Auditory Neuroscience, Vol. 3(4), pp. 425-433 Reprints available directly from the publisher Photocopying permitted by license only

© 1996 OPA (Overseas Publishers Association) Amsterdam B.V. Published in The Netherlands

by Harwood Academic Publishers Printed in Malaysia

Contralateral Suppression of the Ensemble Background Activity of the Auditory Nerve in Awake Guinea Pigs:

Effects of GentamicinJIRI POPELARab>*, DEISE LIMA DA COSTA3, JEAN-PAUL ERRE3, PAUL AVANac and JEAN-MARIE ARANa

“Laboratoire d ’Audiologie Experimental, Hopital Pellegrin, Place Amelie Raba Leon, 33076 Bordeaux, France bInstitute o f Experimental Medicine, Academy o f Sciences, Videhskd 1083, 142 20 Prague 4, Czech Republic

°Laboratoire de Biophysique, Faculte de Medicine, Universite d ’Auvergne, Clermont-Ferrand, France

(Received 14 February 1996; Accepted 9 December 1996)

Voltage recorded in awake guinea pigs from an electrode implanted at the round window was evaluated using fast-Fourier transformation. Acoustical stimulation was performed with a loudspeaker mounted in an aluminium housing and coupled to the contralateral outer ear canal with a silastic tube. In the absence of acoustical stimulation, the major part of the power spectrum of the round-window activity was localized to the frequency range of 500-2000 Hz, and peaked around 1 kHz. This peak reflects the ensemble back­ground activity (EBA) of the auditory nerve. During the presentation of the white noise (WN) bursts (duration 300 msec, 2.5 msec rise/fall times) to the contralateral ear, the EBA was reduced. The first detectable change was observed with the sound pressure level (SPL) of the WN as low as 20 dB; the maximal suppressive effect (up to 50% reduc­tion of the original power spectrum) occurred with the WN at 50-60 dB SPL. The sup­pressive effect of contralateral white noise on the EBA was reversibly eliminated by a single injection of gentamicin at a dose of 150 mg/kg. However, the basal level of the EBA was not significantly changed after gentamicin injection. The changes of contralateral suppression of the EBA after gentamicin injection were similar to those observed with transient evoked otoacoustic emissions, distortion-product otoacoustic emissions or

■ click-evoked compound action potential of the auditory nerve.

Keywords: Fast-Fourier transformation, round window, efferent system, outer hair cells

INTRODUCTION

Numerous microelectrode studies have revealed that auditory-nerve fibers are spontaneously active, i.e., they discharge in the absence of acoustic stimulation (e.g., see Tasaki, 1954; Evans, 1972; M anley and

Robertson, 1976; Siegel and Dallos, 1986). A recording method introduced by Kiang et al. (1976) and used by others (Dolan et al., 1983; Prijs, 1986; Versnel et al., 1992) confirmed the earlier hypothesis that each dis­charge of an auditory-nerve fiber contributes to a gross potential recorded at the round window. Several

♦Corresponding author. Tel.: (+4202) 475 26 90. Fax: (+4202) 475 27 87. E-mail: jpopelar@biomed.cas.cz.

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studies have shown that the voltage recorded from an electrode placed at the internal auditory meatus, on the round window, or directly on the tympanic membrane reflects the spontaneous activity o f auditory-nerve fibers in the absence of acoustic stimulation (Schreiner and Snyder, 1987; Dolan et al., 1990; Sininger et al., 1992; Cazals and Huang, 1994). These authors demonstrated that the sum of individual discharges of auditory-nerve fibers can be detected as a broad peak in the average power spectrum of the round-window activity evaluated by fast-Fourier transformation.

Activation of the efferent system by electrical stim­ulation of the crossed olivocochlear bundle or by a contralateral sound stimulation caused the reduction of the evoked or spontaneous activity of auditory-nerve fibers (W iederhold and Kiang, 1970; W iederhold, 1970; Burio, 1978; Gifford and Guinan, 1987; Warren and Liberm an, 1989). The reduction of the sponta­neous activity was found to be smaller than that of the responses to low-level sound except in a few very sen­sitive fibers in which the suppression of the sponta­neous activity was larger than average (W iederhold and K iang, 1970; G uinan and G ifford, 1988b). W iederhold and Kiang (1970) interpreted larger sup­pression of very sensitive auditory-nerve fibers as an indication that the spontaneous activ ity in these fibers was, in part, a response to background noise. Guinan and Gifford (1988b) also hypothesized that the spontaneous activity consisted partly of the “true spontaneous” firing and partly of the activity evoked by background sound. Our results were obtained without any ipsilateral stimulation arid experiments were per­formed in a well sound-attenuated chamber. We sup­pose that a substantial part o f the EBA was formed by the spontaneous activity of the auditory nerve fibers.

The effect of contralateral suppression is supposed to be m ediated by the crossed m edial efferent olivo­cochlear system (Gifford and Guinan, 1987; Guinan and Gifford, 1988a). There is considerable evidence indicating that acetylcholine is an important efferent (outer hair cell) transmitter in the mammalian cochlea (Guth et al., 1976; Klinke, 1981). Gifford and Guinan(1987) reported that the intravenous application of strychnine sulfate reduced the efferent-induced inhibi­tion o f the compound action potential (CAP) o f the

auditory nerve. However, the use of specific choliner­gic antagonists or strychnine to block the transmission in the efferent system is problematic in awake and unre­strained animals like those used in our experiments. Another substance which was shown to abolish the con­tralateral suppression of eighth-nerve CAP is gentami­cin (Smith et al., 1994). This agent primarily affects the outer hair cells (OHC), mainly at the base of the cochlea (Hawkins, 1976). M ostrecendy, Aran etal. (1994) and Avan et al. (1996) have shown that a single injection of 150 mg/kg of gentamicin temporarily and reversibly reduces the effect of the contralateral suppression of the sound-evoked CAP, and of the transient click-evoked otoacoustic emissions (OAE) or distortion-product otoacoustic emissions (DPOE) without any measurable changes in either the CAP audiogram, CAP input/out­put functions or in the basic level of the OAEs.

The aim of our experiments was to evaluate the sup­pressive effect of contralateral sound stimulation on the EBA of the auditory nerve in guinea pigs. The role of the crossed medial olivocochlear bundle was tested by injecting a single dose of gentamicin, which has been shown to tem porarily influence the efferent synapses at the outer hair cells (Smith et a l , 1994; Aran et a l , 1994; Avan et al., 1996; Erostegui et al.,1995). All measurements were made in awake guinea pigs with implanted electrode at the round window. This method allowed us to study the efferent effects under physiological conditions, without any interaction with anaesthetic drugs. Recording the EBA is a very simple method which does not require any ipsilateral sound stimulation (i.e., it avoids possible middle-ear muscle effects), needs no averaging, consumes very lit­tle time and it can monitor EBA in awake animals for several weeks or months.

MATERIALS AND METHODS

Experiments were performed on 16 pigmented guinea pigs weighing 2 50-300 grams. U nder ketamine- xylasine anaesthesia (intram uscular injection of 1 ml/kg of a mixture of Ketalar and Rompun [ratio 2:1]), a teflon-coated platinum-iridium ball electrode was im planted at the round window. The electrode was soldered to the pin o f a connector mounted on the

ENSEMBLE BACKGROUND VUIth NERVE ACTIVITY 427

vertex of the skull by small screws and acrylic resin. One screw connected to another pin of the connector served also as a reference electrode. In several animals, the reference electrode was fixed in the neck muscles.

Electrophysiological measurements were performed in a sound-attenuated chamber LA.C, model AC-2. The attenuation of this chamber was measured to be 20-25 dB for 250 Hz, 4 6 -5 0 dB for 500 Hz and more than 55 dB for frequencies above 1 kHz. The chamber was sit­uated in a quiet room in which the background noise did not exceed 3 5 -40 dB SPL. Animal testing was started at least 10 days after the surgery. Awake guinea pigs were put in a holding box which allowed the whole head to be free. Head movement was restricted only by a sliding ring placed over the nose. The guinea pigs usually became accustomed to sitting in the box quietly during the whole testing session (1-2 hours). The movement artifacts were continuously monitored and the analysed records were absolutely artifact-free. Those animals which were not fully calm were slightly sedated by intram uscular injection o f 0.1 ml of xylazine (Rompun) before the session.

Acoustical stimuli were generated with a two-chan­nel PC-based waveform generator and amplified by a power amplifier (Yamaha AX 450). Stimuli were deliv­ered to the ear by a loudspeaker (Sennheiser HD 4 8 0 II) mounted in an aluminium housing and coupled to the outer ear canal via a 7-cm-long silastic tube (outer diameter 5 mm, inner diameter 3 mm). The end of the silastic tube was slightly fixed in the entrance to the outer ear canal with Histoacryl S glue. The glue enabled fixing the tube in the outer ear canal during measurements, but allowed easy removal at the end of the session. Suppression of the ensemble background activity (EBA) was tested by the stimulation of the con­tralateral ear with 300-msec white noise bursts (WN, 2.5-msec rise and fall times) ranging in intensity from 10 to 70 dB SPL. In awake guinea pigs it is impossible, during a testing session, to reliably measure the sound pressure level at the opening of the tube, i.e., near the tympanic membrane. In order to calibrate the sound system, several guinea pigs were slightly anaesthetized with 0.1-0.2 ml of a ketamine-xylazine mixture (ratio 2:1). The sound pressure level and the frequency spec­trum of the white noise near the tympanic membrane

were measured with a calibrated probe connected to a miniature Knowles microphone (BT-1751). The main part of the WN measured in the outer ear canal near the tympanic membrane was localized to the frequency range 1.5-14 kHz. Spectrum curves in all animals were very similar; the maximal differences among individual guinea pigs did not exceed 5-8 dB for frequencies up to9 kHz and 10 dB for the frequency range 9-14 kHz. In individual animals, the frequency spectra of the WN was very stable after several repeated refixations of the stimulating tube in the outer ear canal.

First, the normal cochlear function of each guinea pig and the correct fixation of the stimulating tube in the outer ear canal were tested by measuring the thresh­old of the compound action potential of the auditory nerve (the CAP audiogram) to tone pips (2-msec rise/fall times without plateau) ranging in one-octave steps from 0.5 to 32 kHz. In animals in which the CAP audiogram was within normal values (Popelar et al., 1994), the ongoing activity in the absence of any acoustical stimulation to the ipsilateral ear was recorded with the round-window electrode. The volt­age was amplified 10,000 times and filtered from 10 Hz to 10 kHz. The signal was processed with a CED 1401 (Cambridge Electronic Design) intelligent interface connected to a Tandon PC. The average power spec­trum of the ongoing electrical activity was computed by the CED W aterfall program using fast-Fourier transformation (12-bit A/D converter, sampling rate 25 kHz). The average power spectrum from a 266-msec interval recorded during the contralateral WN presenta­tion and from a 266-msec interval recorded during quiet were compared (Fig. 1). In each evaluated inter­val, 10 overlapping blocks of 40-msec duration were averaged. For the quantitative evaluation of results the sum of power spectra in the bandwith of 500-2000 Hz was computed (inserts in Fig. 1).

The control experiment was performed on one guinea pig with an interrupted middle-ear ossicular chain.

After the basic measurements were completed, the animal was injected with a single intramuscular injec­tion of gentamicin at a dose of 150 mg/kg. This injec­tion did not affect the CAP audiogram or CAP input/output function. The changes in the contralateral WN suppression were checked every 15 minutes over

428 J. POPELAR et al.

E N S E M B L E B A C K G R O U N D A C T IV IT Y

0 100 2 0 0 3 0 0

( contralateral white noise )—

4 00 500

AVERAGE POWER SPECTRA OF THE EBA

during contralateral WN without WN

kHz

FIGURE 1 Top)—A 600-msec period of the ensemble background activity (EBA) recorded at the round window. Segments above the recording represent intervals from which the power spectra were calculated and averaged. BottomSAverage power spectra of the EBA cal­culated from 266-msec intervals during the contralateral white noise (WN) presentation (dotted line) and from 266-msec intervals of quiet (solid line). Inserts represent the sum of power spectra in the bandwith of 500-2000 Hz.

a period of 2 hours following gentamicin injection, and also 6, 24 and 48 hours postinjection.

RESULTS

Average Power Spectrum

Fast-Fourier transformation was used to calculate the power spectrum of the voltage recorded at the round window. Figure 1 shows a recording o f a 600-msec period of round-window activity in one guinea pig. It is evident that the voltage is lower during the first 300 msec, when contralateral W N was presented, than in the following interval, which was free of contralateral WN. Corresponding average power spectra evaluated from a 266-msec interval during contralateral WN presentation and from a 266-msec interval of quiet are presented in

Figure 1-bottom . Curves in both graphs had two maxima: i/ a low-frequency maximum in the frequency range 50-100 Hz and ii/ a maximum in the frequency range 500-2000 Hz, peaking around 1 kHz. This later peak is generally considered to represent the ensemble background activity (EBA) of the auditory nerve fibers without any acoustical stimulation. The basic shapes of both average power spectra were similar, but values of the spectrum calculated from the recording period dur­ing contralateral WN presentation were smaller than those from the quiet period. The sum of the average power spectrum evaluated in the bandwith of 500-2000 Hz during contralateral W N presentation was reduced to about 40% of the sum of power spectrum recorded during quiet in this animal. Suppression of the average power spectra of the EBA (in the absence of ipsilateral acoustical stimulation) by contralateral WN was highly

ENSEMBLE BACKGROUND VUIth NERVE ACTIVITY 429

significant in the whole group of animals (p < 0.001, tested with the t-test) with reductions ranging from 30-50% of those measured during quiet.

The first detectable changes in the average power spectra of the EBA were observed with a SPL as low as 20 dB (Fig. 2), which is 10 dB above the CAP threshold to ipsilateral W N burst stimulation. Increasing contralat­eral W N intensity also increased its suppressive effect. The maximum suppression of the EBA occurred with contralateral W N at 50 dB SPL. Values of the average power spectrum of the EBA obtained with a WN inten­

AVERAGE POW ER SPECTRA OF THE EBA

GP 133

4 -

CM>£

2 '

00 0.5 1 1.5 2 2.5 3

kHz

O Without WN B j jp During WN

80

60CM >E 40

W20

° 0 20 40 60 80 WN intensity (dB SPL)

FIGURE 2 Top— Average power spectra of the ensemble back­ground activity evaluated from recording periods during quiet (solid line) and during the presentation of white noise (WN) of increasing intensities to the contralateral ear (dotted line) in one guinea pig (GP 133). Bottom—The sum of power spectra in the bandwith of 500-2000 Hz. Open circles = activity without contralateral WN; solid circles = activity during contralateral WN presentation.

sity of 70 dB SPL are artificially increased by cross­talk of the WN to the opposite ear, thus evoking height­ened activity in the nerve fibers of the measured ear.

Effect of Gentam icin

A single injection of gentamicin at a dose of 150 mg/kg eliminated temporarily and reversibly the suppressive effect of the contralateral WN presentation. The time pattern of this effect in one guinea pig (GP 73) is demonstrated in Figure 3. Thirty minutes after the

AVERAGE POW ER SPECTRA OF THE EBA contralateral WN = 50 dB SPL

kHz

q Without WN " During WN

100

cn 80 >E 60

w40

0

FIGURE 3 Top—The time course of the effect of single intramus­cular injection of gentamicin (150 mg/kg) on contralateral suppres­sion of the ensemble background activity measured in one guinea pig (GP 73). Bottom—The sum of power spectra in the bandwith of 500-2000 Hz. Open circles = activity without contralateral WN; solid circles = activity during contralateral WN presentation.

430 J. POPELAR et al.

gentamicin injection, the average power spectrum of the EBA was still suppressed by contralateral WN stimula­tion by the same amount as before gentamicin injection. This suppression was almost fully eliminated 1 hour after the injection, and this effect lasted several hours (at least two hours in this animal). Contralateral W N suppression was restored by 24 hours postinjection.

Average data showing the time pattern of the effect of gentamicin injection on contralateral W N suppres­sion of the EBA are shown in Figure 4. The abscissa represents percents o f the preinjection value o f the sum of the average power spectrum of the EBA evalu­ated in the bandwith 500-2000 Hz without contralat­eral W N presentation. In the group o f eight guinea pigs, the contralateral suppression o f the EBA was almost fully eliminated 1 hour after the injection. Six hours postinjection, a slight recovery was observed in several guinea pigs, but full restoration of contralateral W N suppression was obtained 24 or 48 hours after the

gentamicin injection. In the majority of animals, the gentamicin injection did not have any effect on the basic level of the average power spectrum of the EBA (without contralateral W N stimulation). In two guinea pigs, the basic values of the average power spectrum of the EBA continuously increased after the gentam­icin injection and the sum of the average power spec­trum in these two animals evaluated in the bandwith 500-2000 Hz reached 120-130% of the preinjection level within two days. However, in the whole group of guinea pigs, this increase in the basic level of the aver­age power spectrum of the EBA after the gentamicin injection was not statistically significant.

Changes in the contralateral W N suppression of the EBA after a single gentamicin injection were similar to changes in amplitudes of the sound-evoked CAP (Aran et al., personal observations), in the transient OAEs (Aran et al., 1994), and in the DPOEs (Avan et al.,1996) after gentamicin injection (Fig. 4). However,

Contralateral suppressiongentamicin 150 mg/kg

Preinj. Preinj. .J O without WN • during WN

FIGURE 4 Average data showing the time course of the effect of a single gentamicin injection (150 mg/kg) on the contralateral suppres­sion of the ensemble background activity (EBA), of the sound-evoked compound action potential (CAP) (Aran et al., personal observations), of the transient evoked otoacoustic emissions (OAE) (Aran et al., 1994), and of the distortion-product otoacoustic emissions (DPOE) (Avan etal., 1996). Ordinate = percents of the preexposure value without contralateral WN. Open circles = activity without contralateral WN; solid circles = activity during contralateral WN presentation. Bars represent + S.D.

ENSEMBLE BACKGROUND Vlllth NERVE ACTIVITY 431

whereas the full elimination of contralateral suppres­sion was reached 1 hour after gentamicin injection in the cases of EBA, OAE and DPOE, this suppression was eliminated 1 hour later in the case of CAP, i.e., 2 hours after injection. Thus, changes in the EBA were detected earlier than changes in the sound-evoked CAP.

DISCUSSION

This paper demonstrates that the EBA of the auditory nerve can be suppressed by sound presented to the contralateral ear. This effect, which is supposed to be mediated by the crossed medial efferent olivocochlear system (G ifford and Guinan, 1987; Guinan and Gifford, 1988a), was almost completely but reversibly eliminated by a single intramuscular injection of gen­tamicin at a dose of 150 mg/kg.

The peak of the average power spectrum, located at a frequency range of 500-2000 Hz, has been con­firmed by many authors to reflect the EBA of auditory- nerve fibers. The maximum amplitude of the average pow er spectrum of the EBA in our recordings was centered around 1 kHz, which is in accordance with observations of Schreiner and Snyder (1987), Dolan et al. (1990), and Cazals and Huang (1994). Analysis o f the w aveform o f individual nerve discharges revealed that the energy contribution of a given audi­tory-nerve fiber to the round-window power spectrum is in the region of around 1 kHz (Kiang et al., 1976; Dolan e ta l., 1983; Snyder and Schreiner, 1984; Prijs, 1986; Versnel et al., 1992).

Acoustical stimulation of the contralateral ear was previously shown to suppress the amplitude of the sound-evoked CAP (Liberman, 1989; Smith et al., 1994; Aran et al., 1994), the evoked activity of auditory neurons (Klinke et al., 1969; Warren and Liberman,1989), and the magnitude of otoacoustic emissions (Mott etal., 1989; Berlin etal., 1993; Aran etal., 1994; Avan et al., 1996). However, under some conditions, the amplitude of the sound evoked CAP or responses of auditory-nerve fibers could even be increased by con­tralateral noise during the presentation of ipsilateral masking noise (Kawase and Liberman, 1993; Kawase et al., 1993). The amplitude of the sound-evoked CAP

or click-evoked otoacoustic emissions in individual cats or guinea pigs was demonstrated to be 30% to 50% lower with contralateral WN than without contralateral WN presentation, which is equivalent to a 3-8 dB atten­uation of the ipsilateral stimulus (Liberman, 1989; Smith et al., 1994; Aran et al., 1994). However, the spontaneous activity of auditory-nerve fibers was shown to be less suppressed by contralateral sound (Buno, 1978) or by electrical stimulation of the crossed olivocochlear bundle (Wiederhold and Kiang, 1969) than the sound-evoked activity. According to Wiederhold and Kiang (1969), the effect of stimulation of the crossed olivocochlear bundle on spontaneous activity was greatest in fibers whose characteristic fre­quency was in the range at which the cat was most sen­sitive (around 8 kHz). The authors explained these results with the hypothesis that the spontaneous activity of the very sensitive auditory-nerve fibers is due in part to sound which is present within the cochlea. In our experiments, the attenuation of the experimental cham­ber reached more than 55 dB for frequencies above 1 kHz and an additional attenuation was achieved by fix­ation of the tube in the outer ear canal. Thus, the back­ground noise intensity in the ipsilateral ear was very low. Taking this data into account, we can conclude that the EBA recorded at the round window in guinea pigs consisted of the spontaneous activity of auditory nerve fibers and of the activity evoked by internally generated noise. This assumption was confirmed experimentally by a control guinea pig with interrupted middle-ear ossicles (which increased the hearing threshold by 40-60 dB). In this guinea pig, the level of the EBA was similar to those measured in normal animals.

The question arises of whether the “true sponta­neous” activity, originated in inner hair cells (IHCs) and afferent nerve fibers, can be also suppressed by the contralateral WN, which affects the OHCs. Guinan and Gifford (1988c) proposed that activation of the crossed medial olivocochlear bundle induced hyperpo­larization of OHCs and a decrease in the endocochlear potential (EP). Fex (1967) and Guinan and Gifford (1988b) presented evidence that the EP change pro­duces a small hyperpolarization in IHCs which is responsible for the small efferent-induced depression of the spontaneous firing rate. The close relationship

432 J. POPELAR et al.

between the EP and spontaneous discharge rate after furosemide-induced decrease of the EP was demon­strated by Sewell (1984). Thus, it is possible that the “true spontaneous” activity can be suppressed by con­tralateral W N through the changes in the EP.

Am inoglycoside antibiotics are known for their serious side effects, which include ototoxicity, nephrotoxicity and neuromuscular blockage. It was revealed recently that aminoglycosides have an antag­onistic effect on the Ca2+ or K+ channels of isolated outer hair cells (Dulon et al., 1989; Nakagawa et al., 1992; Takeuchi and W angem ann, 1993) or on the cholinergic synapses o f the neuromuscular junction (Fiekers, 1983; Bourret and Mallart, 1989). In addi­tion, aminoglycoside antibiotics were demonstrated to reversibly block the acetylcholine-evoked response in isolated outer hair cells, possibly by blocking the Ca2+ entry necessary to elicit the acetylcholine response (Erostegui et al., 1995). The time pattern of changes in the reduction of contralateral suppression of the EBA followed the pharmacokinetics of gentamicin in peri­lymph (Tran Ba Huy et al., 1981). In our experiments, the first detectable changes in the contralateral W N suppression occurred on average 30 minutes after a single gentamicin injection; 1 hour postinjection, the contralateral suppression was elim inated. The con­tralateral suppression then recovered progressively during the next several hours, but its full restoration occurred only 24 to 48 hours after the gentam icin injection. This long-lasting effect coincides with the long persistence of gentamicin in cochlear tissues and in outer hair cells (Dulon et al., 1993; H iel et al., 1992). Figure 4 demonstrates that gentamicin injec­tion has alm ost the same as an EBA-like effect on amplitudes of the sound-evoked CAP (Aran eta l., per­sonal observations), on transient OAEs (Aran et al., 1994), and on the DPOEs (Avan et al., 1996). Thus, the action of gentamicin on the Ca2+ metabolism in the efferent cholinergic synapses of outer hair cells may be the reason for the elimination of the contralateral suppression of both spontaneous as well as sound- evoked responses. However, since changes in the EBA were detected earlier than changes in the sound- evoked CAP, evaluation of the EBA seems be more sensitive than those o f the CAP. In addition, the sim­

ple method of recording of the EBA can be also used for long-time monitoring of the level of spontaneous activity of the auditory nerve.

Acknowledgements

This research was supported by INSERM , MRT, Conseil Regional d ’Aquitaine and Grant Agency of the Czech Republic No. 309/94/0735.

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