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Communications Biology May 2024Pending questions regarding cochlear amplification and tuning are hinged upon the organ of Corti (OoC) active mechanics: how outer hair cells modulate OoC vibrations....
Pending questions regarding cochlear amplification and tuning are hinged upon the organ of Corti (OoC) active mechanics: how outer hair cells modulate OoC vibrations. Our knowledge regarding OoC mechanics has advanced over the past decade thanks to the application of tomographic vibrometry. However, recent data from live cochlea experiments often led to diverging interpretations due to complicated interaction between passive and active responses, lack of image resolution in vibrometry, and ambiguous measurement angles. We present motion measurements and analyses of the OoC sub-components at the close-to-true cross-section, measured from acutely excised gerbil cochleae. Specifically, we focused on the vibrating patterns of the reticular lamina, the outer pillar cell, and the basilar membrane because they form a structural frame encasing active outer hair cells. For passive transmission, the OoC frame serves as a rigid truss. In contrast, motile outer hair cells exploit their frame structures to deflect the upper compartment of the OoC while minimally disturbing its bottom side (basilar membrane). Such asymmetric OoC vibrations due to outer hair cell motility explain how recent observations deviate from the classical cochlear amplification theory.
Topics: Animals; Gerbillinae; Hair Cells, Auditory, Outer; Vibration; Organ of Corti; Cochlea; Basilar Membrane
PubMed: 38762693
DOI: 10.1038/s42003-024-06293-4 -
Frontiers in Molecular Neuroscience 2024Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some... (Review)
Review
Hearing loss constitutes a major global health concern impacting approximately 1.5 billion people worldwide. Its incidence is undergoing a substantial surge with some projecting that by 2050, a quarter of the global population will experience varying degrees of hearing deficiency. Environmental factors such as aging, exposure to loud noise, and the intake of ototoxic medications are implicated in the onset of acquired hearing loss. Ototoxicity resulting in inner ear damage is a leading cause of acquired hearing loss worldwide. This could be minimized or avoided by early testing of hearing functions in the preclinical phase of drug development. While the assessment of ototoxicity is well defined for drug candidates in the hearing field - required for drugs that are administered by the otic route and expected to reach the middle or inner ear during clinical use - ototoxicity testing is not required for all other therapeutic areas. Unfortunately, this has resulted in more than 200 ototoxic marketed medications. The aim of this publication is to raise awareness of drug-induced ototoxicity and to formulate some recommendations based on available guidelines and own experience. Ototoxicity testing programs should be adapted to the type of therapy, its indication (targeting the ear or part of other medications classes being potentially ototoxic), and the number of assets to test. For multiple molecules and/or multiple doses, screening options are available: (otic cell assays), (cochlear explant), and (in zebrafish). In assessing the ototoxicity of a candidate drug, it is good practice to compare its ototoxicity to that of a well-known control drug of a similar class. Screening assays provide a streamlined and rapid method to know whether a drug is generally safe for inner ear structures. Mammalian animal models provide a more detailed characterization of drug ototoxicity, with a possibility to localize and quantify the damage using functional, behavioral, and morphological read-outs. Complementary histological measures are routinely conducted notably to quantify hair cells loss with cochleogram. Ototoxicity studies can be performed in rodents (mice, rats), guinea pigs and large species. However, in undertaking, or at the very least attempting, all preclinical investigations within the same species, is crucial. This encompasses starting with pharmacokinetics and pharmacology efficacy studies and extending through to toxicity studies. In life read-outs include Auditory Brainstem Response (ABR) and Distortion Product OtoAcoustic Emissions (DPOAE) measurements that assess the activity and integrity of sensory cells and the auditory nerve, reflecting sensorineural hearing loss. Accurate, reproducible, and high throughput ABR measures are fundamental to the quality and success of these preclinical trials. As in humans, otoscopic evaluations are routinely carried out to observe the tympanic membrane and auditory canal. This is often done to detect signs of inflammation. The cochlea is a tonotopic structure. Hair cell responsiveness is position and frequency dependent, with hair cells located close to the cochlea apex transducing low frequencies and those at the base transducing high frequencies. The cochleogram aims to quantify hair cells all along the cochlea and consequently determine hair cell loss related to specific frequencies. This measure is then correlated with the ABR & DPOAE results. Ototoxicity assessments evaluate the impact of drug candidates on the auditory and vestibular systems, de-risk hearing loss and balance disorders, define a safe dose, and optimize therapeutic benefits. These types of studies can be initiated during early development of a therapeutic solution, with ABR and otoscopic evaluations. Depending on the mechanism of action of the compound, studies can include DPOAE and cochleogram. Later in the development, a GLP (Good Laboratory Practice) ototoxicity study may be required based on otic related route of administration, target, or known potential otic toxicity.
PubMed: 38756707
DOI: 10.3389/fnmol.2024.1379743 -
Frontiers in Neurology 2024The optimal placement of a cochlear implant (CI) electrode inside the scala tympani compartment to create an effective electrode-neural interface is the base for a... (Review)
Review
The optimal placement of a cochlear implant (CI) electrode inside the scala tympani compartment to create an effective electrode-neural interface is the base for a successful CI treatment. The characteristics of an effective electrode design include (a) electrode matching every possible variation in the inner ear size, shape, and anatomy, (b) electrically covering most of the neuronal elements, and (c) preserving intra-cochlear structures, even in non-hearing preservation surgeries. Flexible electrode arrays of various lengths are required to reach an angular insertion depth of 680° to which neuronal cell bodies are angularly distributed and to minimize the rate of electrode scalar deviation. At the time of writing this article, the current scientific evidence indicates that straight lateral wall electrode outperforms perimodiolar electrode by preventing electrode tip fold-over and scalar deviation. Most of the available literature on electrode insertion depth and hearing outcomes supports the practice of physically placing an electrode to cover both the basal and middle turns of the cochlea. This is only achievable with longer straight lateral wall electrodes as single-sized and pre-shaped perimodiolar electrodes have limitations in reaching beyond the basal turn of the cochlea and in offering consistent modiolar hugging placement in every cochlea. For malformed inner ear anatomies that lack a central modiolar trunk, the perimodiolar electrode is not an effective electrode choice. Most of the literature has failed to demonstrate superiority in hearing outcomes when comparing perimodiolar electrodes with straight lateral wall electrodes from single CI manufacturers. In summary, flexible and straight lateral wall electrode type is reported to be gentle to intra-cochlear structures and has the potential to electrically stimulate most of the neuronal elements, which are necessary in bringing full benefit of the CI device to recipients.
PubMed: 38756216
DOI: 10.3389/fneur.2024.1348439 -
BMC Neurology May 2024Postural balance impairment can affect the quality of life of patients with Parkinson's disease. Previous studies have described connections of the vestibular system... (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Postural balance impairment can affect the quality of life of patients with Parkinson's disease. Previous studies have described connections of the vestibular system with postural functions, suggesting a potential participation of the basal ganglia in receiving vestibular stimuli. This systematic review aims to summarize the evidence on the effectiveness of vestibular rehabilitation on postural balance in patients with Parkinson's disease.
METHODS
A systematic review was conducted using the electronic databases: PubMed, Embase, Scopus and PEDro. The study selection was independently conducted by two reviewers, and disagreements were evaluated by a third reviewer. The included studies had no restrictions on publication dates or languages and the last update occurred in July 2023.
RESULTS
From the 485 studies found in the searches, only 3 studies were deemed eligible for the systematic review involving a total of 130 participants. The Berg Balance Scale was described as the tool for evaluation of postural balance in all studies. The meta-analysis showed statistically significant results in favor of vestibular rehabilitation (MD = 5.35; 95% CI = 2.39, 8.31; P < 0.001), regardless of the stage of Parkinson's disease. Although the effect size was suggested as a useful functional gain, the analysis was done with caution, as it only included 3 randomized controlled trials. The risk of bias using the RoB-2 was considered as being of "some concern" in all studies. Furthermore, the quality of the evidence based on the Grading of Recommendations Assessment Development and Evaluation system, produced by pooling the included studies was considered very low.
CONCLUSION
Compared to other interventions, vestibular rehabilitation has potential to assist the postural balance of patients with Parkinson's disease. However, the very low quality of the evidence demonstrates uncertainty about the impact of this clinical practice. More robust studies are needed to confirm the benefits of this therapy in patients with Parkinson's disease. This study was prospectively registered in PROSPERO: CRD42020210185.
Topics: Postural Balance; Humans; Parkinson Disease; Randomized Controlled Trials as Topic; Vestibular Diseases; Treatment Outcome; Vestibule, Labyrinth; Neurological Rehabilitation
PubMed: 38745275
DOI: 10.1186/s12883-024-03649-5 -
Frontiers in Molecular Neuroscience 2024Inner ear malformations are predominantly attributed to developmental arrest during the embryonic stage of membranous labyrinth development. Due to the inherent... (Review)
Review
Inner ear malformations are predominantly attributed to developmental arrest during the embryonic stage of membranous labyrinth development. Due to the inherent difficulty in clinically assessing the status of the membranous labyrinth, these malformations are diagnosed with radiographic imaging, based on the morphological characteristics of the bony labyrinth. While extensive research has elucidated the intricacies of membranous labyrinth development in mouse models, comprehensive investigations into the developmental trajectory of the bony labyrinth, especially about its calcification process, have been notably lacking. One of the most prominent types of inner ear malformations is known as incomplete partition (IP), characterized by nearly normal external cochlear appearance but pronounced irregularities in the morphology of the modiolus and inter-scalar septa. IP type II (IP-II), also known as Mondini dysplasia, is generally accompanied by an enlargement of the vestibular aqueduct and is primarily attributed to mutations in the gene. In the case of IP-II, the modiolus and inter-scalar septa of the cochlear apex are underdeveloped or missing, resulting in the manifestation of a cystic structure on radiographic imaging. In this overview, we not only explore the normal development of the bony labyrinth in mice but also present our observations on otolith mineralization. Furthermore, we investigated the specifics of bony labyrinth and otolith mineralization in -deficient mice, which served as an animal model for IP-II. We ensured that these findings promise to provide valuable insights for the establishment of therapeutic interventions, optimal timing, targeted sites, and preventive measures when considering the management of this condition.
PubMed: 38742227
DOI: 10.3389/fnmol.2024.1384764 -
Scientific Reports May 2024Transforming growth factor-β (TGF-β) signaling plays a significant role in multiple biological processes, including inflammation, immunity, and cell death. However,...
Transforming growth factor-β (TGF-β) signaling plays a significant role in multiple biological processes, including inflammation, immunity, and cell death. However, its specific impact on the cochlea remains unclear. In this study, we aimed to investigate the effects of TGF-β signaling suppression on auditory function and cochlear pathology in mice with kanamycin-induced ototoxicity. Kanamycin and furosemide (KM-FS) were systemically administered to 8-week-old C57/BL6 mice, followed by immediate topical application of a TGF-β receptor inhibitor (TGF-βRI) onto the round window membrane. Results showed significant TGF-β receptor upregulation in spiral ganglion neurons (SGNs) after KM-FA ototoxicity, whereas expression levels in the TGF-βRI treated group remained unchanged. Interestingly, despite no significant change in cochlear TGF-β expression after KM-FS ototoxicity, TGF-βRI treatment resulted in a significant decrease in TGF-β signaling. Regarding auditory function, TGF-βRI treatment offered no therapeutic effects on hearing thresholds and hair cell survival following KM-FS ototoxicity. However, SGN loss and macrophage infiltration were significantly increased with TGF-βRI treatment. These results imply that inhibition of TGF-β signaling after KM-FS ototoxicity promotes cochlear inflammation and SGN degeneration.
Topics: Animals; Kanamycin; Signal Transduction; Ototoxicity; Transforming Growth Factor beta; Mice; Spiral Ganglion; Mice, Inbred C57BL; Cochlea; Hair Cells, Auditory; Furosemide; Male
PubMed: 38740884
DOI: 10.1038/s41598-024-61630-1 -
The Journal of the Acoustical Society... May 2024Medial olivocochlear (MOC) efferents modulate outer hair cell motility through specialized nicotinic acetylcholine receptors to support encoding of signals in noise....
Medial olivocochlear (MOC) efferents modulate outer hair cell motility through specialized nicotinic acetylcholine receptors to support encoding of signals in noise. Transgenic mice lacking the alpha9 subunits of these receptors (α9KOs) have normal hearing in quiet and noise, but lack classic cochlear suppression effects and show abnormal temporal, spectral, and spatial processing. Mice deficient for both the alpha9 and alpha10 receptor subunits (α9α10KOs) may exhibit more severe MOC-related phenotypes. Like α9KOs, α9α10KOs have normal auditory brainstem response (ABR) thresholds and weak MOC reflexes. Here, we further characterized auditory function in α9α10KO mice. Wild-type (WT) and α9α10KO mice had similar ABR thresholds and acoustic startle response amplitudes in quiet and noise, and similar frequency and intensity difference sensitivity. α9α10KO mice had larger ABR Wave I amplitudes than WTs in quiet and noise. Other ABR metrics of hearing-in-noise function yielded conflicting findings regarding α9α10KO susceptibility to masking effects. α9α10KO mice also had larger startle amplitudes in tone backgrounds than WTs. Overall, α9α10KO mice had grossly normal auditory function in quiet and noise, although their larger ABR amplitudes and hyperreactive startles suggest some auditory processing abnormalities. These findings contribute to the growing literature showing mixed effects of MOC dysfunction on hearing.
Topics: Animals; Mice, Knockout; Evoked Potentials, Auditory, Brain Stem; Noise; Auditory Threshold; Receptors, Nicotinic; Acoustic Stimulation; Reflex, Startle; Perceptual Masking; Behavior, Animal; Mice; Mice, Inbred C57BL; Cochlea; Male; Phenotype; Olivary Nucleus; Auditory Pathways; Female; Auditory Perception; Hearing
PubMed: 38738939
DOI: 10.1121/10.0025985 -
Trends in Hearing 2024Cochlear synaptopathy, a form of cochlear deafferentation, has been demonstrated in a number of animal species, including non-human primates. Both age and noise exposure... (Review)
Review
Cochlear synaptopathy, a form of cochlear deafferentation, has been demonstrated in a number of animal species, including non-human primates. Both age and noise exposure contribute to synaptopathy in animal models, indicating that it may be a common type of auditory dysfunction in humans. Temporal bone and auditory physiological data suggest that age and occupational/military noise exposure also lead to synaptopathy in humans. The predicted perceptual consequences of synaptopathy include tinnitus, hyperacusis, and difficulty with speech-in-noise perception. However, confirming the perceptual impacts of this form of cochlear deafferentation presents a particular challenge because synaptopathy can only be confirmed through post-mortem temporal bone analysis and auditory perception is difficult to evaluate in animals. Animal data suggest that deafferentation leads to increased central gain, signs of tinnitus and abnormal loudness perception, and deficits in temporal processing and signal-in-noise detection. If equivalent changes occur in humans following deafferentation, this would be expected to increase the likelihood of developing tinnitus, hyperacusis, and difficulty with speech-in-noise perception. Physiological data from humans is consistent with the hypothesis that deafferentation is associated with increased central gain and a greater likelihood of tinnitus perception, while human data on the relationship between deafferentation and hyperacusis is extremely limited. Many human studies have investigated the relationship between physiological correlates of deafferentation and difficulty with speech-in-noise perception, with mixed findings. A non-linear relationship between deafferentation and speech perception may have contributed to the mixed results. When differences in sample characteristics and study measurements are considered, the findings may be more consistent.
Topics: Humans; Cochlea; Tinnitus; Animals; Speech Perception; Hyperacusis; Noise; Auditory Perception; Synapses; Hearing Loss, Noise-Induced; Loudness Perception
PubMed: 38738337
DOI: 10.1177/23312165241239541 -
Laryngoscope Investigative... Jun 2024Otosclerosis is characterized by abnormal bone growth in the otie capsule. Nowadays, stapedotomy is commonly used for otosclerosis treatment. Currently, postoperative...
BACKGROUND
Otosclerosis is characterized by abnormal bone growth in the otie capsule. Nowadays, stapedotomy is commonly used for otosclerosis treatment. Currently, postoperative dizziness has been associated with stapedotomy. In 1981, intratympanic dexamethasone was utilized to manage inner ear disorders like tinnitus and acute sensorineural hearing loss. However, there is much uncertainty regarding the effect and safety of topical steroid therapy in the middle ear during stapedotomy. In the present study, we assessed the effect of topical steroid therapy during stapedotomy on postoperative dizziness.
METHODS
Otosclerosis patients eligible for stapedotomy were randomly divided into two groups based on dexamethasone administration or placebo. Audiometric and tympanometry results were observed and recorded for the involved frequencies. The Dizziness Handicap Inventory was used to quantify patient perceptions of dizziness and balance issues. Audiometry and dizziness assessments were repeated at discharge and 4 months after the operation.
RESULTS
The study comprised 72 otosclerosis patients undergoing stapedotomy. At discharge, the intervention group showed a significant reduction in the incidence of dizziness compared to the placebo group. However, in the 4-month follow-up after the operation, both groups experienced a decrease in dizziness incidence, with no significant difference between them. There was also no significant difference in audiometric levels between the two groups. Interestingly, the intervention group had a significantly lower need for systemic anti-dizziness drugs after surgery compared to the control group.
CONCLUSION
Topical dexamethasone during stapedotomy effectively minimizes dizziness at discharge and reduces the need for postoperative anti-dizziness medication.
LEVEL OF EVIDENCE
2.
PubMed: 38736941
DOI: 10.1002/lio2.1257 -
Nature Communications May 2024Accurate perception and behavior rely on distinguishing sensory signals arising from unexpected events from those originating from our own voluntary actions. In the...
Accurate perception and behavior rely on distinguishing sensory signals arising from unexpected events from those originating from our own voluntary actions. In the vestibular system, sensory input that is the consequence of active self-motion is canceled early at the first central stage of processing to ensure postural and perceptual stability. However, the source of the required cancellation signal was unknown. Here, we show that the cerebellum combines sensory and motor-related information to predict the sensory consequences of active self-motion. Recordings during attempted but unrealized head movements in two male rhesus monkeys, revealed that the motor-related signals encoded by anterior vermis Purkinje cells explain their altered sensitivity to active versus passive self-motion. Further, a model combining responses from ~40 Purkinje cells accounted for the cancellation observed in early vestibular pathways. These findings establish how cerebellar Purkinje cells predict sensory outcomes of self-movements, resolving a long-standing issue of sensory signal suppression during self-motion.
Topics: Animals; Purkinje Cells; Male; Macaca mulatta; Head Movements; Cerebellum; Vestibule, Labyrinth; Motion Perception
PubMed: 38734715
DOI: 10.1038/s41467-024-48376-0