scholarly journals Enhancing the sensitivity of the envelope-following response for cochlear synaptopathy screening in humans: the role of stimulus envelope

2020 ◽  
Author(s):  
Viacheslav Vasilkov ◽  
Markus Garrett ◽  
Manfred Mauermann ◽  
Sarah Verhulst
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Auditory Nerve ◽  
Outer Hair Cell ◽  
Cell Damage ◽  
Modulation Depth ◽  
Auditory Evoked Potential ◽  
Sensorineural Hearing ◽  
Age Related

AbstractAuditory de-afferentation, a permanent reduction in the number of innerhair-cells and auditory-nerve synapses due to cochlear damage or synaptopathy, can reliably be quantified using temporal bone histology and immunostaining. However, there is an urgent need for non-invasive markers of synaptopathy to study its perceptual consequences in live humans and to develop effective therapeutic interventions. While animal studies have identified candidate auditory-evoked-potential (AEP) markers for synaptopathy, their interpretation in humans has suffered from translational issues related to neural generator differences, unknown hearing-damage histopathologies or lack of measurement sensitivity. To render AEP-based markers of synaptopathy more sensitive and differential to the synaptopathy aspect of sensorineural hearing loss, we followed a combined computational and experimental approach. Starting from the known characteristics of auditory-nerve physiology, we optimized the stimulus envelope to stimulate the available auditory-nerve population optimally and synchronously to generate strong envelope-following-responses (EFRs). We further used model simulations to explore which stimuli evoked a response that was sensitive to synaptopathy, while being maximally insensitive to possible co-existing outer-hair-cell pathologies. We compared the model-predicted trends to AEPs recorded in younger and older listeners (N=44, 24f) who had normal or impaired audiograms with suspected age-related synaptopathy in the older cohort. We conclude that optimal stimulation paradigms for EFR-based quantification of synaptopathy should have sharply rising envelope shapes, a minimal plateau duration of 1.7-2.1 ms for a 120-Hz modulation rate, and inter-peak intervals which contain near-zero amplitudes. From our recordings, the optimal EFR-evoking stimulus had a rectangular envelope shape with a 25% duty cycle and a 95% modulation depth. Older listeners with normal or impaired audiometric thresholds showed significantly reduced EFRs, which were consistent with how (age-induced) synaptopathy affected these responses in the model.Significance StatementCochlear synaptopathy was in 2009 identified as a new form of sensorineural hearing loss (SNHL) that also affects primates and humans. However, clinical practice does not routinely screen for synaptopathy, and hence its consequences for degraded sound and speech perception remain unclear. Cochlear synaptopathy may thus remain undiagnosed and untreated in the aging population who often report self-reported hearing difficulties. To enable an EEG-based differential diagnosis of synaptopathy in humans, it is crucial to develop a recording method that evokes a robust response and emphasizes inter-individual differences. These differences should reflect the synaptopathy aspect of SNHL, while being insensitive to other aspects of SNHL (e.g. outer-hair-cell damage). This study uniquely combines computational modeling with experiments in normal and hearing-impaired listeners to design an EFR stimulation and recording paradigm that can be used for the diagnosis of synaptopathy in humans.

scholarly journals Noise-induced and age-related hearing loss:  new perspectives and potential therapies

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 927 ◽  
Author(s):  
M Charles Liberman
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Auditory Nerve ◽  
Cell Loss ◽  
Sensorineural Hearing ◽  
Hair Cell Loss ◽  
Age Related ◽  
Age Related Hearing Loss

The classic view of sensorineural hearing loss has been that the primary damage targets are hair cells and that auditory nerve loss is typically secondary to hair cell degeneration. Recent work has challenged that view. In noise-induced hearing loss, exposures causing only reversible threshold shifts (and no hair cell loss) nevertheless cause permanent loss of >50% of the synaptic connections between hair cells and the auditory nerve. Similarly, in age-related hearing loss, degeneration of cochlear synapses precedes both hair cell loss and threshold elevation. This primary neural degeneration has remained a “hidden hearing loss” for two reasons: 1) the neuronal cell bodies survive for years despite loss of synaptic connection with hair cells, and 2) the degeneration is selective for auditory nerve fibers with high thresholds. Although not required for threshold detection when quiet, these high-threshold fibers are critical for hearing in noisy environments. Research suggests that primary neural degeneration is an important contributor to the perceptual handicap in sensorineural hearing loss, and it may be key to the generation of tinnitus and other associated perceptual anomalies. In cases where the hair cells survive, neurotrophin therapies can elicit neurite outgrowth from surviving auditory neurons and re-establishment of their peripheral synapses; thus, treatments may be on the horizon.

scholarly journals Towards a differential diagnosis of cochlear synaptopathy and outer-hair-cell deficits in mixed sensorineural hearing loss pathologies

2019 ◽  
Author(s):  
Viacheslav Vasilkov ◽  
Sarah Verhulst
Keyword(s):  
Hearing Loss ◽  
Differential Diagnosis ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Noise Exposure ◽  
Outer Hair Cell ◽  
Cell Damage ◽  
Sensorineural Hearing ◽  
Inner Hair Cell ◽  
Hearing Thresholds

AbstractDamage to the auditory periphery is more widespread than predicted by the gold-standard clinical audiogram. Noise exposure, ototoxicity and aging can destroy cochlear inner-hair-cell afferent synapses and result in a degraded subcortical representation of sound while leaving hearing thresholds unaffected. Damaged afferent synapses, i.e. cochlear synaptopathy, can be quantified using histology, but a differential diagnosis in living humans is difficult: histology cannot be applied and existing auditory evoked potential (AEP) metrics for synaptopathy become insensitive when other sensorineural hearing impairments co-exist (e.g., outer-hair-cell damage associated with elevated hearing thresholds). To develop a non-invasive diagnostic method which quantifies synaptopathy in humans and animals with normal or elevated hearing thresholds, we employ a computational model approach in combination with human AEP and psychoacoustics. We propose the use of a sensorineural hearing loss (SNHL) map which comprises two relative AEP-based metrics to quantify the respective degrees of synaptopathy and OHC damage and evaluate to which degree our predictions of AEP alterations can explain individual data-points in recorded SNHL maps from male and female listeners with normal or elevated audiometric thresholds. We conclude that SNHL maps can offer a more precise diagnostic tool than existing AEP methods for individual assessment of the synaptopathy and OHC-damage aspect of sensorineural hearing loss.Significance StatementHearing loss ranks fourth in global causes for disability and risk factors include noise exposure, ototoxicity and aging. The most vulnerable parts of the cochlea are the inner-hair-cell afferent synapses and their damage (cochlear synaptopathy) results in a degraded subcortical representation of sound. While synaptopathy can be estimated reliably using histology, it cannot be quantified this way in living humans. Secondly, other co-existing sensorineural hearing deficits (e.g., outer-hair-cell damage) can complicate a differential diagnosis. To quantify synaptopathy in humans and animals with normal or elevated hearing thresholds, we adopt a theoretical and interdisciplinary approach. Sensitive diagnostic metrics for synaptopathy are crucial to assess its prevalence in humans, study its impact on sound perception and yield effective hearing restoration strategies.

scholarly journals Towards personalized auditory models: predicting individual sensorineural-hearing-loss profiles from recorded human auditory physiology

2020 ◽  
Author(s):  
Sarineh Keshishzadeh ◽  
Markus Garrett ◽  
Sarah Verhulst
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Auditory Processing ◽  
Auditory Evoked Potential ◽  
Sensorineural Hearing ◽  
Model Parameters ◽  
Non Invasive ◽  
Auditory Models ◽  
Auditory Physiology

AbstractOver the past decades, different types of auditory models have been developed to study the functioning of normal and impaired auditory processing. Several models can simulate frequency-dependent sensorineural hearing loss (SNHL), and can in this way be used to develop personalized audio-signal processing for hearing aids. However, to determine individualized SNHL profiles, we rely on indirect and non-invasive markers of cochlear and auditory-nerve (AN) damage. Our progressive knowledge of the functional aspects of different SNHL subtypes stresses the importance of incorporating them into the simulated SNHL profile, but has at the same time complicated the task of accomplishing this on the basis of non-invasive markers. In particular, different auditory evoked potential (AEP) types can show a different sensitivity to outer-hair-cell (OHC), inner-hair-cell (IHC) or AN damage, but it is not clear which AEP-derived metric is best suited to develop personalized auditory models. This study investigates how simulated and recorded AEPs can be used to derive individual AN- or OHC-damage patterns and personalize auditory processing models. First, we individualized the cochlear-model parameters using common methods of frequency-specific OHC-damage quantification, after which we simulated AEPs for different degrees of AN-damage. Using a classification technique, we determined the recorded AEP metric that best predicted the simulated individualized CS profiles. We cross-validated our method using the dataset at hand, but also applied the trained classifier to recorded AEPs from a new cohort to illustrate the generalisability of the method.

scholarly journals Deletion of Clusterin Protects Cochlear Hair Cells against Hair Cell Aging and Ototoxicity

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Xiaochang Zhao ◽  
Heidi J. Henderson ◽  
Tianying Wang ◽  
Bo Liu ◽  
Yi Li
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Sensorineural Hearing ◽  
Cell Aging ◽  
Supporting Cells ◽  
Drug Induced ◽  
Cochlear Hair Cells ◽  
Age Related

Hearing loss is a debilitating disease that affects 10% of adults worldwide. Most sensorineural hearing loss is caused by the loss of mechanosensitive hair cells in the cochlea, often due to aging, noise, and ototoxic drugs. The identification of genes that can be targeted to slow aging and reduce the vulnerability of hair cells to insults is critical for the prevention of sensorineural hearing loss. Our previous cell-specific transcriptome analysis of adult cochlear hair cells and supporting cells showed that Clu, encoding a secreted chaperone that is involved in several basic biological events, such as cell death, tumor progression, and neurodegenerative disorders, is expressed in hair cells and supporting cells. We generated Clu-null mice (C57BL/6) to investigate its role in the organ of Corti, the sensory epithelium responsible for hearing in the mammalian cochlea. We showed that the deletion of Clu did not affect the development of hair cells and supporting cells; hair cells and supporting cells appeared normal at 1 month of age. Auditory function tests showed that Clu-null mice had hearing thresholds comparable to those of wild-type littermates before 3 months of age. Interestingly, Clu-null mice displayed less hair cell and hearing loss compared to their wildtype littermates after 3 months. Furthermore, the deletion of Clu is protected against aminoglycoside-induced hair cell loss in both in vivo and in vitro models. Our findings suggested that the inhibition of Clu expression could represent a potential therapeutic strategy for the alleviation of age-related and ototoxic drug-induced hearing loss.

Active Hair Bundle Movements and the Cochlear Amplifier

2003 ◽  
Vol 14 (06) ◽  
pp. 325-338 ◽  
Author(s):  
Anthony Ricci
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Outer Hair Cell ◽  
Sensorineural Hearing ◽  
Hair Bundle ◽  
Cochlear Amplifier ◽  
Active Process ◽  
Slow Adaptation ◽  
Active Processes

The “active process” is a term used to describe amplification and filtering processes that are essential for obtaining the exquisite sensitivity of hearing organs. Understanding the components of the active process is important both for our understanding of the normal physiology of hearing and because perturbations of the cochlear amplifier may lead to such maladies as threshold shifts (both temporary and permanent), tinnitus, sensorineural hearing loss and presbicusis. To date the cochlear amplifier has largely been attributed to outer hair cell electro motility; however, recent evidence suggests, that active properties of the hair bundle may also be important. Most likely both somatic motility and active hair bundle movements contribute to establishing the cochlear active process. This paper reviews recent evidence regarding known active processes in the hair bundle gating compliance, and fast and slow adaptation.

scholarly journals Towards Personalized Auditory Models: Predicting Individual Sensorineural Hearing-Loss Profiles From Recorded Human Auditory Physiology

2021 ◽  
Vol 25 ◽  
pp. 233121652098840 ◽  
Author(s):  
Sarineh Keshishzadeh ◽  
Markus Garrett ◽  
Sarah Verhulst
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Auditory Processing ◽  
Auditory Evoked Potential ◽  
Sensorineural Hearing ◽  
Model Parameters ◽  
Auditory Models ◽  
Auditory Physiology ◽  
Noninvasive Markers

Over the past decades, different types of auditory models have been developed to study the functioning of normal and impaired auditory processing. Several models can simulate frequency-dependent sensorineural hearing loss (SNHL) and can in this way be used to develop personalized audio-signal processing for hearing aids. However, to determine individualized SNHL profiles, we rely on indirect and noninvasive markers of cochlear and auditory-nerve (AN) damage. Our progressive knowledge of the functional aspects of different SNHL subtypes stresses the importance of incorporating them into the simulated SNHL profile, but has at the same time complicated the task of accomplishing this on the basis of noninvasive markers. In particular, different auditory-evoked potential (AEP) types can show a different sensitivity to outer-hair-cell (OHC), inner-hair-cell (IHC), or AN damage, but it is not clear which AEP-derived metric is best suited to develop personalized auditory models. This study investigates how simulated and recorded AEPs can be used to derive individual AN- or OHC-damage patterns and personalize auditory processing models. First, we individualized the cochlear model parameters using common methods of frequency-specific OHC-damage quantification, after which we simulated AEPs for different degrees of AN damage. Using a classification technique, we determined the recorded AEP metric that best predicted the simulated individualized cochlear synaptopathy profiles. We cross-validated our method using the data set at hand, but also applied the trained classifier to recorded AEPs from a new cohort to illustrate the generalizability of the method.

Hearing Loss Associated with Xylene Exposure in a Laboratory Worker

2012 ◽  
Vol 23 (10) ◽  
pp. 824-830 ◽  
Author(s):  
Adrian Fuente ◽  
Bradley McPherson ◽  
Linda J. Hood
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Otoacoustic Emissions ◽  
Outer Hair Cell ◽  
Cell Damage ◽  
Auditory Brainstem ◽  
Sensorineural Hearing ◽  
Auditory Brainstem Responses ◽  
Initial Assessment ◽  
Laboratory Worker

Background: Xylene is an organic solvent, widely used in histology laboratories and other occupational settings. Research in animals has demonstrated that xylene induces outer hair cell damage. Evidence regarding the effects of xylene in humans is only available from studies investigating workers exposed to mixtures of solvents containing xylene. These data indicate that mixtures of solvents containing xylene may induce hearing loss and central auditory dysfunction. Purpose: To comprehensively evaluate the peripheral and central auditory system of a histology laboratory worker exposed to xylene, who had presented with bilateral mild sensorineural hearing loss at an initial assessment. Research Design: A case report of a male histology laboratory worker who has been exposed to xylene for over 20 yr. Results: A diagnosis of bilateral mild sensorineural hearing loss of cochlear origin was made on the basis of otological, neuroimaging, and audiological examinations. Results indicating the absence of transient-evoked otoacoustic emissions, and auditory brainstem responses as expected for a mild cochlear hearing loss, were obtained. Conclusions: The observed bilateral mild sensorineural hearing loss was considered to have been induced by xylene exposure, due to the absence of any other etiological factors related to the onset of hearing loss. The results found in this patient are in agreement with animal data indicating xylene-induced ototoxicity. Xylene-exposed individuals should be audiologically monitored on a regular basis.

Outer hair cell receptor current and sensorineural hearing loss

1989 ◽  
Vol 42 (1) ◽  
pp. 47-72 ◽  
Author(s):  
R.B. Patuzzi ◽  
G.K. Yates ◽  
B.M. Johnstone
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Outer Hair Cell ◽  
Cell Receptor ◽  
Sensorineural Hearing

scholarly journals Is Sensorineural Hearing Loss Related to Chronic Rhinosinusitis Caused by Outer Hair Cell Injury?

2019 ◽  
Vol 25 ◽  
pp. 627-636 ◽  
Author(s):  
Xi Lin ◽  
Xin Shan ◽  
Shaolian Lin ◽  
Bo Shu ◽  
Yingge Wang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Chronic Rhinosinusitis ◽  
Cell Injury ◽  
Outer Hair Cell ◽  
Sensorineural Hearing

scholarly journals Prevention of acquired sensorineural hearing loss in mice by in vivo Htra2 gene editing

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Xi Gu ◽  
Daqi Wang ◽  
Zhijiao Xu ◽  
Jinghan Wang ◽  
Luo Guo ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Protective Effect ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Auditory Brainstem Response ◽  
Gene Editing ◽  
Auditory Brainstem ◽  
Sensorineural Hearing ◽  
Brainstem Response

Abstract Background Aging, noise, infection, and ototoxic drugs are the major causes of human acquired sensorineural hearing loss, but treatment options are limited. CRISPR/Cas9 technology has tremendous potential to become a new therapeutic modality for acquired non-inherited sensorineural hearing loss. Here, we develop CRISPR/Cas9 strategies to prevent aminoglycoside-induced deafness, a common type of acquired non-inherited sensorineural hearing loss, via disrupting the Htra2 gene in the inner ear which is involved in apoptosis but has not been investigated in cochlear hair cell protection. Results The results indicate that adeno-associated virus (AAV)-mediated delivery of CRISPR/SpCas9 system ameliorates neomycin-induced apoptosis, promotes hair cell survival, and significantly improves hearing function in neomycin-treated mice. The protective effect of the AAV–CRISPR/Cas9 system in vivo is sustained up to 8 weeks after neomycin exposure. For more efficient delivery of the whole CRISPR/Cas9 system, we also explore the AAV–CRISPR/SaCas9 system to prevent neomycin-induced deafness. The in vivo editing efficiency of the SaCas9 system is 1.73% on average. We observed significant improvement in auditory brainstem response thresholds in the injected ears compared with the non-injected ears. At 4 weeks after neomycin exposure, the protective effect of the AAV–CRISPR/SaCas9 system is still obvious, with the improvement in auditory brainstem response threshold up to 50 dB at 8 kHz. Conclusions These findings demonstrate the safe and effective prevention of aminoglycoside-induced deafness via Htra2 gene editing and support further development of the CRISPR/Cas9 technology in the treatment of non-inherited hearing loss as well as other non-inherited diseases.

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