Carboplatin, a second-generation antineoplastic drug, is much less ototoxic than cisplatin in humans and many laboratory animals. However, when a moderate dose of carboplatin is administered to chinchillas, it can selectively destroy inner hair cells (IHCs) and type-I ganglion neurons without damaging the outer hair cells (OHCs). One of the earliest signs of injury from carboplatin is damage to type I, spiral ganglion neurons. Selective destruction of IHCs has no effect on the cochlear microphonic (CM) potential and distortion product otoacoustic emissions (DPOAEs). However, very high doses of carboplatin can destroy both OHCs and IHCs resulting in a decline in CM and DPOAE amplitude. In cases where carboplatin partially destroys the IHCs, the auditory nerve fibers that contact the residual IHCs have normal thresholds and tuning, but their spontaneous and driven discharge rates are reduced. These results suggest that OHCs are responsible for the sharp tuning and exquisite sensitivity of the cochlea. IHC loss leads to a reduction in neural input (i.e., sensory deprivation) to the central auditory system. Surprisingly, although the neural input to the central auditory system is reduced, evoked response amplitudes recorded from the auditory cortex are often enhanced. These results indicate that when the neural input to the central auditory brain is reduced, the central auditory system compensates for the reduced input by increasing its gain.
Keywords: carboplatin, hair cell loss, ototoxicity, chinchilla, spiral ganglion neurons auditory evoked potentials
|How to cite this article:|
Salvi R J, Ding D, Wang J, Jiang H Y. A review of the effects of selective inner hair cell lesions on distortion product otoacoustic emissions, cochlear function and auditory evoked potentials. Noise Health 2000;2:9-25
|How to cite this URL:|
Salvi R J, Ding D, Wang J, Jiang H Y. A review of the effects of selective inner hair cell lesions on distortion product otoacoustic emissions, cochlear function and auditory evoked potentials. Noise Health [serial online] 2000 [cited 2019 Oct 17];2:9-25. Available from: http://www.noiseandhealth.org/text.asp?2000/2/6/9/32648
| Introduction|| |
Cisplatin, a common anti-cancer drug, has long been known to be ototoxic (Fanning and Hilgers, 1993; Freilich et al., 1996). However, the risk of ototoxicity from platinum based anti-tumor drugs has been greatly reduced with the introduction of carboplatin (cis-diammine-1,1cyclobutane dicarboxylate platinum (II), CBDCA), a second generation, antineoplastic agents (Calvert et al., 1982). Carboplatin is extensively used in the treatment of ovarian and testicular cancer (Group, 1991; Misawa et al., 1995). However, the main complications associated with using this drug are its haematological and myelosuppresive side effects. Nevertheless, carboplatin ototoxicity can be problematic if the drug is administered at high doses over a prolonged time period (Calvert et al., 1982; Madden et al., 1992; van der Hulst et al., 1988).
The ototoxic effects of carboplatin have been studied in two common laboratory species, the guinea pig and the chinchilla, but the effects observed vary significantly between these two species. Guinea pigs are relatively resistant to carboplatin, but damage sometimes occurs when high doses of the drug are administered. In such cases, guinea pigs develop a high frequency hearing loss and a hair cell lesion that progresses from base to apex. Like other ototoxic drugs, carboplatin destroys the outer hair cells (OHCs) first followed by the inner hair cells (IHCs) (Saito et al., 1989; Taudy et al., 1992). These anatomical findings are consistent with the audiometric data seen in humans (van der Hulst et al., 1988).
In contrast to guinea pigs and humans, chinchillas treated with carboplatin invariably develop an IHC lesion (Takeno et al., 1994b; Trautwein et al., 1996a; Wake et al., 1994; Wake et al., 1993). The effects of these lesions are strikingly different from that seen previously. During the past five years, we have systematically examined the anatomical and physiological consequences of carboplatininduced IHC and OHC lesions in the chinchilla. The results of these studies have provided new insights into the functional role of IHCs and OHCs and have shed new light on how the central auditory system responds when it is deprived of sensory input. The following sections highlight some of the important results obtained from animals with selective IHC lesions.
| Results|| |
As shown in [Figure - 1], chinchillas treated with a low to moderate dose of carboplatin develop an IHC lesion. Unlike other ototoxic lesions, the pattern of IHC loss is relatively uniform along the length of the cochlea. [Figure - 2]A shows the average cochleogram from a group of chinchillas treated with a low dose (38 mg/kg, i.p.) of carboplatin. Position in the cochlea is related to frequency using a generalized frequency-place map (Greenwood, 1990). This dose of carboplatin destroyed approximately 20-30% of the IHCs throughout most of the cochlea whereas all of the OHCs remained intact (Trautwein et al., 1996a). Carboplatin can destroy OHCs, but only when extremely high doses are used (~200 mg/kg, i.p.). When an OHC lesion develops, it decreases from base to apex, much like the pattern seen with other ototoxic drugs. The pattern of OHC loss resulting from a high dose (200 mg/kg, i.p.) of carboplatin is illustrated in [Figure - 2]B. The IHC loss ranged from 80-100% over most of the cochlea while the OHC lesion decreased from 100% in the extreme base to less than 20% in the apical half of the cochlea.
Dose Response Function: The ability to selectively eliminate OHCs while retaining IHCs depends on the carboplatin dose (Hofstetter et al., 1997b). As shown in [Figure - 3], a dose of 38 mg/kg is just high enough to destroy approximately 20% of the IHCs throughout the cochlea, but has little or no effect on the OHCs. Increasing the dose to 76 mg/kg results in a dramatic increase in IHC loss (~85%). A dose of 150 mg/kg destroy roughly 97% of the IHCs, but only a small percentage (~15%) of OHCs in the base of the cochlea. Only after the carboplatin dose is increased to 200 mg/kg is there is a significant increase in the size of the IHC lesion (~50%). Thus, the dose of carboplatin that just begins to cause significant OHC loss in the base of the cochlea (200 mg/kg) is roughly five times higher than the dose that produces a small IHC lesion (38 mg/kg).
Species Differences: To determine if carboplatin might be ototoxic to other common laboratory animals, we administered high doses of the drug to two strains of mice. The CBA mouse was selected because it shows little hair cell loss as a function of age. By contrast, the C57 mouse shows an early onset, age-related hair cell loss that progresses from base to apex (Spongr et al., 1997). We hypothesized that the C57 mouse might be extremely susceptible to carboplatin because of its genetic predisposition to age-related hearing loss. [Figure - 4]a shows the cochleogram from a typical 3-month-old, CBA mouse treated with 100 mg/kg. Although this dose was high enough to be lethal to many animals, it failed to produce any significant hair cell loss. [Figure - 4]B show the mean (n=4) cochleogram from a group of 3 month old, C57 mice treated with 100 mg/kg. The C57 mice had a small OHC lesion in the base of the cochlea, but this lesion was comparable to that seen in other age-matched control animals (Spongr et al., 1997). In other words, the lesion is most likely the result of age-related hair cell loss rather than carboplatin ototoxicity.
emissions are believed to arise from a nonlinear, active process that presumably originates in the electromotile response of the cell body of OHCs (Ashmore and Brownell, 1986; Brown et al., 1989; Brownell et al., 1985; Kemp, 1986). The hypothesis that OHCs are the sole source of DPOAEs has been challenged on several grounds. First, DPOAEs can be recorded from animals, such as birds, that lack OHCs (Froymovich et al., 1995; Trautwein et al., 1996b). Second, the Bronx Waltzer mutant mouse, that develop IHC lesions early in life, shows a 10-20 dB reduction in DPOAE amplitude compared to control mice with normal hair cells (Schrott et al., 1991). These results suggest that the IHCs partially contribute to the generation of DPOAEs. A generic mechanism for producing distortion products in a wide range of species is the nonlinearity observed in the gating compliance of stereocilia bundle movement (Jaramillo et al., 1993). To test this hypothesis, we measured DPOAEs (2f1-f2, stimulus frequencies: f2/f1 =1.2, primary tone levels: L1=L2) in chinchillas before and after carboplatin treatment (Hofstetter et al., 1997a; Trautwein et al., 1996a). The chinchilla shown in [Figure - 5]A developed an IHC loss that ranged from 70-90% over most of the cochlea after a 76mg/kg dose of carboplatin. Despite the massive IHC loss, most of the OHCs were present. [Figure - 5]B shows the DPOAE input/output functions measured before and approximately 45 weeks after carboplatin treatment. Despite the large (~70-90%) IHC lesion, there was little or no difference between the pre- and posttreatment DPOAE input/output functions. These results suggest that the IHCs make little or no contribution to generation of DPOAEs.
When very high doses of carboplatin were administered to chinchillas, some animals developed massive IHC lesions throughout the cochlea plus OHC lesions that decreased from base to apex as shown in [Figure - 6]A (Hofstetter et al., 1997a). In this example, the OHC lesion decreased from 100% near the base of the cochlea (> 3 kHz) to approximately 10% near the apex. In cases such as this, DPOAE amplitude decreased significantly at high frequencies. At the f2 frequency of 9.6 kHz, the DPOAE amplitude had decreased to the noise floor of the system, i.e., the DPOAE was not detectable. The DPOAE elicited by primary tones of 8 and 9.6 kHz was associated with a region of the cochlea in which nearly all of the OHCs were missing.
In contrast, the DPOAE elicited by primary tones of 1 and 1.2 kHz was reduced, but still present. The 1-1.2 kHz region of the cochlea was associated with an OHC lesion of approximately 50%. These results indicate that OHCs are the source of DPOAEs in mammals consistent with earlier reports (Forge and Brown, 1982).
While the preceding results indicate that the OHCs are the dominant source of the DPOAEs, the precise relationship between OHC damage and the reduction in DPOAE amplitude is poorly understood. To address this issue, we measured the reduction in DPOAE amplitude between 7080 dB SPL at f1 and f2 frequencies of 8 and 9.6 kHz (Hofstetter et al., 1997a). The change in DPOAE amplitude was correlated with the amount of OHC loss in a 10% interval of the cochlear corresponding to the frequencies used to elicit the DPOAEs. [Figure - 7]A is a scatter plot showing the reduction in DPOAE amplitude versus percentage OHC loss for the frequencies of 8 and 9.6 kHz. DPOAE amplitude decreased approximately linearly with increasing OHC loss. Linear regression analysis (r=-0.81) performed on the data showed that DPOAE amplitude decreased at the rate of 4.1 dB for every 10% increment of OHC loss (Hofstetter et al., 1997a). [Figure - 7]B shows similar results for the frequencies of 6 and 7.2 kHz. Linear regression (r=-0.73) showed that DPOAE amplitude decreased at the rate of 3.1 dB per 10% OHC loss.
Cochlear Microphonic and Summating Potential: The role that the IHCs and OHCs play in the generation of the cochlear microphonic (CM) potential and summating potential (SP) was evaluated by selectively destroying IHCs or a combination of IHCs plus OHCs. As shown in [Figure - 8], destruction of nearly all of the IHCs had essentially no effect on CM amplitude. This finding is consistent with the notion that OHCs are the dominant generator of the CM (Dallos et al., 1972).
The exact source of the summating potential (SP) has remained a subject of debate. Some evidence points to IHCs as the source of the SP. However, the IHCs in the base of the cochlea produce little in the way of a DC potential that could be used to generate the SP (Russell et al., 1986) whereas those in the apex do (Dallos, 1997). To evaluate the source of the SP, we compared the amplitude of the SP with the size of the IHC lesion or lesions involving the loss of both IHCs and IHCs (Durrant et al., 1998). As shown in [Figure - 9], the SP was reduced by more than 50% when the IHCs were destroyed. Destruction of both IHC plus OHCs caused a further reduction in the SP. These results suggest that the IHCs make a significant contribution to the SP recorded from the round window. OHCs also contribute to the generation of the SP, but to a lesser extent than IHCs.
Compound Action Potential: Approximately 90-95% of all auditory nerve fibers (type I neurons) make synaptic contact with the IHCs (Spoendlin, 1967). The remaining 5-10% of type II neurons synapse on OHCs. Intracellular labeling studies have shown that all auditory nerve fibers that respond to sound contact IHCs (Liberman, 1982; Robertson, 1984). In contrast, labeled fibers that contact OHCs do not appear to generate spike discharges either spontaneously or in response to sound (Robertson, 1984). Thus, virtually all of the information flowing out of the cochlea to the central auditory system is transmitted through the type I auditory nerve fibers that contact the IHCs. The compound action potential (CAP) recorded from the round window is a local field potential that represents the summed response of the auditory nerve fibers activated by the onset of the stimulus. Since carboplatin selectively destroys the IHCs, the amplitude of the compound action potential (CAP) should decrease in proportion to the amount of IHC loss. To test this hypothesis, we measured the CAP from a group of carboplatintreated chinchillas (38 mg/kg, i.p.) with approximately 25-30% IHC loss see [Figure - 2]A. As shown in [Figure - 10]A, the CAP amplitude was reduced by approximately 30%, i.e., CAP amplitude was approximately 70% of the CAP amplitude measured in normal, control animals. Although the amplitude of the CAP was decreased, the visual detection thresholds for the CAP showed almost no increase [Figure - 10]B. These results suggest that the remaining IHCs and their associated auditory nerve fibers have normal thresholds. A second group of chinchillas was treated with a higher dose of carboplatin (76 mg/kg) that resulted in almost total loss of IHCs in the base of the cochlea and an average IHC loss of approximately 88%. In cases such as this, where there was massive IHC loss, the CAP amplitude was extremely low [Figure - 10]A and almost impossible to detect because of background electrical noise from the CM and SP (Wang et al., 1997). In such cases, the CAP threshold could not be measured at the high frequencies where there was almost 100% IHC loss. However, at the low frequencies, the CAP threshold was elevated to a significant degree. The elevation of threshold could be partly due to the fact that there are so few nerve fibers responding to sound. Consequently, the CAP cannot be extracted from background noise and from the residual CM and SP, i.e., a signal to noise problem.
Auditory Nerve Discharge Patterns: In cases where low to moderate doses of carboplatin resulted in partial IHC loss and an intact population of OHCs, one can determine if the tuning and sensitivity of the surviving IHCs is normal. One indirect method of answering this question is to record from single auditory nerve fibers that synapse on the surviving IHCs. [Figure - 11]A shows the frequency-threshold, tuning curve of an auditory nerve fiber from an animal with 20-30% IHC loss and an intact population of OHCs. The threshold at the characteristic frequency (CF) of this neuron was 3 dB SPL, a value comparable to some of the most sensitive neurons in normal animals. In addition, the fiber had a sharply tuned tip. These results suggest that threshold and tuning are unaffected by small to moderate IHC lesions. [Figure - 11]B shows a tuning curve from a carboplatin-treated animal with a large IHC lesion that exceeded 60% over most of the cochlea. In animals such as this, acoustically responsive units were seldom encountered as the recording electrode passed through the auditory nerve. However, when acoustically responsive units were encountered, their tuning curves were sharply tuned [Figure - 11]B. However, CFthreshold were generally higher than in normal animals as shown in [Figure - 11]B (56 dB SPL). One interpretation of these results is that the acoustically responsive nerve fibers contact damaged IHCs. Results similar to these have been seen in acoustically traumatized ears in which the stereocilia on the IHCs were damaged and the OHCs were intact (Liberman et al., 1986). Thus, IHC stereocilia damage could account for the elevated CAP thresholds in these animals.
In normal animals, most auditory nerve fibers discharge spontaneously in the absence of acoustic stimulation. Discharge rates typically range from 0 to slightly more than 100 spikes/s [Figure - 11]C. In normal chinchillas, the distribution of spontaneous rates is typically bimodal with a large peak near 0 spikes/s and a second, broad peak around 70-90 spikes/s. In carboplatin treated animals with small to moderate IHC lesions (<60%), the spontaneous discharge rates were depressed (Wang et al., 1997). A much larger proportion of units had spontaneous rates near 0 spikes/s. In addition, a smaller proportion of units had spontaneous rates above 90 spikes/s. Discharge rates to sound stimulation were also depressed in carboplatintreated ears with small-to-moderate IHC lesions as shown in [Figure - 11]D. In normal control animals, the maximum sound-evoked discharge rate was approximately 250 spike/s whereas in the carboplatin treated animals, the maximum rate was 200 spikes/s or less. Our recent histochemical studies using succinate dehydrogenase (Ding et al., 1999) show depressed staining in the IHCs of carboplatin treated chinchilla whereas the OHCs were intensely stained. These results suggest that the decrease in spontaneous and driven discharge rates may be the result of depressed metabolic activity in the surviving IHCs.
Spiral Ganglion Cell Loss: One of the earliest signs of damage seen after carboplatin treatment is swelling in the afferent dendrites beneath the hair cells (Ding et al., 1997). [Figure - 12] is a transmission electron micrograph showing the condition of the afferent terminal at 6 h and 24 h post-carboplatin (100 mg/kg). Moderate swelling (arrow) is seen in afferent terminals at 6-h post-carboplatin [Figure - 12]A and at 24-h post-carboplatin, the swelling (arrow) is so severe that it distorts the basal pole of the IHC [Figure - 12]B. Carboplatin also causes early damage to the spiral ganglion neurons as illustrated by the transmission electron micrographs in [Figure - 12]C-D. At 6-h postcarboplatin, many small vacuoles (arrow) were present near the plasma membrane [Figure - 12]C. By 24 h, the vesicles (arrow) had increased in size and many were present throughout the cytoplasm. [Figure - 12]E-F shows transmission electron micrographs of the proximal nerve fiber. At 6-h post-carboplatin, many large vesicles (arrow) were present within the cytoplasm of some axons [Figure - 12]E. In addition, vacuoles were occasionally seen within the myelin sheath. After 24 h, the vacuoles (arrow) had increased in size and number [Figure - 12]F. In many cases, the vacuoles occupied more than half the cytoplasm within the fiber. In a few cases, large vacuoles were seen penetrating the myelin sheath.
Evoked Response from Inferior Colliculus (IC) and Auditory Cortex (AC): The preceding anatomical and physiological results show that carboplatin reduces the number of neural inputs to the central auditory system. Although the inputs to the central auditory system are reduced, the surviving neurons have low thresholds and sharp tuning. An obvious question to ask is, how does the central auditory brain respond when it is deprived of its sensory inputs? If one assumes that the central auditory system is a hardwired system, then it would be logical to predict that the loss of peripheral inputs would cause responses in the IC and AC to decrease.
However, it is conceivable that the central auditory system compensates for the diminished inputs by upregulating its responsiveness (Salvi et al., 1992; Salvi et al., 1990; Wang et al., 1996). To evaluate this hypothesis, we recorded the local field potentials from the inferior colliculus (IC) and auditory cortex (AC) before and after carboplatin treatment. As shown in [Figure - 13]A, a 50-mg/kg dose of carboplatin destroyed approximately 20-30% of the IHCs in the apical half of the cochlea. Lesions of this magnitude would normally produce a decrease in CAP amplitude of 20-30% as noted earlier see [Figure - 10]A. Despite a diminished cochlear input (reduced CAP amplitude), the IC input/output functions at 500 Hz showed no significant change in amplitude between 3 days and 5 weeks post-carboplatin. As shown in [Figure - 13]C, the AC input/output function showed a rather striking increase after carboplatin treatment. The post-carboplatin input/output functions were unaffected at low intensities (< 40 dB SPL). However, at high intensities, the AC amplitude increased by as much as 80%. These results suggest that the neurons in the auditory cortex have become hyperactive in response to a diminished cochlear input. It is also important to note that there was little or no change in the threshold at the IC or AC consistent with earlier observations (Burkard et al., 1997; McFadden et al., 1998).
| Conclusion|| |
The classic OHCs lesions produced by aminoglycoside antibiotics and platinum-based cancer drugs have provided researchers with a power tool for establishing the functional role of OHCs (Dallos et al., 1972; Schmiedt et al., 1980). However, methods for selectively destroying the IHCs while retaining a intact population of OHCs have remained elusive until carboplatin was shown to selectively destroy IHCs in the chinchilla (Takeno et al., 1994a; Wake et al., 1994; Wake et al., 1993). Selective IHC loss causes a reduction in CAP amplitude that is proportional to the degree of IHC loss. However, CAP thresholds and single fiber thresholds do not increase significantly until IHC lesions exceed roughly 70%. In addition, auditory nerve fibers that contact the surviving IHCs have normal tuning. These results suggest that the OHCs are responsible for the exquisite sensitivity and sharp tuning of the cochlea. Our results show that selective IHC loss has no effect on DPOAE or CM amplitude. These results suggest that the DPOAEs and the CM are generated by intact OHCs. When the dose of carboplatin was sufficient to destroy both IHCs and OHCs, then DPOAE amplitude decreased in proportion to the amount of OHC loss. This is consistent with the notion that DPOAEs reflect the functional integrity of the OHCs.
The preceding results have important clinical implications. First, DPOAEs are being used to screen for hearing loss in infants. Since the vast majority of infants have sensorineural hearing loss resulting from OHC damage, DPOAEs should be an effective method for screening for hearing loss. However, other cases of cochlear pathology that involve selective damage to the IHCs or type-I neurons would be missed completely by DPOAE testing. For example, patients with auditory neuropathy, a rare disorder, have normal DPOAEs, but lack wave I of the auditory brainstem response (Starr et al., 1996). The histological correlates of auditory neuropathy are poorly understood, but one candidate could be the selective loss of IHCs or type I afferent fibers. Since IHC loss results in a significant reduction of the cochlear summating potential (Durrant et al., 1998), electrocochleography could be used to assess the functional integrity of the IHCs in these patients.
Carboplatin is considerably less ototoxic than cisplatin and our efforts to use carboplatin to produce IHC or OHC lesions in mice and gerbils (M. Mueller, personal communication) have so far proved unsuccessful. Thus, one of the important riddles remaining to be solved is why carboplatin is ototoxic to IHCs in chinchillas. The molecular machinery for importing carboplatin into hair cells could play a crucial role in selective toxicity (Richardson et al., 1997). Conversely, some cell lines are resistant to platinum based drugs due to a drug transporter protein that extrudes platinum from the cell (Berger et al., 1997). Similar platinum export pumps have been implicated in drug resistance in other cell lines (Chuman et al., 1996). Once inside the cell, platinum-based drugs cause uncoupling of oxidative phosphorylation, efflux of calcium from mitochondria, inhibition of ATP synthesis and a reduction of various membrane transport enzymes (Aggarwal, 1993). Understanding the molecular mechanisms of carboplatin ototoxicity in the chinchilla could eventually lead to new methods for preventing ototoxicity.
| Acknowledgements|| |
Work supported in part by NIH grant NIDCD 1P01DC03600. The authors would like to thank Chun-Xiao Qiu, Patricia Trautwein and Phillip Hofstetter for their excellent contributions to the research.
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|35.||Schmiedt, R.A., Zwislocki, J.J. & Hamernik, R.P. (1980) Effects of hair cell lesions on responses of cochlear nerve fibers. I. Lesions, tuning curves, two-tone inhibition, and responses to trapezoidal-wave patterns. J. Neurophysiol. 43: 1367-1389. |
|36.||Schrott, A., Puel, J.L. & Rebillard, G. (1991) Cochlear origin of 2f1-f2 distortion products assessed by using 2 types of mutant mice. Hearing Res. 52: 245-253. |
|37.||Spoendlin, H. (1967) The innervation of the organ of Corti. J. Laryngol. Otol. 81: 717-738. |
|38.||Spongr, V.P., Flood, D.G., Frisina, R.D. & Salvi, R.J. (1997) Quantitative measure of hair cell loss in CBA and C57BL/6 mice throughout their life spans. J. Acoust. Soc. Am. 101: 3546-3553. |
|39.||Starr, A., Picton, T.W., Sininger, Y., Hood, L.J. & Berlin, C.I. (1996) Auditory neuropathy. Brain 119: 741-753. |
|40.||Takeno, S., Harrison, R.V., Ibrahim, D., Wake, M. & Mount, R.J. (1994a) Cochlear function after selective inner hair cell degeneration induced by carboplatin. Hearing Res. 75: 93-102. |
|41.||Takeno, S., Harrison, R.V., Mount, R.J., Wake, M. & Harada, Y. (1994b) Induction of selective inner hair cell damage by carboplatin. Scan. Micros. 8: 97-106. |
|42.||Taudy, M., Syka, J., Popelar, J. & Ulehlova, L. (1992) Carboplatin and cisplatin ototoxicity in guinea pigs. Audiol. 31: 293-299. |
|43.||Trautwein, P., Hofstetter, P., Wang, J., Salvi, R. & Nostrant, A. (1996a) Selective inner hair cell loss does not alter distortion product otoacoustic emissions. Hearing Res. 96: 71-82. |
|44.||Trautwein, P., Salvi, R.J., Miller, K., Shero, M. & Hashino, E. (1996b) Incomplete recovery of chicken distortion product otoacoustic emissions following acoustic overstimulation. Audiol. Neuro-Otol. 1: 86-103. |
|45.||van der Hulst, R.J.A.M., Dreschler, W.A. & Urbanus, N.A.M. (1988) High frequency audiometry in prospective clinical research of ototoxicity due to platinum derivatives. Ann. Otol. Rhinol. Laryngol. 97: 133-137. |
|46.||Wake, M., Takeno, S., Ibrahim, D. & Harrison, R. (1994) Selective inner hair cell ototoxicity induced by carboplatin. Laryngoscope 104: 488-493. |
|47.||Wake, M., Takeno, S., Ibrahim, D., Harrison, R. & Mount, R. (1993) Carboplatin ototoxicity: an animal model. J. Laryngol. Otol. 107: 585-589. |
|48.||Wang, J., Powers, N.L., Hofstetter, P., Trautwein, P., Ding, D. & Salvi, R. (1997) Effects of selective inner hair cell loss on auditory nerve fiber threshold, tuning and spontaneous and driven discharge rate. Hearing Res. 107: 67-82. |
|49.||Wang, J., Salvi, R.J. & Powers, N. (1996) Rapid functional reorganization in inferior colliculus neurons following acute cochlear damage. J. Neurophysiol. 75: 171-183. |
R J Salvi
Hearing Research Lab, 215 Parker Hall, University at Buffalo, Buffalo, NY 14214
Source of Support: None, Conflict of Interest: None
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7], [Figure - 8], [Figure - 9], [Figure - 10], [Figure - 11], [Figure - 12], [Figure - 13]