Alterations of the cerebral microstructure in patients with noise-induced hearing loss: A diffusion tensor imaging study.

OBJECTIVE: To explore the changes in the cerebral microstructure of patients with noise-induced hearing loss (NIHL) using diffusion tensor imaging (DTI). METHOD: Overall, 122 patients with NIHL (mild [MP, n = 79], relatively severe patients [including moderate and severe; RSP, n = 32], and undetermined [lost to follow-up, n = 11]) and 84 healthy controls (HCs) were enrolled. All clinical data, including age, education level, hearing threshold, occupation type, noise exposure time, and some scale scores (including the Mini-Mental State Examination [MMSE], tinnitus handicap inventory [THI], and Hamilton Anxiety Scale [HAMA]), were collected and analyzed. All participants underwent T1WI3DFSPGR and DTI, and tract-based spatial statistics and region of interest (ROI) analysis were used for assessment. RESULTS: The final sample included 71 MP, 28 RSP, and 75 HCs. The HAMA scores of the three groups were significantly different (p < .05). The noise exposure times, hearing thresholds, and HAMA scores of the MP and RSP were significantly different (p < .05). The noise exposure time was positively correlated with the hearing threshold and negatively correlated with the HAMA scores (p < .05), whereas the THI scores were positively correlated with the hearing threshold (p < .05). DTI analysis showed that all DTI parameters (fractional anisotropy [FA], axial diffusivity [AD], mean diffusivity [MD], and radial diffusivity [RD]) were significantly different in the left inferior longitudinal fasciculus (ILF) and left inferior fronto-occipital fasciculus (IFOF) for the three groups (p < .05). In addition, the FA values were significantly lower in the bilateral corticospinal tract (CST), right fronto-pontine tract (FPT), right forceps major, left superior longitudinal fasciculus (temporal part) (SLF), and left cingulum (hippocampus) (C-H) of the MP and RSP than in those of the HCs (p < .05); the AD values showed diverse changes in the bilateral CST, left IFOF, right anterior thalamic radiation, right external capsule (EC), right SLF, and right superior cerebellar peduncle (SCP) of the MP and RSP relative to those of the HC (p < .05). However, there were no significant differences among the bilateral auditory cortex ROIs of the three groups (p > .05). There was a significant negative correlation between the FA and HAMA scores for the left IFOF/ILF, right FPT, left SLF, and left C-H for the three groups (p < .05). There was a significant positive correlation between the AD and HAMA scores for the left IFOF/ILF and right EC of the three groups (p < .05). There were significantly positive correlations between the RD/MD and HAMA scores in the left IFOF/ILF of the three groups (p < .05). There was a significant negative correlation between the AD in the right SCP and noise exposure time of the MP and RSP groups (p < .05). The AD, MD, and RD in the left ROI were significantly positively correlated with hearing threshold in the MP and RSP groups (p < .05), whereas FA in the right ROI was significantly positively correlated with the HAMA scores for the three groups (p < .05). CONCLUSION: The changes in the white matter (WM) microstructure may be related to hearing loss caused by noise exposure, and the WM structural abnormalities in patients with NIHL were mainly located in the syndesmotic fibers of the temporooccipital region, which affected the auditory and language pathways. This confirmed that the auditory pathways have abnormal structural connectivity in patients with NIHL.

Role of Oxidative Stress in Sensorineural Hearing Loss.

Hearing is essential for communication, and its loss can cause a serious disruption to one's social life. Hearing loss is also recognized as a major risk factor for dementia; therefore, addressing hearing loss is a pressing global issue. Sensorineural hearing loss, the predominant type of hearing loss, is mainly due to damage to the inner ear along with a variety of pathologies including ischemia, noise, trauma, aging, and ototoxic drugs. In addition to genetic factors, oxidative stress has been identified as a common mechanism underlying several cochlear pathologies. The cochlea, which plays a major role in auditory function, requires high-energy metabolism and is, therefore, highly susceptible to oxidative stress, particularly in the mitochondria. Based on these pathological findings, the potential of antioxidants for the treatment of hearing loss has been demonstrated in several animal studies. However, results from human studies are insufficient, and future clinical trials are required. This review discusses the relationship between sensorineural hearing loss and reactive oxidative species (ROS), with particular emphasis on age-related hearing loss, noise-induced hearing loss, and ischemia-reperfusion injury. Based on these mechanisms, the current status and future perspectives of ROS-targeted therapy for sensorineural hearing loss are described.

Normal behavioral discrimination of envelope statistics in budgerigars with kainate-induced cochlear synaptopathy.

Cochlear synaptopathy is a common pathology in humans associated with aging and potentially sound overexposure. Synaptopathy is widely expected to cause "hidden hearing loss," including difficulty perceiving speech in noise, but support for this hypothesis is controversial. Here in budgerigars (Melopsittacus undulatus), we evaluated the impact of long-term cochlear synaptopathy on behavioral discrimination of Gaussian noise (GN) and low-noise noise (LNN) signals processed to have a flatter envelope. Stimuli had center frequencies of 1-3kHz, 100-Hz bandwidth, and were presented at sensation levels (SLs) from 10 to 30dB. We reasoned that narrowband, low-SL stimuli of this type should minimize spread of excitation across auditory-nerve fibers, and hence might reveal synaptopathy-related defects if they exist. Cochlear synaptopathy was induced without hair-cell injury using kainic acid (KA). Behavioral threshold tracking experiments characterized the minimum stimulus duration above which animals could reliably discriminate between LNN and GN. Budgerigar thresholds for LNN-GN discrimination ranged from 40 to 60ms at 30dB SL, were similar across frequencies, and increased for lower SLs. Notably, animals with long-term 39-77% estimated synaptopathy performed similarly to controls, requiring on average a ∼7.5% shorter stimulus duration (-0.7±1.0dB; mean difference ±SE) for LNN-GN discrimination. Decision-variable correlation analyses of detailed behavioral response patterns showed that individual animals relied on envelope cues to discriminate LNN and GN, with lesser roles of FM and energy cues; no difference was found between KA-exposed and control groups. These results suggest that long-term cochlear synaptopathy does not impair discrimination of low-level signals with different envelope statistics.

Adult mice with noise-induced hearing loss exhibited temporal ordering memory deficits accompanied by microglia-associated neuroplastic changes in the medial prefrontal cortex.

Acquired peripheral hearing loss in midlife is considered the primary modifiable risk factor for dementia, while the underlying pathological mechanism remains poorly understood. Excessive noise exposure is the most common cause of acquired peripheral hearing loss in modern society. This study was designed to investigate the impact of noise-induced hearing loss (NIHL) on cognition, with a focus on the medial prefrontal cortex (mPFC), a brain region that is involved in both auditory and cognitive processes and is highly affected in patients with cognitive impairment. Adult C57BL/6 J mice were randomly assigned to a control group and seven noise groups: 0HPN, 12HPN, 1DPN, 3DPN, 7DPN, 14DPN, and 28DPN, which were exposed to broadband noise at a 123 dB sound pressure level (SPL) for 2 h and sacrificed immediately (0 h), 12 h, or 1, 3, 7, 14, or 28 days post-noise exposure (HPN, DPN), respectively. Hearing assessment, behavioral tests, and neuromorphological studies in the mPFC were performed in control and 28DPN mice. All experimental animals were included in the time-course analysis of serum corticosterone (CORT) levels and mPFC microglial morphology. The results illustrated that noise exposure induced early-onset transient serum CORT elevation and permanent moderate-to-severe hearing loss in mice. 28DPN mice, in which permanent NIHL has been verified, exhibited impaired performance in temporal order object recognition tasks concomitant with reduced structural complexity of mPFC pyramidal neurons. The time-course immunohistochemical analysis in the mPFC revealed significantly higher morphological microglial activation at 14 and 28 DPN, preceded by a remarkably higher amount of microglial engulfed postsynaptic marker PSD95 at 7 DPN. Additionally, lipid accumulation in microglia was observed in 7DPN, 14DPN and 28DPN mice, suggesting a driving role of lipid handling deficits following excessive phagocytosis of synaptic elements in delayed and sustained microglial abnormalities. These findings provide fundamentally novel information concerning mPFC-related cognitive impairment in mice with NIHL and empirical evidence suggesting the involvement of microglial malfunction in the mPFC neurodegenerative consequences of NIHL.

Oridonin employs interleukin 1 receptor type 2 to treat noise-induced hearing loss by blocking inner ear inflammation.

NOD-like receptor protein 3 (NLRP3) inflammasomes trigger the inflammatory cascades and participate in various inflammatory diseases, including noise-induced hearing loss (NIHL) caused by oxidative stress. Recently, the anti-inflammatory traditional medicine oridonin (Ori) has been reported to provide hearing protection in mice after noise exposure by blocking the NLRP3-never in mitosis gene A-related kinase 7 (NEK7)-inflammasome complex assembly. Using RNA sequencing analysis, we further elucidated that interleukin 1 receptor type 2 (IL1R2) may be another crucial factor regulated by Ori to protect NIHL. We observed that IL1R2 expression was localized in spiral ganglion neurons, inner and outer hair cells, in Ori-treated mouse cochleae. Additionally, we confirmed that ectopic overexpression of IL1R2 in the inner ears of healthy mice using an adeno-associated virus delivery system significantly reduced noise-induced ribbon synapse lesions and hearing loss by blocking the "cytokine storm" in the inner ear. This study provides a novel theoretical foundation for guiding the clinical treatment of NIHL.

HMGB1 accumulation in cytoplasm mediates noise-induced cochlear damage.

Damage-associated molecular pattern molecules (DAMPs) play a critical role in mediating cochlear cell death, which leads to noise-induced hearing loss (NIHL). High-mobility group box 1 (HMGB1), a prototypical DAMP released from cells, has been extensively studied in the context of various diseases. However, whether extracellular HMGB1 contributes to cochlear pathogenesis in NIHL and the potential signals initiating HMGB1 release from cochlear cells are not well understood. Here, through the transfection of the adeno-associated virus with HMGB1-HA-tag, we first investigated early cytoplasmic accumulation of HMGB1 in cochlear hair cells after noise exposure. We found that the cochlear administration of HMGB1-neutralizing antibody immediately after noise exposure significantly alleviated hearing loss and outer hair cells (OHCs) death induced by noise exposure. In addition, activation of signal transducer and activators of transcription 1 (STAT1) and cellular hyperacetylation were verified as potential canonical initiators of HMGB1 cytoplasmic accumulation. These findings reveal the adverse effects of extracellular HMGB1 on the cochlea and the potential signaling events mediating HMGB1 release in hair cells, indicating multiple potential pharmacotherapeutic targets for NIHL.

Acute Noise Causes Down-Regulation of ECM Protein Expression in Guinea Pig Cochlea.

Proteomics technology reveals the marker proteins, potential pathogenesis, and intervention targets after noise-induced hearing loss. To study the differences in cochlea protein expression before and after noise exposure using proteomics to reveal the pathological mechanism of noise-induced hearing loss (NIHL). A guinea pig NIHL model was established to test the ABR thresholds before and after noise exposure. The proteomics technology was used to study the mechanism of differential protein expression in the cochlea by noise stimulation. The average hearing threshold of guinea pigs on the first day after noise exposure was 57.00 ± 6.78 dB Sound pressure level (SPL); the average hearing threshold on the seventh day after noise exposure was 45.83 ± 6.07 dB SPL. The proteomics technology identified 3122 different inner ear proteins, of which six proteins related to the hearing were down-regulation: Tenascin C, Collagen Type XI alpha two chains, Collagen Type II alpha one chain, Thrombospondin 2, Collagen Type XI alpha one chain and Ribosomal protein L38, and are enriched in protein absorption, focal adhesion, and extracellular matrix receptor pathways. Impulse noise can affect the expression of differential proteins through focal adhesion pathways. This data can provide an experimental basis for the research on the prevention and treatment of NIHL.

The Protective Effects of Human Embryonic Stem Cell-Derived Mesenchymal Stem Cells in Noise-Induced Hearing Loss of Rats.

A few prior animal studies have suggested the transplantation or protective effects of mesenchymal stem cells (MSCs) in noise-induced hearing loss. This study intended to evaluate the fates of administered MSCs in the inner ears and the otoprotective effects of MSCs in the noise-induced hearing loss of rats. Human embryonic stem cell-derived MSCs (ES-MSCs) were systematically administered via the tail vein in adult rats. Eight-week-old Sprague-Dawley rats were randomly allocated to the control (n = 8), ES-MSC (n = 4), noise (n = 8), and ES-MSC+noise (n = 10) groups. In ES-MSC and ES-MSC+noise rats, 5 × 105 ES-MSCs were injected via the tail vein. In noise and ES-MSC+noise rats, broadband noise with 115 dB SPL was exposed for 3 h daily for 5 days. The hearing levels were measured using auditory brainstem response (ABR) at 4, 8, 16, and 32 kHz. Cochlear histology was examined using H&E staining and cochlear whole mount immunofluorescence. The presence of human DNA was examined using Sry PCR, and the presence of human cytoplasmic protein was examined using STEM121 immunofluorescence staining. The protein expression levels of heat shock protein 70 (HSP70), apoptosis-inducing factor (AIF), poly (ADP-ribose) (PAR), PAR polymerase (PARP), caspase 3, and cleaved caspase 3 were estimated. The ES-MSC rats did not show changes in ABR thresholds following the administration of ES-MSCs. The ES-MSC+ noise rats demonstrated lower ABR thresholds at 4, 8, and 16 kHz than the noise rats. Cochlear spiral ganglial cells and outer hair cells were more preserved in the ES-MSC+ noise rats than in the noise rats. The Sry PCR bands were highly detected in lung tissue and less in cochlear tissue of ES-MSC+noise rats. Only a few STEM121-positivities were observed in the spiral ganglial cell area of ES-MSC and ES-MSC+noise rats. The protein levels of AIF, PAR, PARP, caspase 3, and cleaved caspase 3 were lower in the ES-MSC+noise rats than in the noise rats. The systemic injection of ES-MSCs preserved hearing levels and attenuated parthanatos and apoptosis in rats with noise-induced hearing loss. In addition, a tiny number of transplanted ES-MSCs were observed in the spiral ganglial areas.

The effectiveness of berberine on noise-induced hearing loss: a rat model.

OBJECTIVE: Noise-induced hearing loss is a preventable form of hearing loss that has serious social and economic impacts. This study aimed to investigate the protective effect of berberine, a potent antioxidant and anti-inflammatory agent, against Noise-induced hearing loss. METHODS: After applying distortion product otoacoustic emission, 28 female Sprague-Dawley rats were randomly divided into four groups. Group 1 was designated as acoustic trauma group, and rats in this group were exposed to white noise for 12 h at an intensity of 4 kHz 110 dB sound pressure level. Group 2 was the control group. Group 3 was designated as the berberine group, and 100 mg/kg of berberine was administered to rats in this group by intragastric lavage for five consecutive days. Group 4 was designated as the acoustic trauma+berberine group. distortion product otoacoustic emission was repeated on the 6th day of the study and cochlear tissues of rats were dissected for histopathological and immunohistochemical analyses after sacrificing rats. RESULTS: The distortion product otoacoustic emission results showed a significant decrease in signal-noise ratio values at higher frequencies in rats of the trauma group compared to those in other groups. Acoustic trauma caused severe histopathological impairment at cochlear structures together with severe 8-hydroxy-2-deoxyguanosine expression. Rats in the acoustic trauma+berberine group showed mild histopathological changes with mild 8-hydroxy-2-deoxyguanosine expression and better signal-noise ratio values. CONCLUSION: The histopathological and audiological findings of this experimental study showed that berberine provides protection in Noise-induced hearing loss and may have the potential for use in acoustic trauma-related hearing losses.

Effects of pyrroloquinoline quinone on noise-induced and age-related hearing loss in mice.

We investigated whether the oxidoreductase cofactor pyrroloquinoline quinone (PQQ) prevents noise-induced and age-related hearing loss (NIHL and ARHL) in mice. To assess NIHL, 8 week-old mice with and without PQQ administration were exposed to noise for 4 h. PQQ was orally administered for one week before and after noise exposure and subcutaneously once before noise exposure. For ARHL evaluation, mice were given drinking water with or without PQQ starting at 2 months of age. In the NIHL model, PQQ-treated mice had auditory brainstem response (ABR) thresholds of significantly reduced elevation at 8 kHz, a significantly increased number of hair cells at the basal turn, and significantly better maintained synapses beneath the inner hair cells compared to controls. In the ARHL model, PQQ significantly attenuated the age-related increase in ABR thresholds at 8 and 32 kHz at 10 months of age compared to controls. In addition, the hair cells, spiral ganglion cells, ribbon synapses, stria vascularis and nerve fibers were all significantly better maintained in PQQ-treated animals compared to controls at 10 months of age. These physiological and histological results demonstrate that PQQ protects the auditory system from NIHL and ARHL in mice.

Downregulation of GJB2 and SLC26A4 genes induced by noise exposure is associated with cochlear damage.

BACKGROUND: Noise-induced hearing loss (NIHL) is one the major causes of acquired hearing loss in developed countries. Noise can change the pattern of gene expression, inducing sensorineural hearing impairment. There is no investigation on the effects of noise frequency on the expression of GJB2 and SLC26A4 genes involved in congenital hearing impairment in cochlear tissue. Here we investigated the impacts of white and purple noise on gene expression and pathologic changes of cochlear tissue. METHODS: In this study, 32 adult male Westar rats were randomly divided into experimental groups: WN, animals exposed to white noise with a frequency range of 100-20000 Hz; PN, animals exposed to purple noise with a frequency range of 4-20 kHz, and control group, without noise. The experimental groups were exposed to a 118-120 dB sound pressure level for 8 h per 3 days and 6 days. 1 h and 1 week after termination of noise exposure, cochlear tissue was prepared for pathology and gene expression analysis. RESULTS: Both white and purple noises caused permanent damage to the cortical, estrosilica systems of hair cells and ganglion of the hearing nerve. GJB2 and SLC26A4 were downregulated in both groups exposed with white and purple noise by increasing the time of noise exposure. However, differences are notably more significant in purple noise, which is more intensified. Also, 1 weak post noise exposure, the downregulation is remarkably higher than 1 h. CONCLUSIONS: Our findings suggest that downregulation of GJB2 and SLC26A4 genes are associated with pathological injury in response to noise exposure in cochlear tissue. It would be suggested the demand for assessment of RNA and protein expression of genes involved in noise-induced hearing loss and subsequently the practice of hearing protection programs.

Combined effects of the exposure to silver nanoparticles and noise on hearing function and cochlea structure of the male rats.

AIMS: This study intended to investigate whether exposure to the combination of noise and Ag-NPs in rats induces cochlear damage and hearing dysfunction. MAIN METHODS: A total of 24Wistar rats were divided into four treatment groups and received/exposed to saline (IP), Ag-NPs (100 mg/kg, 5d/w for 4 weeks), 8 kHz narrowband noise (104 dB SPL, 6 h/day, 5d/w for 4 weeks) and Ag-NPs plus noise. The DPOAE, serum levels of MDA and SOD and changes in body weight were assessed. The rat cochlea was further stained for investigating the mRNA expression (TL-6, NOX3, and TNF-), IHC (TUJ-1 and MHC7), and histological alterations. The Ag-NPs characteristics were also analysed by SEM and XRD. KEY FINDINGS: DPOAE values were remarkably reduced (p < 0.05) among the exposed groups. Furthermore, exposure to noise and Ag-NPs significantly increased MDA levels and decreased the SOD activity in the serum. In comparison to the control group, the expression of IL-6, TNF-, and NOX3 was shown to be elevated in the Ag-NPs plus noise group. The body weight also increased significantly in all groups with the exception of the Ag-NPs plus noise group. IHC tests showed remarkable down-regulation of TUJ1 and MYO7A. Morphological changes confirmed our findings as well. SEM and XRD data validated the production of Ag-NPs. SIGNIFICANCE: According to the findings of this study, sub-acute exposure to noise and Ag-NPs causes permanent damage to the hair cells that are in charge of high-frequency perception.

Dopaminergic and cholinergic innervation in the mouse cochlea after noise-induced or age-related synaptopathy.

Cochlear synaptopathy, the loss of or damage to connections between auditory-nerve fibers (ANFs) and inner hair cells (IHCs), is a prominent pathology in noise-induced and age-related hearing loss. Here, we investigated if degeneration of the olivocochlear (OC) efferent innervation is also a major aspect of the synaptopathic ear, by quantifying the volume and spatial organization of its cholinergic and dopaminergic components, using antibodies to vesicular acetylcholine transporter (VAT) and tyrosine hydroxylase (TH), respectively. CBA/CaJ male mice were examined 1 day to 8 months after a synaptopathic noise exposure, and compared to unexposed age-matched controls and unexposed aged mice at 24-28 months. In normal ears, cholinergic lateral (L)OC terminals were denser in the apical half of the cochlea and on the modiolar side of the inner hair cells (IHCs), where ANFs of low-spontaneous rate are typically found, while dopaminergic terminals were more common in the basal third of the cochlea and, re the IHC axes, were offset towards the habenula with respect to cholinergic terminals. The noise had only small and transient effects on the density of LOC innervation, its spatial organization around the IHC axes, or the extent to which TH and VAT signal were colocalized. The synaptopathic noise also had relatively small and transient effects on cholinergic innervation density in the outer hair cell (OHC) area, which normally peaks in the 16 kHz region and falls monotonically towards higher and lower frequencies. In contrast, in the aged ears, there was massive degeneration of OHC efferents, especially in the apical half of the cochlea, where there was also significant loss of OHCs. In the IHC area, there was significant loss of cholinergic terminals in both apical and basal regions and of dopaminergic innervation in the basal half. Furthermore, the cholinergic terminals in the aged ears spread from their normal clustering near the IHC basolateral pole, where the ANF synapses are found, to positions up and down the IHC somata and regions of the neuropil closer to the habenula. This apparent migration was most striking in the apex, where the hair cell pathology was greatest, and may be a harbinger of impending hair cell death.

Traumatic-noise-induced hair cell death and hearing loss is mediated by activation of CaMKKß.

BACKGROUND: The Ca2+/calmodulin-dependent protein kinase kinases (CaMKKs) are serine/threonine-directed protein kinases that are activated following increases in intracellular calcium, playing a critical role in neuronal signaling. Inner-ear-trauma-induced calcium overload in sensory hair cells has been well documented in the pathogenesis of traumatic noise-induced hair cell death and hearing loss, but there are no established pharmaceutical therapies available due to a lack of specific therapeutic targets. In this study, we investigated the activation of CaMKKß in the inner ear after traumatic noise exposure and assessed the prevention of noise-induced hearing loss (NIHL) with RNA silencing. RESULTS: Treatment with short hairpin RNA of CaMKKß (shCaMKKß) via adeno-associated virus transduction significantly knocked down CaMKKß expression in the inner ear. Knockdown of CaMKKß significantly attenuated noise-induced hair cell loss and hearing loss (NIHL). Additionally, pretreatment with naked CaMKKß small interfering RNA (siCaMKKß) attenuated noise-induced losses of inner hair cell synapses and OHCs and NIHL. Furthermore, traumatic noise exposure activates CaMKKß in OHCs as demonstrated by immunolabeling for p-CaMKI. CaMKKß mRNA assessed by fluorescence in-situ hybridization and immunolabeling for CaMKKß in OHCs also increased after the exposure. Finally, pretreatment with siCaMKKß diminished noise-induced activation of AMPKα in OHCs. CONCLUSIONS: These findings demonstrate that traumatic-noise-induced OHC loss and hearing loss occur primarily via activation of CaMKKß. Targeting CaMKKß is a key strategy for prevention of noise-induced hearing loss. Furthermore, our data suggest that noise-induced activation of AMPKα in OHCs occurs via the CaMKKß pathway.

Review of blast noise and the auditory system.

The auditory system is particularly vulnerable to blast injury due to the ear's role as a highly sensitive pressure transducer. Over the past several decades, studies have used a variety of animal models and experimental procedures to recreate blast-induced acoustic trauma. Given the developing nature of this field and our incomplete understanding of molecular mechanisms underlying blast-related auditory disturbances, an updated discussion about these studies is warranted. Here, we comprehensively review well-established blast-related auditory pathology including tympanic membrane perforation and hair cell loss. In addition, we discuss important mechanistic studies that aim to bridge gaps in our current understanding of the molecular and microstructural events underlying blast-induced cochlear, auditory nerve, brainstem, and central auditory system damage. Key findings from the recent literature include the association between endolymphatic hydrops and cochlear synaptic loss, blast-induced neuroinflammatory markers in the peripheral and central auditory system, and therapeutic approaches targeting biochemical markers of blast injury. We conclude that blast is an extreme form of noise exposure. Blast waves produce cochlear damage that appears similar to, but more extreme than, the standard noise exposure protocols used in auditory research. However, experimental variations in studies of blast-induced acoustic trauma make it challenging to compare and interpret data across studies.

The effects of noise-induced hair cell lesions on cochlear electromechanical responses: A computational approach using a biophysical model.

A biophysically inspired signal processing model of the human cochlea is deployed to simulate the effects of specific noise-induced inner hair cell (IHC) and outer hair cell (OHC) lesions on hearing thresholds, cochlear compression, and the spectral and temporal features of the auditory nerve (AN) coding. The model predictions were evaluated by comparison with corresponding data from animal studies as well as human clinical observations. The hearing thresholds were simulated for specific OHC and IHC damages and the cochlear nonlinearity was assessed at 0.5 and 4 kHz. The tuning curves were estimated at 1 kHz and the contributions of the OHC and IHC pathologies to the tuning curve were distinguished by the model. Furthermore, the phase locking of AN spikes were simulated in quiet and in presence of noise. The model predicts that the phase locking drastically deteriorates in noise indicating the disturbing effect of background noise on the temporal coding in case of hearing impairment. Moreover, the paper presents an example wherein the model is inversely configured for diagnostic purposes using a machine learning optimization technique (Nelder-Mead method). Accordingly, the model finds a specific pattern of OHC lesions that gives the audiometric hearing loss measured in a group of noise-induced hearing impaired humans.

Noise exposure levels predict blood levels of the inner ear protein prestin.

Serological biomarkers of inner ear proteins are a promising new approach for studying human hearing. Here, we focus on the serological measurement of prestin, a protein integral to a human's highly sensitive hearing, expressed in cochlear outer hair cells (OHCs). Building from recent nonhuman studies that associated noise-induced OHC trauma with reduced serum prestin levels, and studies suggesting subclinical hearing damage in humans regularly engaging in noisy activities, we investigated the relation between serum prestin levels and environmental noise levels in young adults with normal clinical audiograms. We measured prestin protein levels from circulating blood and collected noise level data multiple times over the course of the experiment using body-worn sound recorders. Results indicate that serum prestin levels have a negative relation with noise exposure: individuals with higher routine noise exposure levels tended to have lower prestin levels. Moreover, when grouping participants based on their risk for a clinically-significant noise-induced hearing loss, we found that prestin levels differed significantly between groups, even though behavioral hearing thresholds were similar. We discuss possible interpretations for our findings including whether lower serum levels may reflect subclinical levels of OHC damage, or possibly an adaptive, protective mechanism in which prestin expression is downregulated in response to loud environments.

Cochlear Preconditioning as a Modulator of Susceptibility to Hearing Loss.

Significance: Acquired sensorineural hearing loss is a major public health problem worldwide. The leading causes of sensorineural hearing loss are noise, aging, and ototoxic medications, with the key underlying pathology being damage to the cochlea. The review focuses on the phenomenon of preconditioning, in which the susceptibility to cochlear injury is reduced by exposing the ear to a stressful stimulus. Recent Advances: Cochlear conditioning has focused on the use of mono-modal conditioning, specifically conditioning the cochlea with moderate noise exposures before a traumatic exposure that causes permanent hearing loss. Recently, cross-modal conditioning has been explored more thoroughly, to prevent not only noise-induced hearing loss, but also age-related and drug-induced hearing losses. Critical Issues: Noise exposures that cause only temporary threshold shifts (TTSs) can cause long-term synaptopathy, injury to the synapses between the inner hair cells and spiral ganglion cells. This discovery has the potential to significantly alter the field of cochlear preconditioning with noise. Further, cochlear preconditioning can be the gateway to the development of clinically deployable therapeutics. Therefore, understanding the underlying mechanisms of conditioning is crucial for optimizing clinical protection against sensorineural hearing loss. Future Directions: Before the discovery of synaptopathy, noise exposures that caused only TTSs were believed to be either harmless or potentially beneficial. Any considerations of preconditioning with noise must consider the potential for injury to the synapses. Further, the discovery of different methods to precondition the cochlea against injury will yield new avenues for protection against hearing loss in the vulnerable populations. Antioxid. Redox Signal. 36, 1215-1228.

Preloaded D-methionine protects from steady state and impulse noise-induced hearing loss and induces long-term cochlear and endogenous antioxidant effects.

OBJECTIVE: Determine effective preloading timepoints for D-methionine (D-met) otoprotection from steady state or impulse noise and impact on cochlear and serum antioxidant measures. DESIGN: D-met started 2.0-, 2.5-, 3.0-, or 3.5- days before steady-state or impulse noise exposure with saline controls. Auditory brainstem response (ABRs) measured from 2 to 20 kHz at baseline and 21 days post-noise. Samples were then collected for serum (SOD, CAT, GR, GPx) and cochlear (GSH, GSSG) antioxidant levels. STUDY SAMPLE: Ten Chinchillas per group. RESULTS: Preloading D-met significantly reduced ABR threshold shifts for both impulse and steady state noise exposures but with different optimal starting time points and with differences in antioxidant measures. For impulse noise exposure, the 2.0, 2.5, and 3.0 day preloading start provide significant threshold shift protection at all frequencies. Compared to the saline controls, serum GR for the 3.0 and 3.5 day preloading groups was significantly increased at 21 days with no significant increase in SOD, CAT or GPx for any impulse preloading time point. Cochlear GSH, GSSG, and GSH/GSSG ratio were not significantly different from saline controls at 21 days post noise exposure. For steady state noise exposure, significant threshold shift protection occurred at all frequencies for the 3.5, 3.0 and 2.5 day preloading start times but protection only occurred at 3 of the 6 test frequencies for the 2.0 day preloading start point. Compared to the saline controls, preloaded D-met steady-state noise groups demonstrated significantly higher serum SOD for the 2.5-3.5 day starting time points and GPx for the 2.5 day starting time but no significant increase in GR or CAT for any preloading time point. Compared to saline controls, D-met significantly increased cochlear GSH concentrations in the 2 and 2.5 day steady-state noise exposed groups but no significant differences in GSSG or the GSH/GSSG ratio were noted for any steady state noise-exposed group. CONCLUSIONS: The optimal D-met preloading starting time window is earlier for steady state (3.5-2.5 days) than impulse noise (3.0-2.0). At 21 days post impulse noise, D-met increased serum GR for 2 preloading time points but not SOD, CAT, or GpX and not cochlear GSH, GSSG or the GSH/GSSG ratio. At 21 days post steady state noise D-met increased serum SOD and GPx at select preloading time points but not CAT or GR. However D-met did increase the cochlear GSH at select preloading time points but not GSSG or the GSH/GSSG ratio.

Estradiol Protects against Noise-Induced Hearing Loss and Modulates Auditory Physiology in Female Mice.

Recent studies have identified sex-differences in auditory physiology and in the susceptibility to noise-induced hearing loss (NIHL). We hypothesize that 17ß-estradiol (E2), a known modulator of auditory physiology, may underpin sex-differences in the response to noise trauma. Here, we gonadectomized B6CBAF1/J mice and used a combination of electrophysiological and histological techniques to study the effects of estrogen replacement on peripheral auditory physiology in the absence of noise exposure and on protection from NIHL. Functional analysis of auditory physiology in gonadectomized female mice revealed that E2-treatment modulated the peripheral response to sound in the absence of changes to the endocochlear potential compared to vehicle-treatment. E2-replacement in gonadectomized female mice protected against hearing loss following permanent threshold shift (PTS)- and temporary threshold shift (TTS)-inducing noise exposures. Histological analysis of the cochlear tissue revealed that E2-replacement mitigated outer hair cell loss and cochlear synaptopathy following noise exposure compared to vehicle-treatment. Lastly, using fluorescent in situ hybridization, we demonstrate co-localization of estrogen receptor-2 with type-1C, high threshold spiral ganglion neurons, suggesting that the observed protection from cochlear synaptopathy may occur through E2-mediated preservation of these neurons. Taken together, these data indicate the estrogen signaling pathways may be harnessed for the prevention and treatment of NIHL.