The impact of tympanic membrane perforations on middle ear transfer function.

PURPOSE: Injury or inflammation of the middle ear often results in the persistent tympanic membrane (TM) perforations, leading to conductive hearing loss (HL). However, in some cases the magnitude of HL exceeds that attributable by the TM perforation alone. The aim of the study is to better understand the effects of location and size of TM perforations on the sound transmission properties of the middle ear. METHODS: The middle ear transfer functions (METF) of six human temporal bones (TB) were compared before and after perforating the TM at different locations (anterior or posterior lower quadrant) and to different degrees (1 mm, » of the TM, ½ of the TM, and full ablation). The sound-induced velocity of the stapes footplate was measured using single-point laser-Doppler-vibrometry (LDV). The METF were correlated with a Finite Element (FE) model of the middle ear, in which similar alterations were simulated. RESULTS: The measured and calculated METF showed frequency and perforation size dependent losses at all perforation locations. Starting at low frequencies, the loss expanded to higher frequencies with increased perforation size. In direct comparison, posterior TM perforations affected the transmission properties to a larger degree than anterior perforations. The asymmetry of the TM causes the malleus-incus complex to rotate and results in larger deflections in the posterior TM quadrants than in the anterior TM quadrants. Simulations in the FE model with a sealed cavity show that small perforations lead to a decrease in TM rigidity and thus to an increase in oscillation amplitude of the TM mainly above 1 kHz. CONCLUSION: Size and location of TM perforations have a characteristic influence on the METF. The correlation of the experimental LDV measurements with an FE model contributes to a better understanding of the pathologic mechanisms of middle-ear diseases. If small perforations with significant HL are observed in daily clinical practice, additional middle ear pathologies should be considered. Further investigations on the loss of TM pretension due to perforations may be informative.

Evaluation of artifacts of cochlear implant electrodes in cone beam computed tomography.

PURPOSE: Cone Beam Computed Tomography (CBCT) offers a valid alternative to conventional Computed Tomography (CT). A possible radiation dose reduction with the use of CBCT in postoperative imaging of CIs is of great importance. Whether the visualization of Cochlear Implant (CI) electrodes in CBCT correlates with the radiation dose applied was investigated in this study. METHODS: We compared the visualization quality of Contour Advance CIs to Straight CIs from Cochlear using CBCT with varying tube parameters on whole-head specimen. RESULTS: The internal diameter of the cochlea decreases from base to apex, resulting in a significantly different intracochlear positioning of the two tested CI models. While electrodes of the Contour Advance series are located close to the modiolus, thus closer to the spiral ganglion neurons, those of the Straight series are located further away. The artifact portion of the electrode amounts to 50-70% of the radiological diameter of the electrode. An increase in artifact portion from the base (electrode #1 approx. 50%) to the apex (electrode #20 approx. 70%) of the cochlea was observed. The visualization of electrodes in the medial and apical part of the cochlea is limited due to artifact overlapping. There was no correlation between the artifact size and the applied radiation dose. CONCLUSION: The results indicate that a reduction of the radiation dose by up to 45% of the currently applied radiation dose of standard protocols would be possible. Investigations of the effects on subjective image quality still need to be performed.

Phosphoinositol-4,5-Bisphosphate Regulates Auditory Hair-Cell Mechanotransduction-Channel Pore Properties and Fast Adaptation.

Membrane proteins, such as ion channels, interact dynamically with their lipid environment. Phosphoinositol-4,5-bisphosphate (PIP2) can directly or indirectly modify ion-channel properties. In auditory sensory hair cells of rats (Sprague Dawley) of either sex, PIP2 localizes within stereocilia, near stereocilia tips. Modulating the amount of free PIP2 in inner hair-cell stereocilia resulted in the following: (1) the loss of a fast component of mechanoelectric-transduction current adaptation, (2) an increase in the number of channels open at the hair bundle's resting position, (3) a reduction of single-channel conductance, (4) a change in ion selectivity, and (5) a reduction in calcium pore blocking effects. These changes occur without altering hair-bundle compliance or the number of functional stereocilia within a given hair bundle. Although the specific molecular mechanism for PIP2 action remains to be uncovered, data support a hypothesis for PIP2 directly regulating channel conformation to alter calcium permeation and single-channel conductance.SIGNIFICANCE STATEMENT How forces are relayed to the auditory mechanoelectrical transduction (MET) channel remains unknown. However, researchers have surmised that lipids might be involved. Previous work on bullfrog hair cells showed an effect of phosphoinositol-4,5-bisphosphate (PIP2) depletion on MET current amplitude and adaptation, leading to the postulation of the existence of an underlying myosin-based adaptation mechanism. We find similar results in rat cochlea hair cells but extend these data to include single-channel analysis, hair-bundle mechanics, and channel-permeation properties. These additional data attribute PIP2 effects to actions on MET-channel properties and not motor interactions. Further findings support PIP2's role in modulating a fast, myosin-independent, and Ca2+-independent adaptation process, validating fast adaptation's biological origin. Together this shows PIP2's pivotal role in auditory MET, likely as a direct channel modulator.

The how and why of identifying the hair cell mechano-electrical transduction channel.

Identification of the auditory hair cell mechano-electrical transduction (hcMET) channel has been a major focus in the hearing research field since the 1980s when direct mechanical gating of a transduction channel was proposed (Corey and Hudspeth J Neurosci 3:962-976, 1983). To this day, the molecular identity of this channel remains controversial. However, many of the hcMET channel's properties have been characterized, including pore properties, calcium-dependent ion permeability, rectification, and single channel conductance. At this point, elucidating the molecular identity of the hcMET channel will provide new tools for understanding the mechanotransduction process. This review discusses the significance of identifying the hcMET channel, the difficulties associated with that task, as well as the establishment of clear criteria for this identification. Finally, we discuss potential candidate channels in light of these criteria.

The neural basis of Drosophila gravity-sensing and hearing.

The neural substrates that the fruitfly Drosophila uses to sense smell, taste and light share marked structural and functional similarities with ours, providing attractive models to dissect sensory stimulus processing. Here we focus on two of the remaining and less understood prime sensory modalities: graviception and hearing. We show that the fly has implemented both sensory modalities into a single system, Johnston's organ, which houses specialized clusters of mechanosensory neurons, each of which monitors specific movements of the antenna. Gravity- and sound-sensitive neurons differ in their response characteristics, and only the latter express the candidate mechanotransducer channel NompC. The two neural subsets also differ in their central projections, feeding into neural pathways that are reminiscent of the vestibular and auditory pathways in our brain. By establishing the Drosophila counterparts of these sensory systems, our findings provide the basis for a systematic functional and molecular dissection of how different mechanosensory stimuli are detected and processed.

Partial Ossicular Reconstruction With a Novel Ball Joint Prosthesis: The mCLIP ARC Partial Prosthesis.

OBJECTIVE: Middle ear surgery involves reconstruction of the ossicular chain, predominately using rigid implants. New middle ear prostheses strive to mimic the physiologic micromovements of the ossicular chain and prevent dislocation, protrusion, and preloading of the annular ligament due to pressure fluctuations. METHODS: Thirty-five patients were included in a monocentric, prospective observational study. Patients received tympanoplasty with ossicular reconstruction using the mCLIP ARC partial prosthesis. This titanium prosthesis is equipped with a clip mechanism for coupling at the stapes and a ball joint connecting headplate and shaft. At short-term (ST) and mid-term (MT) follow-up, pure-tone audiometry was performed and the pure tone average of 0.5, 1, 2, and 3 kHz (PTA4) was calculated. The audiological outcome was compared with retrospective data of the Dresden titanium clip prosthesis. RESULTS: The new prosthesis shows favorable clinical results. Pure-tone audiometry showed satisfactory results in ST and MT follow-up, with the PTA4 air-bone gap (ABG) decreasing from 24.5 (±11) dB to 17.4 (±7.9) dB at the ST follow-up at 27 days to 15.6 (±10.3) dB at MT follow-up at 196 days (n = 32). A PTA4-ABG value of less than 20 dB was achieved by 63% of patients at ST follow-up and by 77% at MT follow-up. There was no significant difference in PTA4 ABG compared to the Dresden titanium clip prosthesis during ST follow-up (p = 0.18). CONCLUSION: The mCLIP ARC partial prosthesis, a new middle ear prosthesis with a balanced ball joint, shows promising audiological results and is a safe and effective choice for patients with chronic ear disease. LEVEL OF EVIDENCE: 3 Laryngoscope, 134:3323-3328, 2024.

A Partial Ossicular Replacement Prosthesis With a Concentric Ball Joint in the Headplate.

OBJECTIVE: In passive middle ear prosthetics, rigid implants have proven successful in reconstructing the ossicular chain. However, these cannot fully replicate the physiology of the ossicular chain. Pressure fluctuations cause high stresses in rigid passive prostheses, which can result in dislocation, protrusion, and pre-tension in the annular ligament resulting in unsatisfactory hearing results. METHODS: In collaboration with MED-EL, we developed a new passive middle ear prosthesis that features a balanced, centered ball joint between the headplate and shaft of the prosthesis. We compared the sound transmission properties of this new prosthesis with those of a standard rigid prosthesis. Using Laser-Doppler-Vibrometry, we measured the sound-induced velocity of the stapes footplate relative to a given acoustic stimulus. RESULTS: The new prosthesis showed equivalent sound transmission characteristics compared to the rigid prosthesis, whereas retaining the ability to compensate for pressure fluctuations due to its ball joint. This ensures good transmission properties even during displacements of the tympanic membrane. CONCLUSION: This development is a further step toward a physiological reconstruction of the ossicular chain. LEVEL OF EVIDENCE: NA Laryngoscope, 133:1717-1721, 2023.

Recent advances in cochlear hair cell nanophysiology: subcellular compartmentalization of electrical signaling in compact sensory cells.

In recent years, genetics, physiology, and structural biology have advanced into the molecular details of the sensory physiology of auditory hair cells. Inner hair cells (IHCs) and outer hair cells (OHCs) mediate two key functions: active amplification and non-linear compression of cochlear vibrations by OHCs and sound encoding by IHCs at their afferent synapses with the spiral ganglion neurons. OHCs and IHCs share some molecular physiology, e.g. mechanotransduction at the apical hair bundles, ribbon-type presynaptic active zones, and ionic conductances in the basolateral membrane. Unique features enabling their specific function include prestin-based electromotility of OHCs and indefatigable transmitter release at the highest known rates by ribbon-type IHC active zones. Despite their compact morphology, the molecular machineries that either generate electrical signals or are driven by these signals are essentially all segregated into local subcellular structures. This review provides a brief account on recent insights into the molecular physiology of cochlear hair cells with a specific focus on organization into membrane domains.

Nitinol in Passive Ossicular Reconstruction-First Results From Temporal Bone Experiments.

HYPOTHESIS: Nitinol is a suitable material for passive middle ear prosthesis. BACKGROUND: In modern ear microsurgery, the restitution of hearing is tremendously important. In passive ossicular reconstruction, rigid alloplastic materials are widespread in use. However, rigid prostheses fail to adapt to atmospheric pressure changes. We describe the use of the super-elastic material nitinol in passive ossicular reconstruction to overcome this limitation. METHODS: Together with an industrial partner, we developed a nitinol clip prosthesis equipped with a flexible prosthesis headplate. The new prosthesis was evaluated for flexibility and its sound transmission properties were compared with standard clip prostheses. For this purpose, the sound-induced acceleration of the stapes footplate was measured by laser-doppler vibrometry in temporal bones. Furthermore, the flexibility of the prosthesis plate was tested in a load-cell experiment. RESULTS: On average, the pure tone transmission characteristics of the nitinol prosthesis is statistically not distinguishable from standard titanium clip prostheses. The tests in the load cell confirmed the flexibility of the prosthesis. Any measured prosthesis returns to its original state after deformation. CONCLUSION: The newly developed nitinol clip prosthesis shows similar sound transmission properties in comparison to established prostheses with high flexibility indicating a step forward to a physiological ossicular chain reconstruction.

Designer aminoglycosides prevent cochlear hair cell loss and hearing loss.

Bacterial infections represent a rapidly growing challenge to human health. Aminoglycosides are widely used broad-spectrum antibiotics, but they inflict permanent hearing loss in up to ~50% of patients by causing selective sensory hair cell loss. Here, we hypothesized that reducing aminoglycoside entry into hair cells via mechanotransducer channels would reduce ototoxicity, and therefore we synthesized 9 aminoglycosides with modifications based on biophysical properties of the hair cell mechanotransducer channel and interactions between aminoglycosides and the bacterial ribosome. Compared with the parent aminoglycoside sisomicin, all 9 derivatives displayed no or reduced ototoxicity, with the lead compound N1MS 17 times less ototoxic and with reduced penetration of hair cell mechanotransducer channels in rat cochlear cultures. Both N1MS and sisomicin suppressed growth of E. coli and K. pneumoniae, with N1MS exhibiting superior activity against extended spectrum ß lactamase producers, despite diminished activity against P. aeruginosa and S. aureus. Moreover, systemic sisomicin treatment of mice resulted in 75% to 85% hair cell loss and profound hearing loss, whereas N1MS treatment preserved both hair cells and hearing. Finally, in mice with E. coli-infected bladders, systemic N1MS treatment eliminated bacteria from urinary tract tissues and serially collected urine samples, without compromising auditory and kidney functions. Together, our findings establish N1MS as a nonototoxic aminoglycoside and support targeted modification as a promising approach to generating nonototoxic antibiotics.

Adaptation of mammalian auditory hair cell mechanotransduction is independent of calcium entry.

Adaptation is a hallmark of hair cell mechanotransduction, extending the sensory hair bundle dynamic range while providing mechanical filtering of incoming sound. In hair cells responsive to low frequencies, two distinct adaptation mechanisms exist, a fast component of debatable origin and a slow myosin-based component. It is generally believed that Ca(2+) entry through mechano-electric transducer channels is required for both forms of adaptation. This study investigates the calcium dependence of adaptation in the mammalian auditory system. Recordings from rat cochlear hair cells demonstrate that altering Ca(2+) entry or internal Ca(2+) buffering has little effect on either adaptation kinetics or steady-state adaptation responses. Two additional findings include a voltage-dependent process and an extracellular Ca(2+) binding site, both modulating the resting open probability independent of adaptation. These data suggest that slow motor adaptation is negligible in mammalian auditory cells and that the remaining adaptation process is independent of calcium entry.

Direct gating and mechanical integrity of Drosophila auditory transducers require TRPN1.

The elusive transduction channels for hearing are directly gated mechanically by the pull of gating springs. We found that the transient receptor potential (TRP) channel TRPN1 (NOMPC) is essential for this direct gating of Drosophila auditory transduction channels and that the channel-spring complex was disrupted if TRPN1 was lost. Our results identify TRPN1 as a mechanical constituent of the fly's auditory transduction complex that may act as the channel and/or gating spring.

NompC TRP channel is essential for Drosophila sound receptor function.

The idea that the NompC TRPN1 channel is the Drosophila transducer for hearing has been challenged by remnant sound-evoked nerve potentials in nompC nulls. We now report that NompC is essential for the function of Drosophila sound receptors and that the remnant nerve potentials of nompC mutants are contributed by gravity/wind receptor cells. Ablating the sound receptors reduces the amplitude and sensitivity of sound-evoked nerve responses, and the same effects ensued from mutations in nompC. Ablating the sound receptors also suffices to abolish mechanical amplification, which arises from active receptor motility, is linked to transduction, and also requires NompC. Calcium imaging shows that the remnant nerve potentials in nompC mutants are associated with the activity of gravity/wind receptors and that the sound receptors of the mutants fail to respond to sound. Hence, Drosophila sound receptors require NompC for mechanical signal detection and amplification, demonstrating the importance of this transient receptor potential channel for hearing and reviving the idea that the fly's auditory transducer might be NompC.

Antennal hearing in insects--new findings, new questions.

Mosquitoes, certain Drosophila species, and honey bees use Johnston's organ in their antennae to detect the wing-beat sounds of conspecifics. Recent studies on these insects have provided novel insights into the intricacies of insect hearing and sound communication, with main discoveries including transduction and amplification mechanisms as known from vertebrate hearing, functional and molecular diversifications of mechanosensory cells, and complex mating duets that challenge the frequency-limits of insect antennal ears. This review discusses these recent advances and outlines potential avenues for future research.

Transcuticular optical imaging of stimulus-evoked neural activities in the Drosophila peripheral nervous system.

The nervous system of Drosophila is widely used to study neuronal signal processing because the activities of neurons can be controlled and monitored by cell type-specific expression of genetically encoded actuator and sensor proteins. Measuring neural activities in adult flies, however, usually requires surgical approaches to penetrate the firm and pigmented cuticular exoskeleton. Interfering with this exoskeleton is critical in the case of the peripheral nervous system (PNS), as sensory neurons are often located directly beneath the cuticle and are associated with specialized stimulus-receiving and -conducting cuticular structures. In this article, we describe how the activities of these neurons can be probed nondestructively through the cuticle if a genetically encoded fluorescent protein sensor with strong baseline fluorescence is used. The method is exemplified for mechanosensory neurons in the adult antenna but can also be applied to many other PNS neurons, as is shown for the femoral chordotonal organ located in the fly's leg.

Using Drosophila for studying fundamental processes in hearing.

Apart from detecting sounds, vertebrate ears occasionally produce sounds. These spontaneous otoacoustic emissions are the most compelling evidence for the existence of the cochlear amplifier, an active force-generating process within the cochlea that resides in the motility of the hair cells. Insects have neither a cochlea nor hair cells, yet recent studies demonstrate that an active process that is equivalent to the cochlear amplifier occurs in at least some insect ears; like hair cells, the chordotonal sensory neurons that mediate hearing in Drosophila actively generate forces that augment the minute vibrations they transduce. This neuron-based force-generation, its impact on the ear's macroscopic performance, and the underlying molecular mechanism are the topics of this article, which summarizes some of the recent findings on how the Drosophila organ of hearing works. Functional parallels with vertebrate auditory systems are described that recommend the fly for the study of fundamental processes in hearing.