||Differential effects of salicylate on auditory evoked potentials in the tinnitus animal model
||Department of Physiology
耳鳴是一種沒有外界聲音的時候感覺有聲音出現的現象,人類受試者報告出耳鳴的現象是高頻的聲音。 過量的水楊酸(阿斯匹靈的有效成分)已知可以在動物模式與人類受試者造成耳鳴。 之前的研究顯示水楊酸誘發耳鳴會造成高頻音域聽覺閾值上升 15分貝。 這種閾值上升的現象至今機制不明。了解耳鳴對於不同聲音的影響機制十分重要。 為了紀錄自由行動而且清醒動物的聽覺誘發電位，我們使用植入電極來記錄。 植入電極放在接近聽覺中腦下丘的位置。在注射連續注射五天水楊酸前後的誘發電位反應，改變不同聲音(純音刺激與廣譜變化的聲音)的刺激強度來記錄電位的改變。我們發現水楊酸注射對於廣譜變化的聲音造成聽覺誘發電位閾值上升，高頻純音刺激促進聽覺誘發電位反應，低頻純音刺激則沒有改變聽覺誘發電位反應。這是第一次在同一隻動物中發現到這種現象。我們解釋這種現象是歸因於不同的聲音刺激的特性及頻率組成所致。這個發現指出耳鳴的機制會涉及在高聲音刺激強度的時候開啟自主調節系統，低強度的聲音刺激強度則是由於水楊酸抑制耳蝸輸出所致。
Tinnitus is the phantom sensation of sound in the absence of the corresponding external stimuli. Multiple over-doses of salicylate (SA) induced reversible tinnitus in humans and animals. Previous studies showed that SA-induced tinnitus was associated with an elevated hearing threshold (of about 15 dB) especially affecting high frequency regions (~10-16 kHz). On the other hand, SA was also reported in amplification of auditory evoked potentials. Whether SA produces same effects to different sound stimuli remained unclear. This knowledge is important for the understanding of pathophysiological mechanism of tinnitus. Brainstem auditory evoked potential (BAEP) reflect the electrophysiological activity of large numbers of neurons in the brainstem auditory pathway with acoustic stimulation. Here, we recorded BAEP from intra-cranial electrodes chronically implanted in freely moving rats before and after daily doses of SA (250 mg/kg/day, i.p.) over a period of 5 consecutive days. In order to assess the SA effect on the auditory brainstem including the inferior colliculus, which presumably is involved in the genesis of tinnitus, the active epi-dural recording electrode was placed about inferior colliculus (2mm from lamda on one side), and the reference electrode at the bregma. Average BAEP integrals in the post-stimulus 10 ms were taken as the response measure to clicks or tone bursts of systemically varied intensities. We found an elevation of threshold (about 10 dB) of BAEP to clicks after SA treatment and in addition signs of loudness recruitment. But, the BAEP to tone bursts of 16 kHz was sensitized (about 10 dB) after the same SA treatment and in addition signs of hyperacusis. Such enhanced sensitivity was not obvious in the low frequency region of 4 kHz. This is the first time that a differential effect of SA on BAEP from different sounds was observed in the same animal. We explain that such differential effect could be related, among other factors, to the different threshold of BAEP to clicks and to tones, and to the difference in the frequency composition of acoustic stimuli. The present results suggested that the mechanisms of tinnitus could involve turning on the automatic gain control of the descending auditory system at higher intensity levels after SA suppresses the cochlear inputs at low intensity levels.
Acknowledge (Chinese) ．．．．．．．．．．．．．．．．．．．．．．．． 5
List of figures．．．．．．．．．．．．．．．．．．．．．．．．．．．．8
1.1 Tinnitus and its pathophysiological mechanisms．．．．．．．．．．．10
1.2 Tinnitus animal models and salicylate (SA) effects on the auditory system．12
1.2.1 SA reduces the electromotility of outer hair cells．．．．．．．．．13
1.2.2 SA elevates threshold in an auditory nerve．．．．．．．．．．．14
1.2.3 SA effects on cochlear nucleus．．．．．．．．．．．．．．．．15
1.2.4 SA effects on superior olivary nucleus．．．．．．．．．．．．．16
1.2.5 SA increases neural activity of the inferior colliculus．．．．．．．17
1.2.6 SA enhances neural activities of the auditory cortex．．．．．．．18
1.3 Brainstem auditory evoked potential (BAEP) ．．．．．．．．．．．18
1.4 Aims of study．．．．．．．．．．．．．．．．．．．．．．．．20
2. MATERIALS AND METHODS
2.1 Chronic animal preparation．．．．．．．．．．．．．．．．．．．21
2.2 SA injections and recording paradigm．．．．．．．．．．．．．．．22
2.3 Electrophysiological recordings．．．．．．．．．．．．．．．．．23
2.4 Acoustic stimuli．．．．．．．．．．．．．．．．．．．．．．．．23
2.5 Video recordings of animal movements．．．．．．．．．．．．．．24
2.6 Data analyses．．．．．．．．．．．．．．．．．．．．．．．．．25
2.6.1 Video analysis of animal movements．．．．．．．．．．．．．．25
2.6.2 BAEP data pre-processing: rejection of over-sized trials．．．．．．25
2.6.3 BAEP response intensity functions．．．．．．．．．．．．．．27
3.1 SA elevated click BAEP threshold．．．．．．．．．．．．．．．．28
3.2 Time profiles of SA effects on click BAEP．．．．．．．．．．．．．29
3.3 SA enhanced 16 kHz tone burst BAEP．．．．．．．．．．．．．．．30
3.4 SA did not alter 4 kHz tone burst BAEP．．．．．．．．．．．．．．30
4.1 Origins of the BAEP．．．．．．．．．．．．．．．．．．．．．．31
4.2 SA enhanced 16 kHz but not 4 kHz BAEP．．．．．．．．．．．．．32
4.3 Dynamic range was compressed in click BAEP．．．．．．．．．．．33
4.4 Possible involvements of automatic gain control in SA effects on BAEP．34
Appendix Ⅰ Acoustic calibration of the sound delivering system．．．．．67
Appendix Ⅱ Matlab programs of data analysis．．．．．．．．．．．．68
Achor, L. J. and Starr, A. Auditory brain stem responses in the cat. II. Effects of lesions. Electroencephalogr Clin Neurophysiol 48:174-190, 1980.
Axelsson, A. and Ringdahl, A. Tinnitus--a study of its prevalence and characteristics. Br J Audiol 23:53-62, 1989.
Bancroft, B. R., Boettcher, F. A., Salvi, R. J. and Wu, J. Effects of noise and salicylate on auditory evoked-response thresholds in the chinchilla. Hear Res 54:20-28, 1991.
Basta, D. and Ernst, A. Effects of salicylate on spontaneous activity in inferior colliculus brain slices. Neurosci Res 50:237-243, 2004.
Bauer, C. A., Brozoski, T. J., Holder, T. M. and Caspary, D.M. Effects of chronic salicylate on GABAergic activity in rat inferior colliculus. Hear Res 147:175-182, 2000.
Bauer, C. A., Brozoski, T. J., Rojas, R., Boley, J. and Wyder, M. Behavioral model of chronic tinnitus in rats. Otolaryngol Head Neck Surg 121:457-62, 1999.
Berninger, E, Karlsson, K. K. and Alvan, G. Quinine reduces the dynamic range of the human auditory system. Acta Otolaryngol 118:46-51, 1998.
Burkard, R., Feldman, M. and Voigt, H. F. Brainstem auditory-evoked response in the rat. Normative studies, with observations concerning the effects of ossicular disruption. Audiology 29:146-162, 1990.
Cazals, Y. Auditory sensori-neural alterations induced by salicylate.
Prog Neurobiol 62:583-631, 2000.
Chatterjee, M. and Zwislocki, J. J. Cochlear mechanisms of frequency and intensity coding. II. Dynamic range and the code for loudness. Hear Res 124:170-81, 1998.
Chen, G. D. and Jastreboff, P. J. Salicylate-induced abnormal activity in the inferior colliculus of rats. Hear Res 82:158-178, 1995.
Devanne, H., Cohen, L. G., Kouchtir-Devanne, N. and Capaday, C. Integrated motor cortical control of task-related muscles during pointing in humans. J Neurophysiol 87:3006-3017, 2002.
Evans, E. F. and Borerwe, T. A. Ototoxic effects of salicylates on the responses of single cochlear nerve fibres and on cochlear potentials. Br J Audiol 16:101-108, 1982.
Eggermont, J. J. Tinnitus: neurobiological substrates. Drug Discov Today 10:1283-1290, 2005.
Eggermont, J. J. and Roberts, L. E. The neuroscience of tinnitus. Trends Neurosci 27:676-682, 2004.
Eggermont, J. J. and Kenmochi, M. Salicylate and quinine selectively increase spontaneous firing rates in secondary auditory cortex. Hear Res 117:149-160, 1998.
Gelli, F., Del-Santo, F., Mazzocchio, R. and Rossi, A. Force estimation processing as a function of the input--output relationship of the corticospinal pathway in humans.
Eur J Neurosci 22:1127-1134, 2005.
Groff, J. A. and Liberman, M. C. Modulation of cochlear afferent response by the lateral olivocochlear system: activation via electrical stimulation of the inferior colliculus. J Neurophysiol 90:3178-3200, 2003.
Guitton, M. J., Caston, J., Ruel, J., Johnson, R. M., Pujol, R. and Puel, J. L. Salicylate induces tinnitus through activation of cochlear NMDA receptors. J Neurosci 23:3944-3952, 2003.
Hamernik, R. P., Ahroon, W. A., Jock, B. M. and Bennett, J. A. Noise-induced threshold shift dynamics measured with distortion-product otoacoustic emissions and auditory evoked potentials in chinchillas with inner hair cell deficient cochleas. Hear Res 118:73-82, 1998.
Heinz, M. G., Issa, J. B. and Young, E. D. Auditory-nerve rate responses are inconsistent with common hypotheses for the neural correlates of loudness recruitment. J Assoc Res Otolaryngol 6:91-105, 2005.
Huffman, R. F. and Henson, O. W. The descending auditory pathway and acousticomotor systems: connections with the inferior colliculus. Brain Res Brain Res Rev 15:295-323, 1990.
Jastreboff, P. J. Phantom auditory perception (tinnitus): mechanisms of generation and perception. Neurosci Res 8:221-254, 1990.
Jastreboff, P. J. and Sasaki, C. T. Salicylate-induced changes in spontaneous activity of single units in the inferior colliculus of the guinea pig. J Acoust Soc Am 80:1384-1391, 1986.
Jastreboff, P. J., Hansen, R., Sasaki, P. G. and Sasaki, C. T. Differential uptake of salicylate in serum, cerebrospinal fluid, and perilymph. Arch Otolaryngol Head Neck Surg 112:1050-1053, 1986.
Jastreboff, P. J. and Sasaki, C.T. An animal model of tinnitus: a decade of development. Am J Otol 15:19-27, 1994.
Jastreboff, P. J., Brennan J.F., Coleman, J. K. and Sasaki, C.T. Phantom auditory sensation in rats: an animal model for tinnitus. Behav Neurosc 102:811-822, 1988.
Jastreboff, P. J. and Hazell, J. W. A neurophysiological approach to tinnitus: clinical implications. Br J Audiol 27:7-17, 1993.
Jastreboff, P. J., Hansen, R., Sasaki, P. G. and Sasaki, C.T. Differential uptake of salicylate in serum, cerebrospinal fluid, and perilymph. Arch Otolaryngol Head Neck Surg 112:1050-1053, 1986.
Kakehata, S. and Santos-Sacchi, J. Effects of salicylate and lanthanides on outer hair cell motility and associated gating charge. J Neurosci 16:4881-4889, 1996.
Kaltenbach, J. A., Zacharek, M. A., Zhang, J. and Frederick, S. Activity in the dorsal cochlear nucleus of hamsters previously tested for tinnitus following intense tone exposure. Neurosci Lett 355:121-125, 2004.
Kaltenbach, J. A., Zhang, J. and Finlayson, P. Tinnitus as a plastic phenomenon and its possible neural underpinnings in the dorsal cochlear nucleus. Hear Res 206:200-226, 2005
Kaltenbach, J. A. Summary of evidence pointing to a role of the dorsal cochlear nucleus in the etiology of tinnitus. Acta Otolaryngol Suppl 556:20-26, 2006.
Kano, Y. and Starr, A. Temporal relationship between single unit activity in superior olivary complex and scalp-derived auditory brainstem response in guinea pig
Brain Res 419:262-271, 1987.
Lockwood, A. H., Salvi, R. J. and Burkard, R. F. Tinnitus. N Engl J Med 347:904-10, 2002.
Mahlke, C. and Wallhäusser-Franke, E. Evidence for tinnitus-related plasticity in the auditory and limbic system, demonstrated by arg3.1 and c-fos immunocytochemistry.
Hear Res 195:17-34, 2004.
McFadden, D. and Plattsmier, H. S. Frequency patterns of TTS for different exposure intensities. J Acoust Soc Am 74:1178-1184, 1983.
Meikle, M. and Taylor-Walsh, E. Characteristics of tinnitus and related observations in over 1800 tinnitus clinic patients. J Laryngol Otol Suppl 9:17-21, 1984.
Melcher, J. R., Knudson, I. M., Fullerton, B. C., Guinan, J. J. Jr., Norris, B. E. and Kiang, N. Y. Generators of the brainstem auditory evoked potential in cat. I. An experimental approach to their identification. Hear Res 93:1-27, 1996a.
Melcher, J. R., Guinan, J. J. Jr., Knudson, I. M. and Kiang, N. Y. Generators of the brainstem auditory evoked potential in cat. II. Correlating lesion sites with waveform changes. Hear Res 93:28-51, 1996b.
Melcher, J. R., Kiang, N. Y. Generators of the brainstem auditory evoked potential in cat. III: Identified cell populations. Hear Res 93:52-71, 1996c.
Moore, D. R. Anatomy and physiology of binaural hearing. Audiology 30:125-34, 1991.
Müller, M., Klinke, R., Arnold, W. and Oestreicher, E. Auditory nerve fibre responses to salicylate revisited. Hear Res 183:37-43, 2003.
Mitchell, C. R. and Creedon, T. A. Psychophysical tuning curves in subjects with tinnitus suggest outer hair cell lesions. Otolaryngol Head Neck Surg 113:223-233, 1995.
Martin, W. H., Schwegler, J. W., Scheibelhoffer, J. and Ronis, M.L. Salicylate-induced changes in cat auditory nerve activity. Laryngoscope 103:600-604, 1993.
Manabe, Y., Yoshida, S., Saito, H. and Oka, H. Effects of lidocaine on salicylate-induced discharge of neurons in the inferior colliculus of the guinea pig
Hear Res 103:192-198, 1997.
Nizami, L. Dynamic range relations for auditory primary afferents. Hear Res 208:26-46, 2005.
Ochi, K. and Eggermont, J. J. Effects of salicylate on neural activity in cat primary auditory cortex. Hear Res 95:63-76, 1996.
Penner, M. J. Linking spontaneous otoacoustic emissions and tinnitus. Br J Audiol 26:115-23,1992.
Qiu, C., Salvi, R., Ding, D. and Burkard, R. Inner hair cell loss leads to enhanced response amplitudes in auditory cortex of unanesthetized chinchillas: evidence for increased system gain. Hear Res 139:153-171, 2000.
Salvi, R. J., Wang, J., Lockwood, A. H., Burkard, R. and Ding, D. Noise and Drug Induced Cochlear Damage Leads to Functional Reorganisation in the Central Auditory System. Noise Health 1:28-42, 1999.
Santos-Sacchi, J., Song, L., Zheng, J. and Nuttall, A. L. Control of mammalian cochlear amplification by chloride anions. J Neurosci 26:3992-3998, 2006.
Seligmann, H., Podoshin, L., Ben-David, J., Fradis, M. and Goldsher, M. Drug-induced tinnitus and other hearing disorders. Drug Saf 14:198-212, 1996.
Shehata, W. E., Brownell, W. E. and Dieler, R. Effects of salicylate on shape, electromotility and membrane characteristics of isolated outer hair cells from guinea pig cochlea. Acta Otolaryngol 111:707-718, 1991.
Shaw, N. A. Auditory evoked potentials recorded from different skull locations in the rat. Int J Neurosci 70:277-283, 1993.
Shaw, N. A. The temporal relationship between the brainstem and primary cortical auditory evoked potentials. Prog Neurobiol 47:95-103, 1995.
Shaw, N. A. A possible collicular component of the auditory evoked potential and its relationship to brainstem and cerebellar auditory potentials. Electromyogr Clin Neurophysiol 32:579-590, 1992.
Stypulkowski, P. H. Mechanisms of salicylate ototoxicity. Hear Res 46:113-145, 1990.
Tunstall, M. J., Gale, J. E. and Ashmore, J. F. Action of salicylate on membrane capacitance of outer hair cells from the guinea-pig cochlea. J Physiol 15:739-752, 1995.
Tonndorf, J. Stereociliary dysfunction, a case of sensory hearing loss, recruitment, poor speech discrimination and tinnitus. Acta Otolaryngol 91:469-79, 1981.
Wallhäusser-Franke, E., Mahlke, C., Oliva, R., Braun, S., Wenz, G. and Langner, G. Expression of c-fos in auditory and non-auditory brain regions of the gerbil after manipulations that induce tinnitus. Exp Brain Res 153:649-654, 2003.
Wang, H. T., Luo, B., Zhou, K. Q., Xu, T. L. and Chen, L. Sodium salicylate reduces inhibitory postsynaptic currents in neurons of rat auditory cortex. Hear Res 215:77-83, 2006.
Wada, S. I. and Starr, A. Generation of auditory brain stem responses (ABRs). III. Effects of lesions of the superior olive, lateral lemniscus and inferior colliculus on the ABR in guinea pig. Electroencephalogr Clin Neurophysiol 56:352-366, 1983.
Wersall, J. Ototoxic antibiotics: a review. Acta Otolaryngol Suppl 519:26-29, 1995.
Wu, J. L., Chiu, T. W. and Poon, P.W. Differential changes in Fos-immunoreactivity at the auditory brainstem after chronic injections of salicylate in rats. Hear Res 176:80-93, 2003.
Xiao, Z. and Suga, N. Asymmetry in corticofugal modulation of frequency-tuning in mustached bat auditory system. Proc Natl Acad Sci U S A 102:19162-19167, 2005.
Yang, G.., Lobarinas, E., Zhang, L., Turner, J., Stolzberg, D., Salvi R., and Sun, W. Salicylate induced tinnitus: behavioral measures and neural activity in auditory cortex of awake rats. Hear Res 226:244-53, 2007.
Zaaroor, M. and Starr, A. Auditory brain-stem evoked potentials in cat after kainic acid induced neuronal loss. I. Superior olivary complex. Electroencephalogr Clin Neurophysiol 80:422-35, 1991.
Zaaroor, M. and Starr, A. Auditory brain-stem evoked potentials in cat after kainic acid induced neuronal loss. II. Cochlear nucleus. Electroencephalogr Clin Neurophysiol 80:436-445, 1991.
Zhang, J. S. and Kaltenbach, J. A. Increases in spontaneous activity in the dorsal cochlear nucleus of the rat following exposure to high-intensity sound.
Neurosci Lett 250:197-200, 1998.
Zheng, Y., Seung-Lee, H., Smith, P. F. and Darlington, C. L. Neuronal nitric oxide synthase expression in the cochlear nucleus in a salicylate model of tinnitus. Brain Res 1123:201-206, 2006.
Zheng, Y., Baek, J. H., Smith, P. F. and Darlington, C. L. Cannabinoid receptor down-regulation in the ventral cochlear nucleus in a salicylate model of tinnitus. Hear Res 228:105-111, 2007.