Jaro-Journal of the Association for Research in Otolaryngology最新文献

Purpose: Hearing and balance disorders are among the most prevalent sensory impairments globally, yet their cellular and molecular basis remains poorly understood. This gap stems from the inaccessibility of the inner ear, which is encased in the temporal bone (TB)-the hardest bone in the body-and cannot be biopsied in living patients. Conventional histopathology workflows, particularly the century-old celloidin method, are time-consuming, labor-intensive, and incompatible with modern molecular analyses. We aimed to develop a faster, more versatile histology workflow for human TBs that preserves both morphology and molecular integrity.

Methods: We developed a reversible polymethyl methacrylate (rPMMA) embedding protocol for formalin-fixed, calcified TBs using low-temperature resin infiltration (-40 to +4 °C). Precision near-serial sections (10-50 µm) were generated via femtosecond laser microtomy or precision diamond wire sawing. Deacrylation was performed to restore tissue accessibility for histological staining, multiplex immunofluorescence, whole-genome sequencing, and in situ RNA detection (RNAscope™).

Results: Compared to the celloidin workflow, our method reduced processing time and costs by over 90% while preserving histomorphology of comparable quality (n = 7 human TBs). It maintained antigenicity for multiplexed immunofluorescence, preserved native tissue-implant interfaces in implant-containing specimens, yielded high-quality DNA suitable for whole-genome sequencing (mean coverage 7.4 × in specimens with postmortem intervals < 24 h), and enabled mRNA detection at single-cell resolution. Celloidin-embedded controls consistently failed to support these molecular assays.

Conclusion: This rPMMA-based workflow combines gold-standard histomorphology with full compatibility for advanced molecular analyses. With dramatically reduced time and cost, it offers a new benchmark for integrated, spatially resolved studies of human hearing and balance pathologies.

In mammals, the accurate and high-fidelity representation of sound largely depends on the cochlea, the sensory organ specialized for transducing acoustic signals into neural activity with remarkable temporal precision. Prior to hearing onset, which occurs around postnatal day 12 in most altricial rodents, the immature cochlea plays an active role in the refinement of neural circuits along the auditory pathway. To accomplish this function, sensory hair cells and glia-like supporting cells in the immature cochlea generate distinct patterns of spontaneous Ca²⁺ signals. Synchronized Ca²⁺-dependent activity across multiple hair cells is conveyed to the ascending auditory neurons, where it contributes to the emergence of tonotopic maps that enable frequency discrimination. Within the cochlea itself, this spontaneous Ca²⁺ activity serves to promote cellular and synaptic refinement. In this review, we summarize the current insights into the cellular and molecular mechanisms responsible for generating and modulating these spontaneous Ca²⁺ signals in the developing cochlea, and how they regulate the activation of auditory afferent fibres.

Purpose: Auditory neuropathy (AN) is a hearing disorder that is often overlooked due to its hidden cochlear activity and hearing loss profiles. Diphtheria toxin (DT) is commonly used to induce deafness in conditional gene knockout mouse models, but its ototoxic targets in wild-type animals remain controversial. This study aimed to characterize the pathogenic effects of DT on the cochlea of wild-type mice and establish a reliable model of AN.

Methods: Adult CBA/CaJ mice of both sexes (n = 81) were administered by DT for three consecutive days. AN was confirmed by electrophysiological profiles: abnormal auditory brainstem response (ABR) with preserved distortion product otoacoustic emissions (DPOAE), followed by histopathological evaluation of the cochlear auditory pathway.

Results: DT induced a characteristic AN-characteristic hearing loss in mice. It initiated with ribbon synapse degeneration in inner hair cells (IHCs) within 24 h, coinciding with a significant reduction in ABR amplitude peak I. By post-injection day 3, extensive damage was observed, including IHC loss, degeneration of type I spiral ganglion neurons (SGNs), and demyelination of their axons. Despite a minimal loss of OHCs (~ 2.1%), OHC function remained intact as evidenced by DPOAE. A progressive degeneration of SGNs and demyelination of axons persisted over the 21-day observation period.

Conclusion: Our findings demonstrate that DT selectively targets the IHCs and type I afferent pathway in wild-type mice, resulting in a progressive AN- characteristic pathology. This study establishes a mouse model of AN that can serve as a basis for further investigation into the mechanisms underlying similar pathologies.

This paper evaluates the current performance of hearing aids, based on research findings and my experiences with hearing aids. The type of acoustic coupling to the ear is important. The fitting can be "closed" (sealing the ear canal), but this can lead to the occlusion effect; the user's own voice sounds too loud or too boomy. Alternatively, the fitting can be open (the eartip has a vent). This alleviates the occlusion effect, but it introduces comb-filtering (heard as perceptual coloration) and leads to little or no gain at low frequencies. Also, the highest frequency at which useful gain can be achieved is often about 5 kHz, which is lower than optimal. While acoustic feedback cancellation systems have improved markedly, they can still introduce artifacts and impair sound quality, especially for music. Hearing aids use multi-channel amplitude compression to compensate for the reduced dynamic range of hearing-impaired people, but they often fail to restore the audibility of soft sounds, especially at high frequencies, and the amount of compression is often limited (and less than indicated by the manufacturers' fitting software), leading to loudness discomfort (and sometimes reduced speech intelligibility) at high sound levels. Also, compression systems introduce cross-modulation, impairing sound quality. Most hearing aids incorporate directional processing and noise-reduction systems intended to improve the ability to understand speech in noisy situations. These systems can be effective with a closed fitting, but much of the benefit is lost with an open fitting because of leakage of background sounds through the vent.

Purpose: To assess system properties of the human auditory system, such as cochlear gain, frequency selectivity, and their dependence on frequency and level, it is essential to examine the interrelation of various readouts. By measuring and analyzing otoacoustic emission (OAE) and auditory brainstem response (ABR) latencies, among others, predictions of cochlear models and applicability of properties such as the minimum-phase principle, level dependence of latencies, or related changes of the gain of a presumed positive-feedback mechanism can be investigated.

Methods: Here, we present measurements of the latency of the nonlinear-distortion component of pulsed distortion-product otoacoustic emissions (DPOAE) ( $f_2$ = 1-14 kHz, $L_2$ = 25-85 dB SPL) in 20 ears (12 female, 8 male). This yields a direct estimate of intracochlear traveling-wave build-up by recording the time elapsed between the $f_2$ primary stimulus and the distortion-product pulse response. Thus, this technique does not require deriving latency from phase gradients of the coherent-reflection component of different frequencies, as is done using swept-tone DPOAE or SFOAE.

Results: At low stimulus levels ( $L_2$ = 35 dB), DPOAE latency was 13 ms at $f_2$ = 1 kHz, exponentially to  2 ms at $f_2$ = 12-14 kHz. In periods of the corresponding frequency, this rose from $\approx$ 13 periods at 1 kHz to $\ge$ 25 periods above 6 kHz. Between 3 and 6 kHz, latency showed a steeper rise, departing from a pure exponential relation. Level dependence of latencies varied among subjects, with changes ranging from -2 to -12% per 10 dB level increase. Test-retest reliability of latency determination with pulsed DPOAE was excellent.

Conclusion: For frequencies above 1 kHz and up to 14 kHz, OAE latency data align with a scaling law of $\approx$ 0.3 dB/dB. A transition region between 3 and 6 kHz shows scaling in some ears approaching 1 dB/dB, violating local scaling symmetry. Although comparison with ABR literature reveals some unresolved discrepancies, latencies of pulsed DPOAE allow a way to estimate cochlear tuning properties.

Vestibular and spiral ganglion neurons (VGNs and SGNs) developed in the inner ear, where they extend fibers to innervate the vestibular and cochlear hair cells and project centrally to the vestibular and cochlear nuclei. This review focuses on representative molecular factors that regulate key processes in the development of inner ear neurons, including their specification, differentiation, axon targeting, and functional diversification. A temporal regulatory cascade defines the initial precursors through factors such as Smarca4, Six1, Eya1, followed by Sox2. While Sox2 deletion abolishes hair cell formation, a subset of inner ear neurons transiently develops but undergoes apoptosis before birth. In contrast, Neurog1 deletion eliminates all ear-derived neurons but results in differential reductions in cochlear and vestibular hair cells. The development and survival of inner ear neurons depend on TrkB and TrkC signaling. Although deletion of TrkB and TrkC results in a complete loss of neurons, each shows distinct effects on VGN and SGN survival and innervation. Downstream of early transcriptional regulators, Neurod1 and Isl1 promote neuronal differentiation, survival, migration, and the formation of peripheral and central projections. The development of VGNs depends on at least two progenitor populations that give rise to three neuronal subtypes that differ in their innervation of vestibular hair cells but show incomplete segregation in the vestibular nuclei. In contrast, SGNs develop later and exhibit sequential segregation into four neuronal subtypes, corresponding to the two types of cochlear hair cells, with tonotopically organized projections to both the cochlea and cochlear nuclei.

Age-related auditory dysfunction affects half of all individuals 60 years and older, yet its causes are poorly understood. While commonly associated with cochlear dysfunction, a growing body of literature suggests that dysfunction originating in the auditory cortex itself is also a major contributor. Here, we review recent literature that describes the effects of aging on the primary auditory cortex in humans, non-human primates, rodents, and a variety of other species. During aging, individuals with auditory cortical dysfunction experience deficits in spectral and temporal processing of sounds, resulting not only from a loss of inhibition but also from an extensive restructuring of cortical circuits. Importantly, aging in the auditory cortex is sex-dependent, yet few studies account for this variable. A lack of comprehensive knowledge on aging in the auditory cortex hinders the path toward restoring cortical function through auditory training or broader cortical rehabilitation paradigms. Thus, we propose a cohesive mechanism of aging in the primary auditory cortex that involves a complex interaction between excitatory and inhibitory neurons, which several factors can modify. These factors include input from higher-order cortical areas, such as the orbitofrontal cortex, as well as the wide-ranging effects of neuromodulators and the external sensory environment, which must be accounted for in a sex-dependent manner.

Birds have contributed to important hearing-science discoveries. Examples include cochlear development, hair cell regeneration and brainstem circuit organization in chickens, sound localization in owls, vocal learning in songbirds, and cognition in parrots and corvids. Recent findings demonstrate the power and relevance of the avian cortex in studying auditory function.

Inner ear research has experienced exponential growth for the last fifty years spurring the creation of novel scientific approaches and clinical intervention strategies. Here we utilize data mining of publicly available records (PubMed, NIHReporter, and ClinicalTrials.gov) to assess the rate of inner ear research output quantitatively. We combined this approach with systematic review of published literature to understand the prevalence and monetary costs of seeking treatment for hearing and balance. The data show that the expansive growth period of inner ear research presents a new challenge for scientists and clinicians as auditory research output metrics have begun to significantly outpace vestibular research. There are unique challenges associated with diagnosing and treating patients with vestibular dysfunction that may explain some of the discrepancies in research output. A renewed enthusiasm to investigate the vestibular system may help facilitate broader understanding of the inner ear and has potential to produce improved scientific methods and clinical interventions for patients.