides of the PTCs obtained from some of the listeners in the present experiment had no obvious breakpoint (i.e., appeared as a straight line), we decided to fit a single line to each side of the PTC. This avoided a situation in which the breakpoint, and hence the number of points on which the fits were based, varied across listeners. The resulting lines provided reasonable fits to the data, with an average r 2 of 0.965.

4. Discussion

4.1. Effects of signal level A possible explanation for the broadening of the PTCs observed here arises from the fact that, because we equated the sensation levels of the signals in the two drug condi-

114

H.A. BeL~eridge, R.P. Carlyon / Hearing Research 99 (1996) 110-118

tions, the threshold elevation produced by aspirin resulted in the signals being set to slightly higher SPLs than in the placebo condition. A number of authors (e.g., Widin and Viemeister, 1979; Nelson and Freyman, 1984) have shown that PTCs broaden with increasing signal level, and so one might argue that the broadening observed here is simply due to the higher absolute levels of the signal necessitated by the administration of aspirin. However, Green et al. (1981) have presented evidence that the shape of the PTC is determined not by the absolute level of the signal, but by its sensation level, which, as mentioned above, was the same in our aspirin and placebo conditions. When they measured forward-masked PTCs over a 29-dB range of signal levels, keeping the sensation level of the signal constant by adding background noise, PTCs were independent of the absolute level of the signal. More recently, Moore et al. (1984) measured PTCs over a 10-dB range of signal SPLs and equated the sensation levels of the signals using a notched noise. They found that the low-frequency slope of the PTC became slightly broader with increasing level, but that the high-frequency slope actually became steeper, consistent with the sharpening of the highfrequency side of the auditory filter (Patterson and Moore, 1986). Indeed, even when sensation level is not held constant, increases in signal SPL either have little effect on the high-frequency slope or cause it to become steeper (Moore, 1978; Weber et al., 1980, Fig. 2; Moore et al., 1984), in contrast to the reduction in slope consistently observed on the low-frequency side. Our finding that, in simultaneous masking, aspirin exerted its greatest effect by reducing the high-frequency slope of the PTC is therefore inconsistent with an explanation based on increases in signal level.

4.2. Quality differences and off:frequency listening Two factors other than suppression have been implicated in the difference between PTCs measured in forward and simultaneous masking Weber and Green, 1978; O'Loughlin and Moore, 1981; Moore et al., 1984; Neff, 1985). One of these is that the fluctuations inherent in a forward masker consisting of a narrowband of noise may be mistaken for the signal, particularly when the center frequency of the noise is close to fs- This was minimised in our experiments by gating a lowpass noise on and off with the masker. The other factor, 'off-frequency listening', occurs when listeners detect the signal by attending to the outputs of auditory filters with center frequencies (CF) remote from f~. It is relevant because of evidence that it has a slightly bigger effect in forward than in simultaneous masking (O'Loughlin and Moore, 1981). Although significant differences remain when the outputs of off-frequency filters are masked by notched noise, the fact that we did not use such a noise means that off-frequency listening may have contributed to differences between our forwardand simultaneous-masked PTCs. However, we reasoned

that unless aspirin produced a steeply sloping hearing loss, it would be unlikely to affect the usefulness of offfrequency listening, and would be even less likely to do so in a way which differed between simultaneous and forward masking. Generally, aspirin produces a loss which is either uniform across frequency (Myers and Bernstein, 1965; Bernstein and Weiss, 1967; Mongan et al., 1973; Bond!ng, 1979a; Koegel, 1985), or slightly greater at high than at low frequencies (e.g., McCabe and Dey, 1965; Jardini et al., 1978; McFadden and Plattsmier, 1983; McFadden and Plattsmier, 1984) 3. There are no reports of steeply sloping losses.

4.3. Physiological accounts of PTCs and suppression The data presented here show that aspirin has a roughly similar effect on PTCs measured in forward and simultaneous masking. In this subsection we argue that our results are consistent with current physiological data on suppression and on the effects of aspirin on OHCs. The next subsection compares this account to that provided by psychophysical models of suppression. Early physiological evidence for two-tone suppression was provided by Sachs and Kiang (1968) and by Arthur et al. (1971) They reported that the auditory-nerve (AN) response to a probe tone could be reduced by the addition of a second, simultaneous, 'suppressor' tone. Delgutte (1990) has presented AN data which suggest that the simultaneous masking of a signal by a lower-frequency tone is determined partly or completely by suppression. In contrast, no suppression of the signal occurs in forward masking, because two-tone suppression only occurs when the tones are simultaneous. This means that, for fm fs, but that its effect was smaller than when fm
3 This statement applies to the gross pattern of threshold change across frequency. Long et al. (1986) and Long and Tubis (1988b) have reported effects of aspirin on detection threshold microstructure as well as on thresholds at audiometric frequencies.

H.A. Beveridge, R.P. Carlyon / Hearing Research 99 (1996) 110-118

flow of current through the OHCs, which in turn controls the motor. This distinction is important because of evidence that salicylate does affects OHC motility per se, rather than the mechano-electrical transduction: for example, Tunstall et al. (1994a,b have shown that the motility is reduced in vitro where, of course, there is no BM motion to detect (see also Russell and Schauz, 1995). Thus it may be that aspirin affects frequency selectivity both in the presence (simultaneous masking) and absence (forward masking) of suppression because the two manipulations affect different stages of the positive feedback process 4. Presumably, however, if the effects of suppression had been so strong as to eliminate OHC motility completely, then aspirin could have had no further effect on this process. This implies that either some OHC motility remains in the presence of a simultaneous masker, or that aspirin can affect frequency selectivity via some other route. 4.4. Psychophysical accounts o f PTCs and suppression

The first psychophysical evidence for two-tone suppression was observed by Houtgast (1972, 1973, who reported that the non-simultaneous masking produced by a sinusoid could be reduced by a second 'suppressing' tone gated on and off with the masker. He argued that the suppressor reduced the 'internal' response to the masker, and that such unmasking effects were not observed in simultaneous masking because the masker and signal were suppressed equally. The combinations of suppressor level and frequency necessary to produce the unmasking bore a striking resemblance to those shown to reduce AN responses to a probe. Although the existence of some differences between psychophysical and physiological suppression (e.g., Champlin and Wright, 1993), suggest that more central processes may affect psychophysical measurements, this resemblance suggests that the two phenomena share a common basis. Houtgast's arguments that psychophysical suppression should be observable only in non-simultaneous masking led Moore and Glasberg (1982) to propose an account of the role of suppression in PTCs that was markedly different from the physiological account described above. According to them, the peak of a forward masker's excitation pattern could suppress its skirts, thereby 'sharpening up' its internal representation. They argued that this sharpening would not be observed in simultaneous masking for the same reason proposed by Houtgast: the signal would also

4 In this regard it is worth noting that Patuzzi and Rajan (1992) have presented a model which successfully predicts the threshold shifts produced by combinations of manipulations affecting OHC motility. Interestingly, Patuzzi and Rajan argue that the effect of combiningtwo manipulations can be predicted on the assumption that they act independently, even when they both affect the same stage of the active process.

115

be suppressed, and so the internal signal-to-masker ratio would be unaffected. This explanation differs from that proposed by Delgutte and from a similar psychophysical explanation proposed by Vogten (1978) and by Wightman et al. (1977), in a way which can be characterised as follows: Moore and Glasberg (1982) argue that suppression sharpens PTCs in forward masking, whereas Delgutte (1990), Wightman et al. (1977), and Vogten (1978) argue that it broadens PTCs in simultaneous masking. One inconsistency between Moore and Glasberg's explanation and current physiological thinking arises from the fact that the upper skirts of a forward masker's excitation pattern reflect the outputs of auditory filters having CFs well above fm' If we assume that auditory filters correspond roughly to discrete regions of the BM (Greenwood, 1990), then one would not expect the outputs of filters well above fm to be affected by the operation of OHCs, because this is not the case for regions of the BM tuned to frequencies well above that of the stimulus (Sellick et al., 1982). However, it may be that the effect of suppression on PTCs can be accounted for by modifying the alternative explanation, which is more in line with current physiological evidence, that suppression is responsible for elevating thresholds in simultaneous masking (Wightman et al., 1977; Vogten, 1978; Delgutte, 1990). The main evidence against this class of explanation comes from an experiment by Moore and Glasberg (1982), who showed that off-frequency simultaneous maskers do not completely suppress the response to the signal, indicating that some other mechanism must be involved in simultaneous masking 5. However, it is possible for a simultaneous masker to suppress the signal only partially but for this suppression to increase the effectiveness of the masker. This is illustrated by Fig. 3, in which the solid curve describes the FTC of an AN fiber for the case where the operation of the OHCs is not affected by suppression; the response to the signal is shown by the dot just above the tip of the curve. The ' F ' shows the level of an off-frequency forward masker necessary to mask the signal, on the assumption that masking occurs when the masker lies above the tuning curve by the same amount as does the signal. In simultaneous masking, the tip of the tuning curve is effectively raised because OHC motility is compromised by suppression, and the new curve is shown by the dotted line; note that the signal is still above threshold. However, because the signal now exceeds threshold by a

5 They first measured simultaneous masked PTCs for a 1000-Hz sinusoidal signal and narrowband noise maskers with CFs ranging from 600 to 1400 Hz. They reasoned that, if the response to the signal were completely suppressed, then the combination of the masker and signal should produce no activity in the frequency region tuned to 1000 Hz, over and above that present in quiet. They measured this activity by using the noise-tone combinations as a forward masker in the second stage of their experiment, and found that the new masker elevated the threshold for a subsequent 15-ms, 1000-Hz sinusoid by up to 20-25 dB.

116

H.A. Beceridge, R.P. Carlyon/Hearing Research 99 (1996) 110-118

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FREQUENCY, Hz--> Fig. 3. The solid line shows a schematic frequency threshold curve for a condition where OHC motility is unaffected by suppression. The level and frequency of the signal is shown by the dot. In order for a forward masker to mask the signal, it is assumed that its level must exceed threshold by the same amount as the signal does. The level of one such forward masker is shown by the 'F'. In simultaneous masking OHC motility is reduced by suppression, and the effective tip of the threshold curve is elevated, as shown by the dotted line. The off-frequency masker (S) can now be set to a lower level while still masking the signal. The decay of forward masking, which we assume to be due to characteristics of temporal processing central to the auditory nerve (Moore et al., 1988), has been ignored in this figure.

smaller amount, the level of the off-frequency masker, shown by the ' S ' , can be reduced. Given the evidence that suppression does not affect thresholds when the masker and signal frequencies are equal (Delgutte, 1990), this means that the low-frequency slope of the PTC will be broader in simultaneous than in forward masking. Hence the existing psychophysical and physiological evidence are consistent with the effect o f suppression on tuning curves being to broaden PTCs in simultaneous masking while having no effect in forward masking. 4.5. Effects o f salicylate in physiological and psychophysical experiments

The effect o f aspirin on the PTCs obtained in the present study is consistent with the general pattern of results observed both in the auditory nerve (Evans and Borerwe, 1982; Stypulkowski, 1990) and inferior colliculus (Boettcher et al., 1989). Our data are also consistent with the finding o f Carlyon and Butt (1993) that human auditory filter shapes are broadened by aspirin ingestion. One advantage o f the present technique over that used by Carlyon and Butt is that it allows a direct comparison with the observation of Stypulkowski (1990) that some chinchilla A N fibers exhibited W-shaped tuning curves after administration o f salicylate. As Carlyon and Butt pointed out, their own use of broadband maskers meant that they could not determine whether listeners' underlying tuning curves simply became broader with aspirin, or whether they acquired the W-shape suggested by some of Styp u l k o w s k i ' s data. (This was because, even if the frequency regions which produced the most masking were remote

from the signal frequency, those regions would be stimulated by broadband maskers with both wide and narrow notches.) The data in Figs. 1 and 2 show conclusively that the doses of aspirin used in the present study result in PTCs which are broader than after placebo ingestion, but which maintain their classic V-shape. When comparing the present data to those obtained in physiological experiments, it is important to bear in mind that the aspirin dosage used here produced only modest threshold shifts for the 10-ms, 4-kHz signal, with the largest elevation being 11.8 dB for listener L1. This is considerably smaller than the elevations produced in animals by the large acute doses administered in physiological experiments (e.g., Evans and Borerwe, 1982), or in humans by the longer-term and often larger doses administered clinically (e.g., Myers and Bernstein, 1965). Thus we cannot rule out the possibility that if it had been ethically acceptable to administer larger doses, we would have observed non-monotonic effects such as the W-shaped tuning curves reported by Stypulkowski (1990). In this regard it is worth noting that the fibers in which Stypulkowski observed W - s h a p e d tuning curves also showed above-average tip elevations. Fibers showing smaller elevations, more similar in size to the tip elevations observed here, typically showed a simple broadening in tuning which was qualitatively similar to that seen in Figs. 1 and 2.

Acknowledgements This work was funded by a Wellcome Trust Prize Scholarship (H.A.B.) and by a Royal Society University Research Fellowship (R.P.C.). We thank Dr. P. LeSeve of Sussex University Health Centre for screening the medical records of many of our subjects, and Mr. Brian Jones of Shionogi Qualicaps plc and Mr. John Morrissey of Boots plc for pharmaceutical supplies. Brian Moore, Ian Winter, and two reviewers provided helpful comments on a previous version of this article.

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