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Hearing Disorders: HELP
Articles by Guang-Di Chen
Based on 21 articles published since 2010
(Why 21 articles?)
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Between 2010 and 2020, G-D Chen wrote the following 21 articles about Hearing Disorders.
 
+ Citations + Abstracts
1 Review Salicylate-induced cochlear impairments, cortical hyperactivity and re-tuning, and tinnitus. 2013

Chen, Guang-Di / Stolzberg, Daniel / Lobarinas, Edward / Sun, Wei / Ding, Dalian / Salvi, Richard. ·Center for Hearing & Deafness, SUNY at Buffalo, 137 Cary Hall, Buffalo, NY 14214, USA. gchen7@buffalo.edu ·Hear Res · Pubmed #23201030.

ABSTRACT: High doses of sodium salicylate (SS) have long been known to induce temporary hearing loss and tinnitus, effects attributed to cochlear dysfunction. However, our recent publications reviewed here show that SS can induce profound, permanent, and unexpected changes in the cochlea and central nervous system. Prolonged treatment with SS permanently decreased the cochlear compound action potential (CAP) amplitude in vivo. In vitro, high dose SS resulted in a permanent loss of spiral ganglion neurons and nerve fibers, but did not damage hair cells. Acute treatment with high-dose SS produced a frequency-dependent decrease in the amplitude of distortion product otoacoustic emissions and CAP. Losses were greatest at low and high frequencies, but least at the mid-frequencies (10-20 kHz), the mid-frequency band that corresponds to the tinnitus pitch measured behaviorally. In the auditory cortex, medial geniculate body and amygdala, high-dose SS enhanced sound-evoked neural responses at high stimulus levels, but it suppressed activity at low intensities and elevated response threshold. When SS was applied directly to the auditory cortex or amygdala, it only enhanced sound evoked activity, but did not elevate response threshold. Current source density analysis revealed enhanced current flow into the supragranular layer of auditory cortex following systemic SS treatment. Systemic SS treatment also altered tuning in auditory cortex and amygdala; low frequency and high frequency multiunit clusters up-shifted or down-shifted their characteristic frequency into the 10-20 kHz range thereby altering auditory cortex tonotopy and enhancing neural activity at mid-frequencies corresponding to the tinnitus pitch. These results suggest that SS-induced hyperactivity in auditory cortex originates in the central nervous system, that the amygdala potentiates these effects and that the SS-induced tonotopic shifts in auditory cortex, the putative neural correlate of tinnitus, arises from the interaction between the frequency-dependent losses in the cochlea and hyperactivity in the central nervous system.

2 Article Intermittent Low-level Noise Causes Negative Neural Gain in the Inferior Colliculus. 2019

Sheppard, Adam / Liu, Xiaopeng / Alkharabsheh, Anaam / Chen, Guang-Di / Salvi, Richard. ·Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. Electronic address: asheppar@buffalo.edu. · Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. · Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA; Department of Audiology and Speech-Language Pathology, Asia University, Taichung, Taiwan, ROC. ·Neuroscience · Pubmed #30458217.

ABSTRACT: The central auditory system shows a remarkable ability to rescale its neural representation of loudness following long-term, low-level acoustic exposures; even when the noise is presented intermittently. Circadian rhythms exert potent biological effects, but it remains unclear if acoustic exposures occurring during the light or dark cycle affect the neurophysiological changes involved in loudness rescaling. To address this issue we exposed rats to intermittent (12 h/day), low-level noise (10-20 kHz, 75 dB SPL) for 5 weeks; exposures occurred during either the light (inactive) or dark (active) phase of the circadian cycle. The 12-h exposures, whether occurring during the light or dark phase, did not significantly alter cochlear function as reflected in distortion product otoacoustic emissions and compound action potential responses. However, neural activity in the inferior colliculus demonstrated negative gain in a frequency- and intensity-specific manner compared to unexposed controls; the magnitude and direction of the neuroplastic changes in the inferior colliculus were largely the same regardless of whether the 12-h noise exposures occurred during the light or dark phase of the circadian cycle. These neuroplastic changes could become relevant for low-level sound therapies used to treat hyperacusis.

3 Article Hidden Age-Related Hearing Loss and Hearing Disorders: Current Knowledge and Future Directions. 2018

Salvi, Richard / Ding, Dalian / Jiang, Haiyan / Chen, Guang-Di / Greco, Antonio / Manohar, Senthilvelan / Sun, Wei / Ralli, Massimo. ·Center for Hearing and Deafness, 137 Cary Hall, University at Buffalo, Buffalo, NY, 14214 USA. · Department of Sense Organs, Sapienza University of Rome, Rome, Italy. · Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Rome, Italy. ·Hearing Balance Commun · Pubmed #30931204.

ABSTRACT: Age-related hearing loss, which affects roughly 35% of those over the age of 70, is the second most common disorder among the elderly. The severity of age related hearing loss may actually be worse if assessments are made under more realistic conditions, such as communicating in noise. Emerging data from humans and animal models suggest that damage to the inner hair cells and/or type I neurons, that relay sound information to the brain may contribute to hearing deficits in a noisy background. Data obtained from carboplatin-treated chinchillas suggest that tone-in-noise thresholds are a sensitive and frequency dependent method of detecting damage to the IHC/type I system. Therefore, tone detection thresholds measured in broadband noise may provide an efficient method of detecting the deficits in specific frequency regions. Preliminary data obtained in elderly subject with normal thresholds in quiet compared to young subjects illustrate the importance of repeating these measurements in broadband noise because thresholds in noise were worse for our elderly subjects than young subjects, even though both groups had similar hearing thresholds in quiet. N-acetyl cysteine supplementation which protects against inner hair cell loss in animal models, may represent a viable therapy for protecting the inner hair cell/type I neurons.

4 Article Hyperexcitability of inferior colliculus and acoustic startle reflex with age-related hearing loss. 2017

Xiong, Binbin / Alkharabsheh, Ana'am / Manohar, Senthilvelan / Chen, Guang-Di / Yu, Ning / Zhao, Xiaoming / Salvi, Richard / Sun, Wei. ·Department of Otolaryngology, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong, 519000, PR China; Center for Hearing & Deafness, Department of Communicative Disorders and Science, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, United States. · Center for Hearing & Deafness, Department of Communicative Disorders and Science, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, United States. · Research Institute of Otolaryngology, General Hospital of PLA, 28 Fuxing Road, Beijing, 100853, PR China. · Department of Otolaryngology, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong, 519000, PR China. · Center for Hearing & Deafness, Department of Communicative Disorders and Science, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, United States. Electronic address: weisun@buffalo.edu. ·Hear Res · Pubmed #28431308.

ABSTRACT: Chronic tinnitus and hyperacusis often develop with age-related hearing loss presumably due to aberrant neural activity in the central auditory system (CAS) induced by cochlear pathologies. However, the full spectrum of physiological changes that occur in the CAS as a result age-related hearing loss are still poorly understood. To address this issue, neurophysiological measures were obtained from the cochlea and the inferior colliculus (IC) of 2, 6 and 12 month old C57BL/6J mice, a mouse model for early age-related hearing loss. Thresholds of the compound action potentials (CAP) in 6 and 12 month old mice were significantly higher than in 2 month old mice. The sound driven and spontaneous firing rates of IC neurons, recorded with 16 channel electrodes, revealed mean IC thresholds of 22.8 ± 6.5 dB (n = 167) at 2 months, 37.9 ± 6.2 dB (n = 132) at 6 months and 47.1 ± 15.3 dB (n = 151) at 12 months of age consistent with the rise in CAP thresholds. The characteristic frequencies (CF) of IC neurons ranged from 3 to 32 kHz in 2 month old mice; the upper CF ranged decreased to 26 kHz and 16 kHz in 6 and 12 month old mice respectively. The percentage of IC neurons with CFs between 8 and 12 kHz increased from 36.5% in 2 month old mice, to 48.8% and 76.2% in 6 and 12 month old mice, respectively, suggesting a downshift of IC CFs due to the high-frequency hearing loss. The average spontaneous firing rate (SFRs) of all recorded neurons in 2 month old mice was 3.2 ± 2.5 Hz (n = 167). For 6 and 12 month old mice, the SFRs of low CF neurons (<8 kHz) was maintained at 3-6 spikes/s; whereas SFRs of IC neurons with CFs > 8 kHz increased to 13.0 ± 15.4 (n = 68) Hz at 6 months of age and then declined to 4.8 ± 7.4 (n = 110) spikes/s at 12 months of age. In addition, sound-evoked activity at suprathreshold levels at 6 months of age was much higher than at 2 and 12 months of age. To evaluate the behavioral consequences of sound evoked hyperactivity in the IC, the amplitude of the acoustic startle reflex was measured at 4, 8 and 16 kHz using narrow band noise bursts. Acoustic startle reflex amplitudes in 6 and 12 month old mice (n = 4) were significantly larger than 2 month old mice (n = 4) at 4 and 8 kHz, but not 16 kHz. The enhanced reflex amplitudes suggest that high-intensity, low-frequency sounds are perceived as louder than normal in 6 and 12 month old mice compared to 2 month olds. The increased spontaneous activity, particularly at 6 months, may be related to tinnitus whereas the increase in sound-evoked activity and startle reflex amplitudes may be related to hyperacusis.

5 Article Tinnitus and hyperacusis: Contributions of paraflocculus, reticular formation and stress. 2017

Chen, Yu-Chen / Chen, Guang-Di / Auerbach, Benjamin D / Manohar, Senthilvelan / Radziwon, Kelly / Salvi, Richard. ·Department of Radiology, Nanjing First Hospital, Nanjing Medical University, 210006 Nanjing, China; Center for Hearing and Deafness, SUNY at Buffalo, Buffalo, NY 14214, USA. · Center for Hearing and Deafness, SUNY at Buffalo, Buffalo, NY 14214, USA. Electronic address: gchen7@buffalo.edu. · Center for Hearing and Deafness, SUNY at Buffalo, Buffalo, NY 14214, USA. ·Hear Res · Pubmed #28286099.

ABSTRACT: Tinnitus and hyperacusis are common and potentially serious hearing disorders associated with noise-, age- or drug-induced hearing loss. Accumulating evidence suggests that tinnitus and hyperacusis are linked to excessive neural activity in a distributed brain network that not only includes the central auditory pathway, but also brain regions involved in arousal, emotion, stress and motor control. Here we examine electrophysiological changes in two novel non-auditory areas implicated in tinnitus and hyperacusis: the caudal pontine reticular nucleus (PnC), involved in arousal, and the paraflocculus lobe of the cerebellum (PFL), implicated in head-eye coordination and gating tinnitus and we measure the changes in corticosterone stress hormone levels. Using the salicylate-induced model of tinnitus and hyperacusis, we found that long-latency (>10 ms) sound-evoked response components in both the brain regions were significantly enhanced after salicylate administration, while the short-latency responses were reduced, likely reflecting cochlear hearing loss. These results are consistent with the central gain model of tinnitus and hyperacusis, which proposes that these disorders arise from the amplification of neural activity in central auditory pathway plus other regions linked to arousal, emotion, tinnitus gating and motor control. Finally, we demonstrate that salicylate results in an increase in corticosterone level in a dose-dependent manner consistent with the notion that stress may interact with hearing loss in tinnitus and hyperacusis development. This increased stress response has the potential to have wide-ranging effects on the central nervous system and may therefore contribute to brain-wide changes in neural activity.

6 Article Plastic changes along auditory pathway during salicylate-induced ototoxicity: Hyperactivity and CF shifts. 2017

Jiang, Chen / Luo, Bin / Manohar, Senthilvelan / Chen, Guang-Di / Salvi, Richard. ·Department of Neurosurgery, Anhui Provincial Hospital, 17 Lujiang Road, Hefei, Anhui 230001, China; Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. · Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. · Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. Electronic address: gchen7@buffalo.edu. ·Hear Res · Pubmed #27989950.

ABSTRACT: High dose of salicylate, the active ingredient in aspirin, has long been known to induce transient hearing loss, tinnitus and hyperacusis making it a powerful experimental tool. These salicylate-induced perceptual disturbances are associated with a massive reduction in the neural output of the cochlea. Paradoxically, the diminished neural output of the cochlea is accompanied by a dramatic increase in sound-evoked activity in the auditory cortex (AC) and several other parts of the central nervous system. Exactly where the increase in neural activity begins and builds up along the central auditory pathway are not fully understood. To address this issue, we measured sound-evoked neural activity in the cochlea, cochlear nucleus (CN), inferior colliculus (IC), and AC before and after administering a high dose of sodium salicylate (SS, 300 mg/kg). The SS-treatment abolished low-level sound-evoked responses along the auditory pathway resulting in a 20-30 dB threshold shift. While the neural output of the cochlea was substantially reduced at high intensities, the neural responses in the CN were only slightly reduced; those in the IC were nearly normal or slightly enhanced while those in the AC considerably enhanced, indicative of a progress increase in central gain. The SS-induced increase in central response in the IC and AC was frequency-dependent with the greatest increase occurring in the mid-frequency range the putative pitch of SS-induced tinnitus. This frequency-dependent hyperactivity appeared to result from shifts in the frequency receptive fields (FRF) such that the response areas of many FRF shifted/expanded toward the mid-frequencies. Our results suggest that the SS-induced threshold shift originates in the cochlea. In contrast, enhanced central gain is not localized to one region, but progressively builds up at successively higher stage of the auditory pathway either through a loss of inhibition and/or increased excitation.

7 Article Early age noise exposure increases loudness perception - A novel animal model of hyperacusis. 2017

Alkharabsheh, Ana'am / Xiong, Fen / Xiong, Binbin / Manohar, Senthilvelan / Chen, Guangdi / Salvi, Richard / Sun, Wei. ·Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14241, USA; Department of Communicative Disorders and Sciences, State University of New York at Buffalo, 122 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. · Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14241, USA. · Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14241, USA; Department of Communicative Disorders and Sciences, State University of New York at Buffalo, 122 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. Electronic address: weisun@buffalo.edu. ·Hear Res · Pubmed #27746216.

ABSTRACT: The neural mechanisms that give rise to hyperacusis, a reduction in loudness tolerance, are largely unknown. Some reports suggest that hyperacusis is linked to childhood hearing loss. However, the evidence for this is largely circumstantial. In order to rigorously test this hypothesis, we studied loudness changes in rats caused by intense noise exposure (12 kHz narrow band noise, 115 dB SPL, 4 h) at postnatal 16 days. Rats without noise exposure were used as controls. The exposed noise group (n = 7) showed a mean 40-50 dB hearing loss compared to the control group (n = 8) at high frequencies (>= 8 kHz) and less hearing loss at lower frequencies. Loudness was evaluated using sound reaction time and loudness response functions in an operant conditioning-based behavioral task using narrow-band noise (40-110 dB SPL, centered at 2, 4 and 12 kHz). Interestingly, the sound reaction time of the noise group was significantly shorter than the control group at supra-threshold levels. The average reaction time was less than 100 ms in the noise group at 100 dB SPL, which was three times shorter than the control group. Our results indicate that early noise-induced hearing loss leads to a significant increase of loudness, a behavior indicative of hyperacusis. Our results are consistent with clinical reports suggesting that hearing loss at an early age is a significant risk factor for hyperacusis.

8 Article Apical hair cell degeneration causes the increase in the amplitude of summating potential. 2016

Wang, Dayong / Xiong, Binbin / Xiong, Fen / Chen, Guang-Di / Hu, Bo Hua / Sun, Wei. ·a Department of Otolaryngology , Chinese PLA General Hospital , Beijing , PR China. · b Center for Hearing & Deafness, Department of Communicative Disorders and Science , State University of New York at Buffalo , Buffalo , NY , USA. · c Department of Otolaryngology , Zhuhai Hospital Affiliated with Jinan University , Guangdong , PR China. ·Acta Otolaryngol · Pubmed #27424625.

ABSTRACT: CONCLUSION: This study indicates that the lesion of hair cells in the apical turn of the cochlea can cause the change in the summating potential (SP)/Compound potential (CAP) ratio. OBJECTIVES: Electrocochleography is a valuable clinic test for diagnosis of cochlear pathologies and the ratio of SP to CAP has been used to identify Meniere's disease. However, it remains controversial whether the increase of the SP/CAP ratio represents exclusively the endolymphatic hydrops. METHOD: This study measured the SP and CAP in mice that displayed outer hair cell (OHC) degeneration in the apical section of the cochlea as their age increased. RESULTS: As compared with the mice aged 8-10 months, the 24-month old mice displayed a significant increase in the amplitude of SP at 12-16 kHz. This result suggests that the degeneration of OHCs in the apical turn leads to the increase of the + SP at the middle frequencies. In contrast, the aging mice did not have a significant change in the CAP amplitude at super-threshold levels.

9 Article Effect of manganese and manganese plus noise on auditory function and cochlear structures. 2016

Muthaiah, Vijaya Prakash Krishnan / Chen, Guang-Di / Ding, Dalian / Salvi, Richard / Roth, Jerome A. ·Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214, USA. · Department of Pharmacology and Toxicology, Cary Hall, University at Buffalo, Buffalo, NY 14214, USA. Electronic address: jaroth@buffalo.edu. ·Neurotoxicology · Pubmed #27235191.

ABSTRACT: The degenerative actions of Mn caused by persistent exposure to high atmospheric levels not only provokes irreversible damage to the CNS with symptoms comparable to that of Parkinson's disease but also may have deleterious consequences to other organs including the auditory system. The putative deleterious consequences of prolonged Mn overexposure on hearing, however, is confounded by the fact that chronically-exposed individuals often work in high noise environments where noise by itself is known to cause hearing loss. Thus, the question as to whether Mn alone is actually ototoxic and whether exposure to Mn when combined with noise increases the risk of hearing loss and cochlear pathology has never been examined. To examine whether noise effects Mn ototoxicity, we exposed rats to a moderate dose of Mn (10mg MnCl2/liter water) alone, a high level of noise (octave band noise, 8-16kHz, presented at 90dB SPL for 8h/d) alone or the combination of Mn plus noise and measured the changes in auditory function and the cochlear histopathologies. Results of these studies, based on various measures of hearing including histological examination of cochlear tissue suggest that noise alone produced significant hearing deficits whereas semi-chronic exposure to moderate levels of Mn in drinking water for 90days either in the presence or absence of noise had, at best, only a minor effect on hearing.

10 Article N-acetyl-cysteine prevents age-related hearing loss and the progressive loss of inner hair cells in γ-glutamyl transferase 1 deficient mice. 2016

Ding, Dalian / Jiang, Haiyan / Chen, Guang-Di / Longo-Guess, Chantal / Muthaiah, Vijaya Prakash Krishnan / Tian, Cong / Sheppard, Adam / Salvi, Richard / Johnson, Kenneth R. ·Center for Hearing and Deafness, University at Buffalo, Buffalo, NY 14214, USA. · The Jackson Laboratory, Bar Harbor, ME 04609, USA. ·Aging (Albany NY) · Pubmed #26977590.

ABSTRACT: Genetic factors combined with oxidative stress are major determinants of age-related hearing loss (ARHL), one of the most prevalent disorders of the elderly. Dwarf grey mice, Ggt1dwg/dwg, are homozygous for a loss of function mutation of the g-glutamyl transferase 1 gene, which encodes an important antioxidant enzyme critical for the resynthesis of glutathione (GSH). Since GSH reduces oxidative damage, we hypothesized that Ggt1dwg/dwg mice would be susceptible to ARHL. Surprisingly, otoacoustic emissions and cochlear microphonic potentials, which reflect cochlear outer hair cell (OHC) function, were largely unaffected in mutant mice, whereas auditory brainstem responses and the compound action potential were grossly abnormal. These functional deficits were associated with an unusual and selective loss of inner hair cells (IHC), but retention of OHC and auditory nerve fibers. Remarkably, hearing deficits and IHC loss were completely prevented by N-acetyl-L-cysteine, which induces de novo synthesis of GSH; however, hearing deficits and IHC loss reappeared when treatment was discontinued. Ggt1dwg/dwg mice represent an important new model for investigating ARHL, therapeutic interventions, and understanding the perceptual and electrophysiological consequences of sensory deprivation caused by the loss of sensory input exclusively from IHC.

11 Article Noise trauma induced plastic changes in brain regions outside the classical auditory pathway. 2016

Chen, G-D / Sheppard, A / Salvi, R. ·Center for Hearing and Deafness, SUNY at Buffalo, Buffalo, NY 14214, USA. Electronic address: gchen7@buffalo.edu. · Center for Hearing and Deafness, SUNY at Buffalo, Buffalo, NY 14214, USA. ·Neuroscience · Pubmed #26701290.

ABSTRACT: The effects of intense noise exposure on the classical auditory pathway have been extensively investigated; however, little is known about the effects of noise-induced hearing loss on non-classical auditory areas in the brain such as the lateral amygdala (LA) and striatum (Str). To address this issue, we compared the noise-induced changes in spontaneous and tone-evoked responses from multiunit clusters (MUC) in the LA and Str with those seen in auditory cortex (AC) in rats. High-frequency octave band noise (10-20 kHz) and narrow band noise (16-20 kHz) induced permanent threshold shifts at high-frequencies within and above the noise band but not at low frequencies. While the noise trauma significantly elevated spontaneous discharge rate (SR) in the AC, SRs in the LA and Str were only slightly increased across all frequencies. The high-frequency noise trauma affected tone-evoked firing rates in frequency and time-dependent manner and the changes appeared to be related to the severity of noise trauma. In the LA, tone-evoked firing rates were reduced at the high-frequencies (trauma area) whereas firing rates were enhanced at the low-frequencies or at the edge-frequency dependent on severity of hearing loss at the high frequencies. The firing rate temporal profile changed from a broad plateau to one sharp, delayed peak. In the AC, tone-evoked firing rates were depressed at high frequencies and enhanced at the low frequencies while the firing rate temporal profiles became substantially broader. In contrast, firing rates in the Str were generally decreased and firing rate temporal profiles become more phasic and less prolonged. The altered firing rate and pattern at low frequencies induced by high-frequency hearing loss could have perceptual consequences. The tone-evoked hyperactivity in low-frequency MUC could manifest as hyperacusis whereas the discharge pattern changes could affect temporal resolution and integration.

12 Article Tinnitus and hyperacusis involve hyperactivity and enhanced connectivity in auditory-limbic-arousal-cerebellar network. 2015

Chen, Yu-Chen / Li, Xiaowei / Liu, Lijie / Wang, Jian / Lu, Chun-Qiang / Yang, Ming / Jiao, Yun / Zang, Feng-Chao / Radziwon, Kelly / Chen, Guang-Di / Sun, Wei / Krishnan Muthaiah, Vijaya Prakash / Salvi, Richard / Teng, Gao-Jun. ·Jiangsu Key Laboratory of Molecular Imaging and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China. · Department of Physiology, Southeast University, Nanjing, China. · Center for Hearing and Deafness, University at Buffalo, The State University of New York, Buffalo, United States. ·Elife · Pubmed #25962854.

ABSTRACT: Hearing loss often triggers an inescapable buzz (tinnitus) and causes everyday sounds to become intolerably loud (hyperacusis), but exactly where and how this occurs in the brain is unknown. To identify the neural substrate for these debilitating disorders, we induced both tinnitus and hyperacusis with an ototoxic drug (salicylate) and used behavioral, electrophysiological, and functional magnetic resonance imaging (fMRI) techniques to identify the tinnitus-hyperacusis network. Salicylate depressed the neural output of the cochlea, but vigorously amplified sound-evoked neural responses in the amygdala, medial geniculate, and auditory cortex. Resting-state fMRI revealed hyperactivity in an auditory network composed of inferior colliculus, medial geniculate, and auditory cortex with side branches to cerebellum, amygdala, and reticular formation. Functional connectivity revealed enhanced coupling within the auditory network and segments of the auditory network and cerebellum, reticular formation, amygdala, and hippocampus. A testable model accounting for distress, arousal, and gating of tinnitus and hyperacusis is proposed.

13 Article Potassium ion channel openers, Maxipost and Retigabine, protect against peripheral salicylate ototoxicity in rats. 2015

Sheppard, Adam M / Chen, Guang-Di / Salvi, Richard. ·Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. Electronic address: asheppar@buffalo.edu. · Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. ·Hear Res · Pubmed #25937133.

ABSTRACT: Sodium Salicylate (SS) reliably induces a sensorineural hearing loss and tinnitus when administered in high doses. Recent animal modeled studies indicate that potassium channel openers such as Maxipost and Retigabine (RTG) can block SS- or noise-induced tinnitus respectively; however, the origins and mechanisms are poorly understood. Since SS blocks the same potassium channels that Maxipost and RTG open, we postulated that these drugs might influence peripheral auditory function. To test this hypothesis Maxipost or RTG were administered alone or in combination with SS in rats. When administered alone, Maxipost and RTG had no effect on distortion product otoacoustic emissions (DPOAE) or compound action potentials (CAPs). However when Maxipost or RTG were administered with SS, Maxipost prevented the SS-reduced CAP amplitudes at high frequencies (≥20 kHz) and RTG prevented SS-reduced CAP amplitudes at low frequencies (≤8 kHz). These results suggest that Maxipost and RTG can protect against peripheral damage and therefore reduce the incidence of tinnitus.

14 Article Prolonged noise exposure-induced auditory threshold shifts in rats. 2014

Chen, Guang-Di / Decker, Brandon / Krishnan Muthaiah, Vijaya Prakash / Sheppard, Adam / Salvi, Richard. ·Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. Electronic address: gchen7@buffalo.edu. · Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. ·Hear Res · Pubmed #25219503.

ABSTRACT: Noise-induced hearing loss (NIHL) initially increases with exposure duration, but eventually reaches an asymptotic threshold shift (ATS) once the exposure duration exceeds 18-24 h. Equations for predicting the ATS have been developed for several species, but not for rats, even though this species is extensively used in noise exposure research. To fill this void, we exposed rats to narrowband noise (NBN, 16-20 kHz) for 5 weeks starting at 80 dB SPL in the first week and then increasing the level by 6 dB per week to a final level of 104 dB SPL. Auditory brainstem responses (ABR) were recorded before, during, and following the exposure to determine the amount of hearing loss. The noise induced threshold shift to continuous long-term exposure, defined as compound threshold shift (CTS), within and above 16-20 kHz increased with noise level at the rate of 1.82 dB threshold shift per dB of noise level (NL) above a critical level (C) of 77.2 dB SPL i.e. CTS = 1.82(NL-77.2). The normalized amplitude of the largest ABR peak measured at 100 dB SPL decreased at the rate of 3.1% per dB of NL above the critical level of 76.9 dB SPL, i.e., %ABR Reduction = 3.1%(NL-76.9). ABR thresholds measured >30 days post-exposure only partially recovered resulting in a permanent threshold shift of 30-40 dB along with severe hair cell loss in the basal, high-frequency region of the cochlea. In the rat, CTS increases with noise level with a slope similar to humans and chinchillas. The critical level (C) in the rat is similar to that of humans, but higher than that of chinchillas.

15 Article Salicylate-induced auditory perceptual disorders and plastic changes in nonclassical auditory centers in rats. 2014

Chen, Guang-Di / Radziwon, Kelly E / Kashanian, Nina / Manohar, Senthilvelan / Salvi, Richard. ·Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. ·Neural Plast · Pubmed #24891959.

ABSTRACT: Previous studies have shown that sodium salicylate (SS) activates not only central auditory structures, but also nonauditory regions associated with emotion and memory. To identify electrophysiological changes in the nonauditory regions, we recorded sound-evoked local field potentials and multiunit discharges from the striatum, amygdala, hippocampus, and cingulate cortex after SS-treatment. The SS-treatment produced behavioral evidence of tinnitus and hyperacusis. Physiologically, the treatment significantly enhanced sound-evoked neural activity in the striatum, amygdala, and hippocampus, but not in the cingulate. The enhanced sound evoked response could be linked to the hyperacusis-like behavior. Further analysis showed that the enhancement of sound-evoked activity occurred predominantly at the midfrequencies, likely reflecting shifts of neurons towards the midfrequency range after SS-treatment as observed in our previous studies in the auditory cortex and amygdala. The increased number of midfrequency neurons would lead to a relative higher number of total spontaneous discharges in the midfrequency region, even though the mean discharge rate of each neuron may not increase. The tonotopical overactivity in the midfrequency region in quiet may potentially lead to tonal sensation of midfrequency (the tinnitus). The neural changes in the amygdala and hippocampus may also contribute to the negative effect that patients associate with their tinnitus.

16 Article Review of salicylate-induced hearing loss, neurotoxicity, tinnitus and neuropathophysiology. 2014

Sheppard, A / Hayes, S H / Chen, G-D / Ralli, M / Salvi, R. ·Center for Hearing and Deafness, SUNY at Buffalo, Buffalo, USA. · Institute of Otolaryngology, Catholic University of Sacred Heart Rome, Italy. ·Acta Otorhinolaryngol Ital · Pubmed #24843217.

ABSTRACT: Salicylate's ototoxic properties have been well established, inducing tinnitus and a sensory hearing loss when administered in high doses. Peripherally, acute dosing of salicylate causes frequency dependent reductions in DPOAEs and CAP amplitudes in low (<10 kHz) and high (>20 kHz) frequencies more than mid frequencies (10-20 kHz), which interestingly corresponds to the pitch of behaviourally-matched salicylate-induced tinnitus. Chronic salicylate dosing affects the peripheral system by causing a compensatory temporary enhancement in DPOAE amplitudes and up-regulation of prestin mRNA and protein expression. Despite salicylate's antioxidant properties, cultured cochlea studies indicate it also impairs spiral ganglion neurons (SGNs) by paradoxically causing an upsurge of superoxide radicals leading to apoptosis. Centrally, salicylate alters γ-aminobutyric acid (GABA) and serotonin mediated neurotransmission in the central nervous system (CNS), which results in classical and non-classical auditory regions showing hyperactivity after salicylate administration. In the auditory cortex (AC) and lateral amygdala (LA), neuron characteristic frequencies (CF) shift upward and downward to mid frequencies (10-20 kHz) altering tonotopy following salicylate administration. Additionally, current source density (CSD) analysis showed enhanced current flow into the supergranular layer of the auditory cortex after a high systemic dose of salicylate. In humans, auditory perception changes following salicylate or aspirin, including decreased word discrimination and temporal integration ability. The results of previous studies have partially identified the mechanisms that are involved in salicylate-induced tinnitus and hearing loss, however to date some interactions remain convoluted. This review discusses current knowledge of salicylate ototoxicity and interactions.

17 Article Active cochlear amplification is dependent on supporting cell gap junctions. 2013

Zhu, Yan / Liang, Chun / Chen, Jin / Zong, Liang / Chen, Guang-Di / Zhao, Hong-Bo. ·Department of Otolaryngology, University of Kentucky Medical School, Lexington, Kentucky 40536, USA. ·Nat Commun · Pubmed #23653198.

ABSTRACT: Mammalian hearing relies upon active cochlear mechanics, which arises from outer hair cell electromotility and hair bundle movement, to amplify acoustic stimulations increasing hearing sensitivity and frequency selectivity. Here we describe the novel finding that gap junctions between cochlear supporting cells also have a critical role in active cochlear amplification in vivo. We find that targeted-deletion of connexin 26 in Deiters cells and outer pillar cells, which constrain outer hair cells standing on the basilar membrane, causes a leftward shift in outer hair cell electromotility towards hyperpolarization, and reduces active cochlear amplification with hearing loss. Coincident with large reduction in distortion product otoacoustic emission and severe hearing loss at high frequencies, the shift is larger in shorter outer hair cells. Our study demonstrates that active cochlear amplification in vivo is dependent on supporting cell gap junctions. These new findings also show that connexin 26 deficiency can reduce active cochlear amplification to induce hearing loss.

18 Article An Src-protein tyrosine kinase inhibitor to reduce cisplatin ototoxicity while preserving its antitumor effect. 2013

Bielefeld, Eric C / Tanaka, Chiemi / Chen, Guang-di / Coling, Donald / Li, Manna / Henderson, Donald / Fetoni, Anna R. ·Department of Speech and Hearing Science, The Ohio State University, Columbus, Ohio 43220, USA. bielefeld.6@osu.edu ·Anticancer Drugs · Pubmed #22828384.

ABSTRACT: Ototoxicity remains a major dose-limiting side effect of cisplatin. The current studies were carried out to evaluate the effectiveness of a novel Src-protein tyrosine kinase inhibitor in protecting the ear from cisplatin ototoxicity without compromising cisplatin's antitumor effects. The Src inhibitor has been shown to be effective in protecting the ear from noise-induced hearing loss. Three studies were carried out to determine whether this compound has otoprotective activity in rats treated with cisplatin. The first two studies used the Src inhibitor as a cotreatment with single doses of cisplatin in Fischer 344/NHsd rats and nude rats, respectively. Cochlear damage was assessed by auditory brainstem response threshold shifts and outer hair cell loss. The third study was carried out in nude rats with implanted HT-29 tumors, and the Src inhibitor was administered as a cotreatment with a lower dose of cisplatin. Cochlear damage and changes in tumor volume were assessed in the third study. In the first two studies, cotreatment with the Src inhibitor reduced cisplatin-induced hearing loss significantly. In the third study, little hearing loss was induced because of the use of a lower dose of cisplatin. However, cotreatment with the Src inhibitor did not exert a negative effect on cisplatin's slowing of tumor growth in the treated rats. The findings suggest that the Src inhibitor may provide an effective cotreatment with cisplatin to reduce cisplatin's ototoxicity, without compromising its antitumor capability.

19 Article Amygdala hyperactivity and tonotopic shift after salicylate exposure. 2012

Chen, Guang-Di / Manohar, Senthilvelan / Salvi, Richard. ·Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. gchen7@buffalo.edu ·Brain Res · Pubmed #22464181.

ABSTRACT: The amygdala, important in forming and storing memories of aversive events, is believed to play a major role in debilitating tinnitus and hyperacusis. To explore this hypothesis, we recorded from the lateral amygdala (LA) and auditory cortex (AC) before and after treating rats with a dose of salicylate that induces tinnitus and hyperacusis-like behavior. Salicylate unexpectedly increased the amplitude of the local field potential (LFP) in the LA making it hyperactive to sounds≥60 dB SPL. Frequency receptive fields (FRFs) of multiunit (MU) clusters in the LA were also dramatically altered by salicylate. Neuronal activity at frequencies below 10 kHz and above 20 kHz was depressed at low intensities, but was greatly enhanced for stimuli between 10 and 20 kHz (frequencies near the pitch of the salicylate-induced tinnitus in the rat). These frequency-dependent changes caused the FRF of many LA neurons to migrate towards 10-20 kHz thereby amplifying activity from this region. To determine if salicylate-induced changes restricted to the LA would remotely affect neural activity in the AC, we used a micropipette to infuse salicylate (20 μl, 2.8 mM) into the amygdala. Local delivery of salicylate to the amygdala significantly increased the amplitude of the LFP recorded in the AC and selectively enhanced the neuronal activity of AC neurons at the mid-frequencies (10-20 kHz), frequencies associated with the tinnitus pitch. Taken together, these results indicate that systemic salicylate treatment can induce hyperactivity and tonotopic shift in the amygdala and infusion of salicylate into the amygdala can profoundly enhance sound-evoked activity in AC, changes likely to increase the perception and emotional salience of tinnitus and loud sounds. This article is part of a Special Issue entitled: Tinnitus Neuroscience.

20 Article Salicylate-induced peripheral auditory changes and tonotopic reorganization of auditory cortex. 2011

Stolzberg, D / Chen, G-D / Allman, B L / Salvi, R J. ·Center for Hearing and Deafness, State University of New York at Buffalo, 137 Cary Hall, 3435 Main Street, Buffalo, NY 14214, USA. djs32@buffalo.edu ·Neuroscience · Pubmed #21310217.

ABSTRACT: The neuronal mechanism underlying the phantom auditory perception of tinnitus remains elusive at present. For over 25 years, temporary tinnitus following acute salicylate intoxication in rats has been used as a model to understand how a phantom sound can be generated. Behavioral studies have indicated that the pitch of salicylate-induced tinnitus in the rat is approximately 16 kHz. In order to better understand the origin of the tinnitus pitch measurements were made at the levels of auditory input and output; both cochlear and cortical physiological recordings were performed in ketamine/xylazine anesthetized rats. Both compound action potentials and distortion product otoacoustic emission measurements revealed a salicylate-induced band-pass-like cochlear deficit in which the reduction of cochlear input was least at 16 kHz and significantly greater at high and low frequencies. In a separate group of rats, frequency receptive fields of primary auditory cortex neurons were tracked using multichannel microelectrodes before and after systemic salicylate treatment. Tracking frequency receptive fields following salicylate revealed a population of neurons that shifted their frequency of maximum sensitivity (i.e. characteristic frequency) towards the tinnitus frequency region of the tonotopic axis (∼16 kHz). The data presented here supports the hypothesis that salicylate-induced tinnitus results from an expanded cortical representation of the tinnitus pitch determined by an altered profile of input from the cochlea. Moreover, the pliability of cortical frequency receptive fields during salicylate-induced tinnitus is likely due to salicylate's direct action on intracortical inhibitory networks. Such a disproportionate representation of middle frequencies in the auditory cortex following salicylate may result in a finer analysis of signals within this region which may pathologically enhance the functional importance of spurious neuronal activity concentrated at tinnitus frequencies.

21 Article Too much of a good thing: long-term treatment with salicylate strengthens outer hair cell function but impairs auditory neural activity. 2010

Chen, Guang-Di / Kermany, Mohammad Habiby / D'Elia, Alessandra / Ralli, Massimo / Tanaka, Chiemi / Bielefeld, Eric C / Ding, Dalian / Henderson, Donald / Salvi, Richard. ·Center for Hearing and Deafness, SUNY at Buffalo, Buffalo, NY, USA. gchen7@buffalo.edu ·Hear Res · Pubmed #20214971.

ABSTRACT: Aspirin has been extensively used in clinical settings. Its side effects on auditory function, including hearing loss and tinnitus, are considered as temporary. A recent promising finding is that chronic treatment with high-dose salicylate (the active ingredient of aspirin) for several weeks enhances expression of the outer hair cell (OHC) motor protein (prestin), resulting in strengthened OHC electromotility and enhanced distortion product otoacoustic emissions (DPOAE). To follow up on these observations, we carried out two studies, one planned study of age-related hearing loss restoration and a second unrelated study of salicylate-induced tinnitus. Rats of different strains and ages were injected with salicylate at a dose of 200 mg/kg/day for 5 days per week for 3 weeks or at higher dose levels (250-350 mg/kg/day) for 4 days per week for 2 weeks. Unexpectedly, while an enhanced or sustained DPOAE was seen, permanent reductions in the amplitude of the cochlear compound action potential (CAP) and the auditory brainstem response (ABR) were often observed after the chronic salicylate treatment. The mechanisms underlying these unexpected, permanent salicylate-induced reductions in neural activity are discussed.