Journal Logo

Hearing Loss and Ototoxicity

Hidden Hearing Loss and Brain Changes from Ototoxic Drugs

Salvi, Richard PhD

Author Information
doi: 10.1097/01.HJ.0000654936.64301.56
  • Free

The term “hidden hearing loss” refers to a form of hearing impairment in which a subject presents with normal otoacoustic emissions and audiometric thresholds but complains of hearing problems such as tinnitus or difficulty understanding speech in noise.1,2 Recent human and animal studies on aging and noise-induced hearing loss suggest that hidden hearing loss may result from ototoxic damage to the inner hair cells (IHC) and/or type I auditory nerve fibers (ANF) that synapse on inner hair cells,3,4 conditions reminiscent of auditory neuropathy.

Ildar Imashev, hearing loss, ototoxic drug, cancer treatment.
Figure 1.
Figure 1.:
(A) Schematic cochleogram from a carboplatin-treated chinchilla with 70 percent inner hair cell (IHC) loss and intact outer hair cells (OHC). Note relatively uniform loss of IHC from the apex (0%) to the base (100%) of the cochlea. Upper abscissa shows the chinchilla cochlear frequency-place map. (B) Schematic showing the pre- and post-carboplatin distortion product otoacoustic emission (DPOAE) input/output function using stimuli near 8 kHz. Despite massive carboplatin-induced IHC lesions (panel A), the post-carboplatin input/output function is nearly identical to the pre-treatment function. (C) Schematic showing the amplitude of the compound action potential (CAP) versus tone burst intensity pre- and post-carboplatin. IHC loss of 70 percent (panel A) reduces the CAP amplitude by approximately 70 percent. (D) Schematic of chinchilla behavioral audiogram measured pre- and post-carboplatin; thresholds largely unchanged by 70 percent IHC loss (panel A). (E) Schematic showing behavioral threshold shifts (hearing loss) versus percent IHC loss. Thresholds shifts begin to increase precipitously once the IHC lesion exceeds 80 percent. (F) Schematic showing chinchilla behavioral masked thresholds measured in broadband noise pre- and post-carboplatin. Masked thresholds increase significantly in chinchillas with significant IHC loss. Hearing loss, ototoxic drug, cancer treatment.
Figure 2.
Figure 2.:
(A) Schematic showing the percent change in neural responses measured at 80 dB SPL versus percent inner hair cell (IHC) loss. Data shown for compound action potential (CAP), inferior colliculus (IC), and auditory cortex (AC). Reduction in IC amplitude is much less than CAP amplitude. AC amplitudes are larger than normal for small to moderate IHC lesion, but AC amplitudes reduced with large IHC lesions. (B) Schematic showing the number of newborn neurons/mm length of the dentate gyrus of the hippocampus in control (Cnt) rats versus cisplatin-treated rats assessed seven days post-cisplatin. Note large reduction in newborn neurons after cisplatin treatment. Hearing loss, ototoxic drug, cancer treatment.

CARBOPLATIN & CISPLATIN OTOTOXICITY

Cisplatin is an ototoxic drug best known for damaging outer hair cells (OHC) and inner hair cells (IHC); however, platinum-based drugs can also affect vulnerable areas of the central nervous system. Carboplatin is considered less ototoxic than cisplatin.5,6 Nevertheless, when carboplatin is administered to chinchillas, it preferentially destroys the IHC and ANF over the length of the cochlea (Fig. 1A) in contrast to the base-to-apex gradient seen with most ototoxic drugs.7 Carboplatin is neurotoxic and causes rapid excitotoxic swelling of the afferent ANF synapses, followed a few days later by IHC loss.8

Cochlear function. Despite massive IHC and ANF damage, otoacoustic emissions (Fig. 1B) and the cochlear microphonic potential generated by the OHC remain normal, indicating that OHC are functioning normally.7 However, the amplitude of the summating potential generated by the IHC and the amplitude of the compound action potential (Fig. 1C) generated by ANF are reduced in proportion to the amount of IHC loss. Therefore, the summating potential and compound action potential (analogous to ABR wave I) can be used to assess the functional status of IHC and ANF in clinical cases of suspected hidden hearing loss. In carboplatin-treated chinchillas with partial loss of IHC and ANF, single auditory nerve fiber recordings can be used to interrogate the functional capacity of the remaining IHC and ANF.7 When measurements are made from a single auditory nerve fiber connected to a cochlear region where 60 to 90 percent of the IHC/ANF are missing, only a few ANF are still available from which to obtain measurements. Surprisingly, the remaining acoustically responsive ANF behave normally (with low thresholds and sharp tuning) despite massive cochlear damage.

Auditory Perception. How well does a carboplatin-treated chinchilla hear when many IHC/ANF are missing and only a few IHC/ANF are left to detect a tone in quiet? When chinchilla audiograms are measured pre- and post-carboplatin treatment, the hearing thresholds remain normal in animals with up to 80 percent IHC loss (Fig. 1D); however, the thresholds increase precipitously once IHC lesions exceed 85 percent (Fig. 1E).9 Apparently, only a few IHC/ANF are needed to detect a sound in quiet. However, if pure-tone thresholds are measured in broadband noise pre- and post-carboplatin, tone thresholds in noise are elevated significantly in chinchillas with large IHC/ANF lesions even though thresholds in quiet are normal.10

Central Gain Compensation. A carboplatin-induced lesion that destroys half the IHC/ANF would reduce the neural output of the cochlea by roughly 50 percent. If the auditory system behaved as a simple linear system, neural responses recorded at higher auditory centers should be reduced by half, unless the brain possessed a neural amplification system that can boost these weak cochlear signals. To test this hypothesis, electrodes were chronically implanted at the level of the cochlea, inferior colliculus, and auditory cortex to record the local field potentials from these regions pre- and post-carboplatin. When 50 percent of the IHC/ANF were destroyed, the compound action potential from the cochlea was reduced by 50 percent (Fig. 2A, intersection of vertical dashed line with solid red line). However, by the time the neural signal reached the inferior colliculus, the response was reduced by only 20 percent (Fig. 2A, dashed green line), evidence of neural amplification between the cochlea and auditory midbrain.11 Surprisingly, the neural responses from the auditory cortex were even larger than normal (Fig. 2A, dashed blue line) as long as the IHC lesions were not too severe. These results provide evidence of additional amplification between the auditory midbrain and auditory cortex. Thus, the central auditory pathway progressively amplifies weak cochlear signals as they are relayed up the central auditory pathway. Similar central amplification has also been observed in cases of noise- and drug-induced hearing loss.12,13

How is the central auditory pathway able to amplify these weak cochlear signals? The central auditory pathway comprises a complex network of inhibitory and excitatory synapses. The strong excitatory signals relayed from a normal cochlea are normally suppressed by strong GABAergic inhibition similar to negative gain control.14,15 One way to enhance weak cochlear signals from a damaged cochlea is to increase the gain of the central auditory pathway by removing GABAergic inhibition. To test this hypothesis, sound-evoked local field potentials were recoded from the auditory cortex of normal chinchillas and compared with those from another group of carboplatin-treated chinchillas with large IHC/ANF lesions. When GABAergic inhibition was pharmacologically suppressed, the neural responses from the auditory cortex nearly doubled in size, evidence of strong GABAergic inhibition in a normal auditory cortex.16 However, when GABAergic inhibition was pharmacologically suppressed in carboplatin-treated chinchillas, it failed to increase sound-evoked responses in the auditory cortex. These results suggest that GABAergic inhibition had been eliminated in the auditory cortex of carboplatin-treated chinchillas. Because these weak excitatory signals entering the auditory cortex were unopposed by inhibition, they were able to evoke a strong cortical response.

BRAIN NEUROTOXICITY

Cisplatin and other platinum-based anticancer drugs are neurotoxic and can damage vulnerable areas of the brain such as the hippocampus.17,18 The hippocampus, which plays an important role in the formation of new memories, is connected with many different parts of the auditory pathway and can be activated by sound.19-21 The hippocampus contains a stem cell niche, and is one of only two areas of the adult brain where new neurons are born (neurogenesis) throughout one's life.22 When hippocampal neurogenesis is suppressed, it becomes much more difficult to form new memories such as recalling where you parked your car after leaving the shopping mall (i.e., spatial navigation).23,24

Anti cancer drugs such as cisplatin suppress cell division, damage hippocampal synapses, and contribute to cognitive dysfunction, a condition referred to as chemobrain.25,26 To determine if cisplatin could suppress hippocampal neurogenesis, we treated rats with cisplatin and measured the number of newborn neurons. Cisplatin suppressed neurogenesis by more than 70 percent at seven days post-treatment and significantly increased the expression of genes that promote cell death in the hippocampus.27,28 Humans and animal studies have shown that loss of sensory information from the vestibular system also reduces neurogenesis and promotes atrophy of the hippocampus.29 These results suggest that the loss of auditory information from a damaged cochlea might also suppress hippocampal neurogenesis. To test this hypothesis, rodents were unilaterally exposed to an intense noise that caused significant unilateral hearing loss and cochlear damage. Importantly, the unilateral hearing loss also suppressed hippocampal neurogenesis by approximately 40 percent30 and impaired performance on a memory spatial navigation task.31,32 Together, these results indicate that platinum-based ototoxic drugs and noise-induced hearing loss can suppress hippocampal neurogenesis, changes that could contribute to cognitive decline among those with hearing loss.33

Thoughts on something you read here? Write to us at HJ@wolterskluwer.com

REFERENCES

1. Schaette R, McAlpine D. Tinnitus with a normal audiogram: physiological evidence for hidden hearing loss and computational model. J Neurosci. 2011;31(38):13452-7.
2. Plack CJ, Barker D, Prendergast G. Perceptual consequences of “hidden” hearing loss. Trends Hear. 2014;18.
3. Viana LM, O'Malley JT, Burgess BJ, Jones DD, Oliveira CA, Santos F, et al. Cochlear neuropathy in human presbycusis: Confocal analysis of hidden hearing loss in post-mortem tissue. Hear Res. 2015;327:78-88.
4. Lin HW, Furman AC, Kujawa SG, Liberman MC. Primary neural degeneration in the Guinea pig cochlea after reversible noise-induced threshold shift. J Assoc Res Otolaryngol. 2011;12(5):605-16.
5. Adams M, Kerby IJ, Rocker I, Evans A, Johansen K, Franks CR. A comparison of the toxicity and efficacy of cisplatin and carboplatin in advanced ovarian cancer. The Swons Gynaecological Cancer Group. Acta Oncol. 1989;28(1):57-60.
6. Lambert MP, Shields C, Meadows AT. A retrospective review of hearing in children with retinoblastoma treated with carboplatin-based chemotherapy. Pediatr Blood Cancer. 2008;50(2):223-6.
7. Wang J, Powers NL, Hofstetter P, Trautwein P, Ding D, Salvi R. Effects of selective inner hair cell loss on auditory nerve fiber threshold, tuning and spontaneous and driven discharge rate. Hear Res. 1997;107(1-2):67-82.
8. Wang J, Ding D, Salvi RJ. Carboplatin-induced early cochlear lesion in chinchillas. Hear Res. 2003;181(1-2):65-72.
9. Lobarinas E, Salvi R, Ding D. Insensitivity of the audiogram to carboplatin induced inner hair cell loss in chinchillas. Hear Res. 2013;302:113-20.
10. Lobarinas E, Salvi R, Ding D. Selective Inner Hair Cell Dysfunction in Chinchillas Impairs Hearing-in-Noise in the Absence of Outer Hair Cell Loss. J Assoc Res Otolaryngol. 2015.
11. Qiu C, Salvi R, Ding D, Burkard R. Inner hair cell loss leads to enhanced response amplitudes in auditory cortex of unanesthetized chinchillas: evidence for increased system gain. Hear Res. 2000;139(1-2):153-71.
12. Salvi RJ, Saunders SS, Gratton MA, Arehole S, Powers N. Enhanced evoked response amplitudes in the inferior colliculus of the chinchilla following acoustic trauma. Hear Res. 1990;50(1-2):245-57.
13. Salvi RJ, Wang J, Ding D. Auditory plasticity and hyperactivity following cochlear damage. Hear Res. 2000;147(1-2):261-74.
14. Wang J, Caspary D, Salvi RJ. GABA-A antagonist causes dramatic expansion of tuning in primary auditory cortex. Neuroreport. 2000;11(5):1137-40.
15. Wang J, McFadden SL, Caspary D, Salvi R. Gamma-aminobutyric acid circuits shape response properties of auditory cortex neurons. Brain Res. 2002;944(1-2):219-31.
16. Salvi R, Sun W, Ding D, Chen GD, Lobarinas E, Wang J, et al. Inner Hair Cell Loss Disrupts Hearing and Cochlear Function Leading to Sensory Deprivation and Enhanced Central Auditory Gain. Front Neurosci. 2016;10:621.
17. Rybak LP, Ramkumar V. Ototoxicity. Kidney Int. 2007;72(8):931-5.
18. Rzeski W, Pruskil S, Macke A, Felderhoff-Mueser U, Reiher AK, Hoerster F, et al. Anticancer agents are potent neurotoxins in vitro and in vivo. Ann Neurol. 2004;56(3):351-60.
19. Shinba T, Andow Y, Shinozaki T, Ozawa N, Yamamoto K. Event-related potentials in the dorsal hippocampus of rats during an auditory discrimination paradigm. Electroencephalogr Clin Neurophysiol. 1996;100(6):563-8.
20. Tang J, Wagner S, Schachner M, Dityatev A, Wotjak CT. Potentiation of amygdaloid and hippocampal auditory-evoked potentials in a discriminatory fear-conditioning task in mice as a function of tone pattern and context. Eur J Neurosci. 2003;18(3):639-50.
21. Chen YC, Li X, Liu L, Wang J, Lu CQ, Yang M, et al. Tinnitus and hyperacusis involve hyperactivity and enhanced connectivity in auditory-limbic-arousal-cerebellar network. Elife. 2015;4:e06576.
22. Altman J, Das GD. Autoradiographic and histological studies of postnatal neurogenesis. I. A longitudinal investigation of the kinetics, migration and transformation of cells incorporating tritiated thymidine in neonate rats, with special reference to postnatal neurogenesis in some brain regions. J Comp Neurol. 1966;126(3):337-89.
23. Snyder JS, Hong NS, McDonald RJ, Wojtowicz JM. A role for adult neurogenesis in spatial long-term memory. Neuroscience. 2005;130(4):843-52.
24. Winocur G, Wojtowicz JM, Sekeres M, Snyder JS, Wang S. Inhibition of neurogenesis interferes with hippocampus-dependent memory function. Hippocampus. 2006;16(3):296-304.
25. Whitney KA, Lysaker PH, Steiner AR, Hook JN, Estes DD, Hanna NH. Is “chemobrain” a transient state? A prospective pilot study among persons with non-small cell lung cancer. J Support Oncol. 2008;6(7):313-21.
26. Andres AL, Gong X, Di K, Bota DA. Low-doses of cisplatin injure hippocampal synapses: a mechanism for ‘chemo’ brain? Exp Neurol. 2014;255:137-44.
27. Hinduja S, Kraus KS, Manohar S, Salvi RJ. D-methionine protects against cisplatin-induced neurotoxicity in the hippocampus of the adult rat. Neurotox Res. 2015;27(3):199-204.
28. Manohar S, Jamesdaniel S, Salvi R. Cisplatin inhibits hippocampal cell proliferation and alters the expression of apoptotic genes. Neurotox Res. 2014;25(4):369-80.
29. Manohar S, Jamesdaniel S, Salvi R. Cisplatin inhibits hippocampal cell proliferation and alters the expression of apoptotic genes. Neurotox Res. 2014;25(4):369-80.
30. Kraus KS, Mitra S, Jimenez Z, Hinduja S, Ding D, Jiang H, et al. Noise trauma impairs neurogenesis in the rat hippocampus. Neuroscience. 2010;167(4):1216-26.
31. Liu L, Shen P, He T, Chang Y, Shi L, Tao S, et al. Noise induced hearing loss impairs spatial learning/memory and hippocampal neurogenesis in mice. Sci Rep. 2016;6:20374.
32. Salvi R, Langguth B, Kraus S, Landgrebe M, Allman B, Ding D, et al. Tinnitus and Hearing Loss and Changes in Hippocampus. Sem Hear. 2011;32(2):203-11.
33. Lin FR, Metter J, O'Brien RJ, Resnick SM, Zonderman AB, Ferrucci L. Hearing Loss and Incident Dementia. Arch Neurol. 2011;68(2):214-20.
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.