Journal of the Association for Research in Otolaryngology 2024-06-01

Tinnitus: Clinical Insights in Its Pathophysiology-A Perspective

B Langguth,D de Ridder,W Schlee,T Kleinjung

Publication date 01-06-2024


Tinnitus, the perception of sound without a corresponding external sound source, and tinnitus disorder, which is tinnitus with associated suffering, present a multifaceted clinical challenge due to its heterogeneity and its incompletely understood pathophysiology and especially due to the limited therapeutic options. In this narrative review, we give an overview on various clinical aspects of tinnitus including its heterogeneity, contributing factors, comorbidities and therapeutic pathways with a specific emphasis on the implications for its pathophysiology and future research directions. Tinnitus exhibits high perceptual variability between affected individuals (heterogeneity) and within affected individuals (temporal variability). Hearing loss emerges as predominant risk factor and the perceived pitch corresponds to areas of hearing loss, supporting the compensatory response theory. Whereas most people who have tinnitus can live a normal life, in 10–20% tinnitus interferes severely with quality of life. These patients suffer frequently from comorbidities such as anxiety, depression or insomnia, acting as both risk factors and consequences. Accordingly, neuroimaging studies demonstrate shared brain networks between tinnitus and stress-related disorders shedding light on the intricate interplay of mental health and tinnitus. The challenge lies in deciphering causative relationships and shared pathophysiological mechanisms. Stress, external sounds, time of day, head movements, distraction, and sleep quality can impact tinnitus perception. Understanding these factors provides insights into the interplay with autonomic, sensory, motor, and cognitive processes. Counselling and cognitive-behavioural therapy demonstrate efficacy in reducing suffering, supporting the involvement of stress and anxiety-related networks. Hearing improvement, especially through cochlear implants, reduces tinnitus and thus indirectly validates the compensatory nature of tinnitus. Brain stimulation techniques can modulate the suffering of tinnitus, presumably by alteration of stress-related brain networks. Continued research is crucial for unravelling the complexities of tinnitus. Progress in management hinges on decoding diverse manifestations, identifying treatment-responsive subtypes, and advancing targeted therapeutic approaches.

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Hampshire Sheep as a Large-Animal Model for Cochlear Implantation

NA Waring,A Chern,BJ Vilarello,YS Cheng,C Zhou,JH Lang,ES Olson,HH Nakajima

Publication date 01-06-2024


Background Sheep have been proposed as a large-animal model for studying cochlear implantation. However, prior sheep studies report that the facial nerve (FN) obscures the round window membrane (RWM), requiring FN sacrifice or a retrofacial opening to access the middle-ear cavity posterior to the FN for cochlear implantation. We investigated surgical access to the RWM in Hampshire sheep compared to Suffolk-Dorset sheep and the feasibility of Hampshire sheep for cochlear implantation via a facial recess approach. Methods Sixteen temporal bones from cadaveric sheep heads (ten Hampshire and six Suffolk-Dorset) were dissected to gain surgical access to the RWM via an extended facial recess approach. RWM visibility was graded using St. Thomas’ Hospital (STH) classification. Cochlear implant (CI) electrode array insertion was performed in two Hampshire specimens. Micro-CT scans were obtained for each temporal bone, with confirmation of appropriate electrode array placement and segmentation of the inner ear structures. Results Visibility of the RWM on average was 83% in Hampshire specimens and 59% in Suffolk-Dorset specimens (p = 0.0262). Hampshire RWM visibility was Type I (100% visibility) for three specimens and Type IIa (> 50% visibility) for seven specimens. Suffolk-Dorset RWM visibility was Type IIa for four specimens and Type IIb (< 50% visibility) for two specimens. FN appeared to course more anterolaterally in Suffolk-Dorset specimens. Micro-CT confirmed appropriate CI electrode array placement in the scala tympani without apparent basilar membrane rupture. Conclusions Hampshire sheep appear to be a suitable large-animal model for CI electrode insertion via an extended facial recess approach without sacrificing the FN. In this small sample, Hampshire specimens had improved RWM visibility compared to Suffolk-Dorset. Thus, Hampshire sheep may be superior to other breeds for ease of cochlear implantation, with FN and facial recess anatomy more similar to humans.

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Echolocating Bats Have Evolved Decreased Susceptibility to Noise-Induced Temporary Hearing Losses

AM Simmons,JA Simmons

Publication date 01-06-2024


Glenis Long championed the application of quantitative psychophysical methods to understand comparative hearing abilities across species. She contributed the first psychophysical studies of absolute and masked hearing sensitivities in an auditory specialist, the echolocating horseshoe bat. Her data demonstrated that this bat has hyperacute frequency discrimination in the 83-k Hz range of its echolocation broadcast. This specialization facilitates the bat’s use of Doppler shift compensation to separate echoes of fluttering insects from concurrent echoes of non-moving objects. In this review, we discuss another specialization for hearing in a species of echolocating bat that contributes to perception of echoes within a complex auditory scene. Psychophysical and behavioral studies with big brown bats show that exposures to long duration, intense wideband or narrowband ultrasonic noise do not induce significant increases in their thresholds to echoes and do not impair their ability to orient through a naturalistic sonar scene containing multiple distracting echoes. Thresholds of auditory brainstem responses also remain low after intense noise exposures. These data indicate that big brown bats are not susceptible to temporary threshold shifts as measured in comparable paradigms used with other mammals, at least within the range of stimulus parameters that have been tested so far. We hypothesize that echolocating bats have evolved a decreased susceptibility to noise-induced hearing losses as a specialization for echolocation in noisy environments.

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Tinnitus in Children

DJ Hoare,H Smith,V Kennedy,K Fackrell

Publication date 01-06-2024


This perspective reviews the current state of the art and literature on tinnitus in children, prevalence and risk factors, clinical management, and future priorities for healthcare provision and research. Most research in the field to date appears to be prevalence studies, which have reached dramatically different estimates; this reflects the lack of a standard language when asking about the presence of tinnitus, or how bothersome, distressing, or negatively impacting it is for the child. Estimates are also likely affected by a lack of awareness of tinnitus amongst children and parents. Children are less likely to spontaneously report tinnitus than adults, and parents are often unaware their child could even develop tinnitus, considering it a disease of older age for example. It is critical that children are asked and learn about tinnitus. In hearing clinics, clinicians should routinely ask about all children about tinnitus and offer tinnitus care and settings that are child- and family-friendly. As well as asking directly, clinicians should be alert to soft signs of tinnitus such as unexplained listening, speech perception, concentration difficulties, worry or anxiety, or difficulties completing hearing tests or using hearing aids. The recently developed impact of Tinnitus in Children Questionnaire (iTICQ) can then be used to assess problems that are most commonly core to children’s experience of tinnitus. Clinical guidelines for tinnitus in children are few but provide recommendations for additional paediatric questionnaires and alternative assessments and for a range of treatment options. Of note, however, is the lack of clinical trials and, therefore, evidence of the effectiveness of any treatment for tinnitus in children. Significant and concerted work is therefore needed to raise awareness of tinnitus in children, understand the scale of clinical need, and standardise and evaluate clinical management options.

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Mechanical Effects of Medical Device Attachment to Human Tympanic Membrane

A Ebrahimian,H Mohammadi,N Maftoon

Publication date 01-06-2024


Purpose Several treatment methods for hearing disorders rely on attaching medical devices to the tympanic membrane. This study aims to systematically analyze the effects of the material and geometrical properties and location of the medical devices attached to the tympanic membrane on middle-ear vibrations. Methods A finite-element model of the human middle ear was employed to simulate the effects of attachment of medical devices. Various types of material and geometrical properties, locations, and modeling scenarios were investigated for the medical device. Results The attachment of the device magnifies the effects of anti-resonances of the middle ear. Additionally, the variations of the material properties of the device significantly alter the middle-ear resonance frequency while changes in the umbo and stapes footplate motions are negligible at frequencies above 5 k Hz. Furthermore, modeling the device as a point mass cannot accurately represent the implanted middle-ear behavior. The variations of the diameter and height of the medical device have negligible effects on the middle-ear vibrations at frequencies below 200 Hz but can have considerable impacts at higher frequencies. The effects of changing the device height were negligible at frequencies above 2 k Hz. We also discuss the effects of medical device attachment on the vibration patterns of the tympanic membrane as well as the impacts of the variations of the location of the device on the stapes footplate responses. Conclusion The findings of our study aid the development and optimization of new therapeutic devices, attached to the tympanic membrane, to have the least adverse effects on middle-ear vibrations.

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FDA-Approved Tedizolid Phosphate Prevents Cisplatin-Induced Hearing Loss Without Decreasing Its Anti-tumor Effect

Z Yao,Y Xiao,W Li,S Kong,H Tu,S Guo,Z Liu,L Ma,R Qiao,S Wang,M Chang,X Zhao,Y Zhang,L Xu,D Sun,X Fu

Publication date 01-06-2024


Purpose Cisplatin is a low-cost clinical anti-tumor drug widely used to treat solid tumors. However, its use could damage cochlear hair cells, leading to irreversible hearing loss. Currently, there appears one drug approved in clinic only used for reducing ototoxicity associated with cisplatin in pediatric patients, which needs to further explore other candidate drugs. Methods Here, by screening 1967 FDA-approved drugs to protect cochlear hair cell line (HEI-OC1) from cisplatin damage, we found that Tedizolid Phosphate (Ted), a drug indicated for the treatment of acute infections, had the best protective effect. Further, we evaluated the protective effect of Ted against ototoxicity in mouse cochlear explants, zebrafish, and adult mice. The mechanism of action of Ted was further explored using RNA sequencing analysis and verified. Meanwhile, we also observed the effect of Ted on the anti-tumor effect of cisplatin. Results Ted had a strong protective effect on hair cell (HC) loss induced by cisplatin in zebrafish and mouse cochlear explants. In addition, when administered systemically, it protected mice from cisplatin-induced hearing loss. Moreover, antitumor studies showed that Ted had no effect on the antitumor activity of cisplatin both in vitro and in vivo. RNA sequencing analysis showed that the otoprotective effect of Ted was mainly achieved by inhibiting phosphorylation of ERK. Consistently, ERK activator aggravated the damage of cisplatin to HCs. Conclusion Collectively, these results showed that FDA-approved Ted protected HCs from cisplatin-induced HC loss by inhibiting ERK phosphorylation, indicating its potential as a candidate for preventing cisplatin ototoxicity in clinical settings.

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Optimal Scale-Invariant Wavelet Representation and Filtering of Human Otoacoustic Emissions

A Moleti

Publication date 24-05-2024


Otoacoustic emissions (OAEs) are generated in the cochlea and recorded in the ear canal either as a time domain waveform or as a collection of complex responses to tones in the frequency domain (Probst et al. J Account Soc Am 89:2027–2067, 1991). They are typically represented either in their original acquisition domain or in its Fourier-conjugated domain. Round-trip excursions to the conjugated domain are often used to perform filtering operations in the computationally simplest way, exploiting the convolution theorem. OAE signals consist of the superposition of backward waves generated in different cochlear regions by different generation mechanisms, over a wide frequency range. The cochlear scaling symmetry (cochlear physics is the same at all frequency scales), which approximately holds in the human cochlea, leaves its fingerprints in the mathematical properties of OAE signals. According to a generally accepted taxonomy (Sher and Guinan Jr, J Acoust Soc Am 105:782–798, 1999), OAEs are generated either by wave-fixed sources, moving with frequency according with the cochlear scaling (as in nonlinear distortion) or by place-fixed sources (as in coherent reflection by roughness). If scaling symmetry holds, the two generation mechanisms yield OAEs with different phase gradient delay: almost null for wave-fixed sources, and long (and scaling as 1/f) for place-fixed sources. Thus, the most effective representation of OAE signals is often that respecting the cochlear scale-invariance, such as the time-frequency domain representation provided by the wavelet transform. In the time-frequency domain, the elaborate spectra or waveforms yielded by the superposition of OAE components from different generation mechanisms assume a much clearer 2-D pattern, with each component localized in a specific and predictable region. The wavelet representation of OAE signals is optimal both for visualization purposes and for designing filters that effectively separate different OAE components, improving both the specificity and the sensitivity of OAE-based applications. Indeed, different OAE components have different physiological meanings, and filtering dramatically improves the signal-to-noise ratio.

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Polygenic Risk Score-Based Association Analysis Identifies Genetic Comorbidities Associated with Age-Related Hearing Difficulty in Two Independent Samples

IS Bhatt,JA Raygoza Garay,SG Bhagavan,V Ingalls,R Dias,A Torkamani

Publication date 23-05-2024


Purpose Age-related hearing loss is the most common form of permanent hearing loss that is associated with various health traits, including Alzheimer’s disease, cognitive decline, and depression. The present study aims to identify genetic comorbidities of age-related hearing loss. Past genome-wide association studies identified multiple genomic loci involved in common adult-onset health traits. Polygenic risk scores (PRS) could summarize the polygenic inheritance and quantify the genetic susceptibility of complex traits independent of trait expression. The present study conducted a PRS-based association analysis of age-related hearing difficulty in the UK Biobank sample (N = 425,240), followed by a replication analysis using hearing thresholds (HTs) and distortion-product otoacoustic emissions (DPOAEs) in 242 young adults with self-reported normal hearing. We hypothesized that young adults with genetic comorbidities associated with age-related hearing difficulty would exhibit subclinical decline in HTs and DPOAEs in both ears. Methods A total of 111,243 participants reported age-related hearing difficulty in the UK Biobank sample (> 40 years). The PRS models were derived from the polygenic risk score catalog to obtain 2627 PRS predictors across the health spectrum. HTs (0.25–16 k Hz) and DPOAEs (1–16 k Hz, L1/L2 = 65/55 dB SPL, F2/F1 = 1.22) were measured on 242 young adults. Saliva-derived DNA samples were subjected to low-pass whole genome sequencing, followed by genome-wide imputation and PRS calculation. The logistic regression analyses were performed to identify PRS predictors of age-related hearing difficulty in the UK Biobank cohort. The linear mixed model analyses were performed to identify PRS predictors of HTs and DPOAEs. Results The PRS-based association analysis identified 977 PRS predictors across the health spectrum associated with age-related hearing difficulty. Hearing difficulty and hearing aid use PRS predictors revealed the strongest association with the age-related hearing difficulty phenotype. Youth with a higher genetic predisposition to hearing difficulty revealed a subclinical elevation in HTs and a decline in DPOAEs in both ears. PRS predictors associated with age-related hearing difficulty were enriched for mental health, lifestyle, metabolic, sleep, reproductive, digestive, respiratory, hematopoietic, and immune traits. Fifty PRS predictors belonging to various trait categories were replicated for HTs and DPOAEs in both ears. Conclusion The study identified genetic comorbidities associated with age-related hearing loss across the health spectrum. Youth with a high genetic predisposition to age-related hearing difficulty and other related complex traits could exhibit sub-clinical decline in HTs and DPOAEs decades before clinically meaningful age-related hearing loss is observed. We posit that effective communication of genetic risk, promoting a healthy lifestyle, and reducing exposure to environmental risk factors at younger ages could help prevent or delay the onset of age-related hearing difficulty at older ages.

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Correction: Something in Our Ears Is Oscillating, but What? A Modeller’s View of Efforts to Model Spontaneous Emissions

HP Wit,A Bell

Publication date 20-05-2024


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The Rapid Decline in Interaural-Time-Difference Sensitivity for Pure Tones Can Be Explained by Peripheral Filtering

MJ Goupell,GC Stecker,BT Williams,A Bilokon,DJ Tollin

Publication date 20-05-2024


Purpose The interaural time difference (ITD) is a primary horizontal-plane sound localization cue computed in the auditory brainstem. ITDs are accessible in the temporal fine structure of pure tones with a frequency of no higher than about 1400 Hz. How listeners’ ITD sensitivity transitions from very best sensitivity near 700 Hz to impossible to detect within 1 octave currently lacks a fully compelling physiological explanation. Here, it was hypothesized that the rapid decline in ITD sensitivity is dictated not by a central neural limitation but by initial peripheral sound encoding, specifically, the low-frequency (apical) portion of the cochlear excitation pattern produced by a pure tone. Methods ITD sensitivity was measured in 16 normal-hearing listeners as a joint function of frequency (900–1500 Hz) and level (10–50 dB sensation level). Results Performance decreased with increasing frequency and decreasing sound level. The slope of performance decline was 90 dB/octave, consistent with the low-frequency slope of the cochlear excitation pattern. Conclusion Fine-structure ITD sensitivity near 1400 Hz may be conveyed primarily by “off-frequency” activation of neurons tuned to lower frequencies near 700 Hz. Physiologically, this could be realized by having neurons sensitive to fine-structure ITD up to only about 700 Hz. A more extreme model would have only a single narrow channel near 700 Hz that conveys fine-structure ITDs. Such a model is a major simplification and departure from the classic formulation of the binaural display, which consists of a matrix of neurons tuned to a wide range of relevant frequencies and ITDs.

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SVPath: A Deep Learning Tool for Analysis of Stria Vascularis from Histology Slides

A Jain,D Perdomo,N Nagururu,JA Li,BK Ward,AM Lauer,FX Creighton

Publication date 17-05-2024


Introduction The stria vascularis (SV) may have a significant role in various otologic pathologies. Currently, researchers manually segment and analyze the stria vascularis to measure structural atrophy. Our group developed a tool, SVPath, that uses deep learning to extract and analyze the stria vascularis and its associated capillary bed from whole temporal bone histopathology slides (TBS). Methods This study used an internal dataset of 203 digitized hematoxylin and eosin-stained sections from a normal macaque ear and a separate external validation set of 10 sections from another normal macaque ear. SVPath employed deep learning methods YOLOv8 and nn Unet to detect and segment the SV features from TBS, respectively. The results from this process were analyzed with the SV Analysis Tool (SVAT) to measure SV capillaries and features related to SV morphology, including width, area, and cell count. Once the model was developed, both YOLOv8 and nn Unet were validated on external and internal datasets. Results YOLOv8 implementation achieved over 90% accuracy for cochlea and SV detection. nn Unet SV segmentation achieved a DICE score of 0.84–0.95; the capillary bed DICE score was 0.75–0.88. SVAT was applied to compare both the ears used in the study. There was no statistical difference in SV width, SV area, and average area of capillary between the two ears. There was a statistical difference between the two ears for the cell count per SV. Conclusion The proposed method accurately and efficiently analyzes the SV from temporal histopathology bone slides, creating a platform for researchers to understand the function of the SV further.

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Conditions Underlying the Appearance of Spontaneous Otoacoustic Emissions in Mammals

GA Manley

Publication date 17-05-2024


Across the wide range of land vertebrate species, spontaneous otoacoustic emissions (SOAE) are common, but not always found. The reasons for the differences between species of the various groups in their emission patterns are often not well understood, particularly within mammals. This review examines the question as to what determines in mammals whether SOAE are emitted or not, and suggests that the coupling between hair-cell regions diminishes when the space constant of frequency distribution becomes larger. The reduced coupling is assumed to result in a greater likelihood of SOAE being emitted.

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Something in Our Ears Is Oscillating, but What? A Modeller’s View of Efforts to Model Spontaneous Emissions

HP Wit,A Bell

Publication date 06-05-2024


When David Kemp discovered “spontaneous ear noise” in 1978, it opened up a whole new perspective on how the cochlea works. The continuous tonal sound emerging from most healthy human ears, now called spontaneous otoacoustic emissions or SOAEs, was an unmistakable sign that our hearing organ must be considered an active detector, not just a passive microphone, just as Thomas Gold had speculated some 30 years earlier. Clearly, something is oscillating as a byproduct of that sensitive inbuilt detector, but what exactly is it? Here, we give a chronological account of efforts to model SOAEs as some form of oscillator, and at intervals, we illustrate key concepts with numerical simulations. We find that after many decades there is still no consensus, and the debate extends to whether the oscillator is local, confined to discrete local sources on the basilar membrane, or global, in which an assembly of micro-mechanical elements and basilar membrane sections, coupled by inner ear fluid, interact over a wide region. It is also undecided whether the cochlear oscillator is best described in terms of the well-known Van der Pol oscillator or the less familiar Duffing or Hopf oscillators. We find that irregularities play a key role in generating the emissions. This paper is not a systematic review of SOAEs and their properties but more a historical survey of the way in which various oscillator configurations have been applied to modelling human ears. The conclusion is that the difference between the local and global approaches is not clear-cut, and they are probably not mutually exclusive concepts. Nevertheless, when one sees how closely human SOAEs can be matched to certain arrangements of oscillators, Gold would no doubt say we are on the right track.

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Measuring Optokinetic Reflex and Vestibulo-Ocular Reflex in Unilateral Vestibular Organ Damage Model of Zebrafish

KH Lim,HK Kim,S Park,E Han,I Song,HS Yoon,J Kim,Y Lee,YH Jang,YC Rah,SH Lee,J Choi

Publication date 01-04-2024


One-sided vestibular disorders are common in clinical practice; however, their models have not been fully established. We investigated the effect of unilateral or bilateral deficits in the vestibular organs on the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) of zebrafish using in-house equipment. For physical dislodgement of the otoliths in the utricles of zebrafish larvae, one or both utricles were separated from the surrounding tissue using glass capillaries. The video data from VOR and OKR tests with the larvae was collected and processed using digital signal processing techniques such as fast Fourier transform and low-pass filters. The results showed that unilateral and bilateral damage to the vestibular system significantly reduced VOR and OKR. In contrast, no significant difference was observed between unilateral and bilateral damage. This study confirmed that VOR and OKR were significantly reduced in zebrafish with unilateral and bilateral vestibular damage. Follow-up studies on unilateral vestibular disorders can be conducted using this tool.

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Swept Along: Measuring Otoacoustic Emissions Using Continuously Varying Stimuli

CA Shera

Publication date 01-04-2024


At the 2004 Midwinter Meeting of the Association for Research in Otolaryngology, Glenis Long and her colleagues introduced a method for measuring distortion-product otoacoustic emissions (DPOAEs) using primary-tone stimuli whose instantaneous frequencies vary continuously with time. In contrast to standard OAE measurement methods, in which emissions are measured in the sinusoidal steady state using discrete tones of well-defined frequency, the swept-tone method sweeps across frequency, often at rates exceeding 1 oct/s. The resulting response waveforms are then analyzed using an appropriate filter (e.g., by least-squares fitting). Although introduced as a convenient way of studying DPOAE fine structure by separating the total OAE into distortion and reflection components, the swept-tone method has since been extended to stimulus-frequency emissions and has proved an efficient and valuable tool for probing cochlear mechanics. One day—a long time coming—swept tones may even find their way into the audiology clinic.

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Exploring the Use of Interleaved Stimuli to Measure Cochlear-Implant Excitation Patterns

F Guérit,JC Middlebrooks,R Gransier,ML Richardson,J Wouters,RP Carlyon

Publication date 01-04-2024


Purpose Attempts to use current-focussing strategies with cochlear implants (CI) to reduce neural spread-of-excitation have met with only mixed success in human studies, in contrast to promising results in animal studies. Although this discrepancy could stem from between-species anatomical and aetiological differences, the masking experiments used in human studies may be insufficiently sensitive to differences in excitation-pattern width. Methods We used an interleaved-masking method to measure psychophysical excitation patterns in seven participants with four masker stimulation configurations: monopolar (MP), partial tripolar (pTP), a wider partial tripolar (pTP + 2), and, importantly, a condition (RP + 2) designed to produce a broader excitation pattern than MP. The probe was always in partial-tripolar configuration. Results We found a significant effect of stimulation configuration on both the amount of on-site masking (mask and probe on same electrode; an indirect indicator of sharpness) and the difference between off-site and on-site masking. Differences were driven solely by RP + 2 producing a broader excitation pattern than the other configurations, whereas monopolar and the two current-focussing configurations did not statistically differ from each other. Conclusion A method that is sensitive enough to reveal a modest broadening in RP + 2 showed no evidence for sharpening with focussed stimulation. We also showed that although voltage recordings from the implant accurately predicted a broadening of the psychophysical excitation patterns with RP + 2, they wrongly predicted a strong sharpening with pTP + 2. We additionally argue, based on our recent research, that the interleaved-masking method can usefully be applied to non-human species and objective measures of CI excitation patterns.

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Frequency-Following Responses in Sensorineural Hearing Loss: A Systematic Review

L Jacxsens,L Biot,C Escera,A Gilles,E Cardon,V Van Rompaey,W De Hertogh,MJW Lammers

Publication date 01-04-2024


Purpose This systematic review aims to assess the impact of sensorineural hearing loss (SNHL) on various frequency-following response (FFR) parameters. Methods Following PRISMA guidelines, a systematic review was conducted using Pub Med, Web of Science, and Scopus databases up to January 2023. Studies evaluating FFRs in patients with SNHL and normal hearing controls were included. Results Sixteen case–control studies were included, revealing variability in acquisition parameters. In the time domain, patients with SNHL exhibited prolonged latencies. The specific waves that were prolonged differed across studies. There was no consensus regarding wave amplitude in the time domain. In the frequency domain, focusing on studies that elicited FFRs with stimuli of 170 ms or longer, participants with SNHL displayed a significantly smaller fundamental frequency (F0). Results regarding changes in the temporal fine structure (TFS) were inconsistent. Conclusion Patients with SNHL may require more time for processing (speech) stimuli, reflected in prolonged latencies. However, the exact timing of this delay remains unclear. Additionally, when presenting longer stimuli (≥ 170 ms), patients with SNHL show difficulties tracking the F0 of (speech) stimuli. No definite conclusions could be drawn on changes in wave amplitude in the time domain and the TFS in the frequency domain. Patient characteristics, acquisition parameters, and FFR outcome parameters differed greatly across studies. Future studies should be performed in larger and carefully matched subject groups, using longer stimuli presented at the same intensity in dB HL for both groups, or at a carefully determined maximum comfortable loudness level.

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Pneumococcal Meningitis Induces Hearing Loss and Cochlear Ossification Modulated by Chemokine Receptors CX3CR1 and CCR2

K Hirose,SZ Li,R Gill,J Hartsock

Publication date 01-04-2024


Purpose Pneumococcal meningitis is a major cause of hearing loss and permanent neurological impairment despite widely available antimicrobial therapies to control infection. Methods to improve hearing outcomes for those who survive bacterial meningitis remains elusive. We used a mouse model of pneumococcal meningitis to evaluate the impact of mononuclear phagocytes on hearing outcomes and cochlear ossification by altering the expression of CX3CR1 and CCR2 in these infected mice. Methods We induced pneumococcal meningitis in approximately 500 C57Bl6 adult mice using live Streptococcus pneumoniae (serotype 3, 1 × 105 colony forming units (cfu) in 10 µl) injected directly into the cisterna magna of anesthetized mice and treated these mice with ceftriaxone daily until recovered. We evaluated hearing thresholds over time, characterized the cochlear inflammatory response, and quantified the amount of new bone formation during meningitis recovery. We used microcomputed tomography (microCT) scans to quantify cochlear volume loss caused by neo-ossification. We also performed perilymph sampling in live mice to assess the integrity of the blood-perilymph barrier during various time intervals after meningitis. We then evaluated the effect of CX3CR1 or CCR2 deletion in meningitis symptoms, hearing loss, macrophage/monocyte recruitment, neo-ossification, and blood labyrinth barrier function. Results Sixty percent of mice with pneumococcal meningitis developed hearing loss. Cochlear fibrosis could be detected within 4 days of infection, and neo-ossification by 14 days. Loss of spiral ganglion neurons was common, and inner ear anatomy was distorted by scarring caused by new soft tissue and bone deposited within the scalae. The blood-perilymph barrier was disrupted at 3 days post infection (DPI) and was restored by seven DPI. Both CCR2 and CX3CR1 monocytes and macrophages were present in the cochlea in large numbers after infection. Neither chemokine receptor was necessary for the induction of hearing loss, cochlear fibrosis, ossification, or disruption of the blood-perilymph barrier. CCR2 knockout (KO) mice suffered the most severe hearing loss. CX3CR1 KO mice demonstrated an intermediate phenotype with greater susceptibility to hearing loss compared to control mice. Elimination of CX3CR1 mononuclear phagocytes during the first 2 weeks after meningitis in CX3CR1-DTR transgenic mice did not protect mice from any of the systemic or hearing sequelae of pneumococcal meningitis. Conclusions Pneumococcal meningitis can have devastating effects on cochlear structure and function, although not all mice experienced hearing loss or cochlear damage. Meningitis can result in rapid progression of hearing loss with fibrosis starting at four DPI and ossification within 2 weeks of infection detectable by light microscopy. The inflammatory response to bacterial meningitis is robust and can affect all three scalae. Our results suggest that CCR2 may assist in controlling infection and maintaining cochlear patency, as CCR2 knockout mice experienced more severe disease, more rapid hearing loss, and more advanced cochlear ossification after pneumococcal meningitis. CX3CR1 also may play an important role in the maintenance of cochlear patency.

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Tinnitus: A Dimensionally Segregated, yet Perceptually Integrated Heterogeneous Disorder

A Yasoda-Mohan,K Adcock,SL Leong,E Meade,B Langguth,M Schecklmann,H Lim,S Vanneste

Publication date 01-04-2024


Objectives Tinnitus subtypes are proposed to lie on a continuum of different symptom dimensions rather than be categorical. However, there is no comprehensive empirical data showing this complex relationship between different tinnitus symptoms. The objective of this study is to provide empirical evidence for the dimensional nature of tinnitus and how different auditory and non-auditory symptoms interact with each other through complex interactions. We do this using graph theory, a mathematical tool that empirically maps this complex interaction. This way, graph theory can be utilised to highlight a new and possibly important outlook on how we can understand the heterogeneous nature of tinnitus. Design In the current study, we use the screening databases of the Treatment Evaluation of Neuromodulation for Tinnitus-Stage A1 (TENT-A1) and A2 (TENT-A2) randomised trials to delineate the dimensional relationship between different clinical measures of tinnitus as a secondary data analysis. We first calculate the empirical relationship by computing the partial correlation. Following this, we use different measures of centrality to describe the contribution of different clinical measures to the overall network. We also calculate the stability of the network and compare the similarity and differences between TENT-A1 and TENT-A2. Results Components of the auditory subnetwork (loudness discomfort level, sound sensitivity, average hearing loss and high frequency hearing loss) are highly inter-connected in both networks with sound sensitivity and loudness discomfort level being highly influential with high measures of centrality. Furthermore, the relationship between the densely connected auditory subnetwork with tinnitus-related distress seems to vary at different levels of distress, hearing loss, duration and age of the participants. Conclusion Our findings provide first-time evidence for tinnitus varying in a dimensional fashion illustrating the heterogeneity of this phantom percept and its ability to be perceptually integrated, yet behaviourally segregated on different symptomatic dimensions.

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A Low Dose of Rapamycin Promotes Hair Cell Differentiation by Enriching SOX2+ Progenitors in the Neonatal Mouse Inner Ear Organoids

W Wu,P Chen,J Yang,Y Liu

Publication date 01-04-2024


Purpose To investigate the impact of rapamycin on the differentiation of hair cells. Methods Murine cochlear organoids were derived from cochlear progenitor cells. Different concentrations of rapamycin were added into the culture medium at different proliferation and differentiation stages. Results Rapamycin exhibited a concentration-dependent reduction in the proliferation of these inner ear organoids. Nevertheless, organoids subjected to a 10-nM dose of rapamycin demonstrated a markedly increased proportion of hair cells. Furthermore, rapamycin significantly upregulated the expression of markers associated with both hair cells and supporting cells, including ATOH1, MYO7A, and SOX2. Mechanistic studies revealed that rapamycin preferentially suppressed cells without Sox2 expression during the initial proliferation stage, thereby augmenting and refining the population of SOX2+ progenitors. These enriched progenitors were predisposed to differentiate into hair cells during the later stages of organoid development. Conversely, the use of the mTOR activator MHY 1485 demonstrated opposing effects. Conclusion Our findings underscore a practical strategy for enhancing the generation of inner ear organoids with a low dose of rapamycin, achieved by enriching SOX2+ progenitors in an in vitro setting.

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