Verification of Estimated Output Signal-to-Noise Ratios From a Phase Inversion Technique Using a Simulated Hearing Aid.

PURPOSE: The signal-to-noise ratio (SNR) for speech presented in background noise may vary after being processed by digital hearing aids with nonlinear signal processing algorithms, such as wide dynamic range compression (WDRC). A phase inversion technique has been previously developed to assess the output SNR of hearing aids. However, systematic validations of this technique have not been conducted. This study aims to validate the phase inversion technique. METHOD: A simulated hearing aid with multichannel WDRC was implemented, from which the output SNRs, computed via shadow filtering, for connected speech in background noise were directly computed. The agreement between the shadow filter output SNRs and those estimated using the phase inversion technique for the same stimuli was utilized to validate the phase inversion technique. The background noise was 2- or 20-talker babble noise, and the speech stimuli were presented at SNRs of -10 to +10 dB at the input of the simulated hearing aid. The simulated hearing aid was configured to provide amplification for four representative audiograms, and the WDRC was set to be fast or slow acting. To investigate the effects of additive noise, independent of the presented noise stimulus, on the phase inversion estimated output SNR, the same simulated hearing aid was implemented with an additive Gaussian noise at its input (45 and 60 dB SPL). RESULTS: Results showed that the phase inversion technique could either overestimate or underestimate output SNR, depending on the test condition; the estimation errors tended to coincide with temporal landmarks, such as natural pauses between consecutive sentences or fricatives; and increasing the simulated noise led to poorer estimates of output SNR. CONCLUSIONS: Results imply that the accuracy of the phase inversion technique is dependent on the test conditions. Thus, the phase inversion technique should be used with caution, and its validity should be evaluated further.

Merging the Psychophysical Function With Response Times for Auditory Detection of One vs. Two Tones.

The purpose of this study is to take preliminary steps to unify psychoacoustic techniques with reaction-time methodologies to address the perceptual mechanisms responsible for the detection of one vs. multiple sounds. We measured auditory redundancy gains for auditory detection of pure tones widely spaced in frequency using the tools of Systems Factorial Technology to evince the system architecture and workload capacity in two different scenarios (SOFT and LOUD). We adopted an experimental design in which the presence or absence of a target at each of two frequencies was combined factorially with two stimulus levels. Replicating previous work, results did not allow an assessment of system architecture due to a failure to observe factor influence at the level of distribution ordering for dual-target stimuli for both SOFT and LOUD scenarios. All subjects demonstrated very modest redundancy gains for the dual-target compared to the single-target stimuli, and results were similar for both LOUD and SOFT. We propose that these results can be predicted by a mental architecture that falls into the class of integrated subadditive parallel systems, using a well-supported assumption that reaction time is driven by loudness. We demonstrate that modeled loudness of the experimental sounds (which ranged between about 0.2 and 14 sones) is highly correlated with mean reaction time (r = -0.87), and we provide a proof-of-concept model based on Steven's Power law that predicts both a failure of distributional ordering for dual-target stimuli and very modest redundancy gains.

Altering gene expression using antisense oligonucleotide therapy for hearing loss.

Hearing loss affects more than 430 million people, worldwide, and is the third most common chronic physical condition in the United States and Europe (GBD Hearing Loss Collaborators, 2021; NIOSH, 2021; WHO, 2021). The loss of hearing significantly impacts motor and cognitive development, communication, education, employment, and overall quality of life. The inner ear houses the sensory organs for both hearing and balance and provides an accessible target for therapeutic delivery. Antisense oligonucleotides (ASOs) use various mechanisms to manipulate gene expression and can be tailor-made to treat disorders with defined genetic targets. In this review, we discuss the preclinical advancements within the field of the highly promising ASO-based therapies for hereditary hearing loss disorders. Particular focus is on ASO mechanisms of action, preclinical studies on ASO treatments of hearing loss, timing of therapeutic intervention, and delivery routes to the inner ear.

Conversations in Cochlear Implantation: The Inner Ear Therapy of Today.

As biomolecular approaches for hearing restoration in profound sensorineural hearing loss evolve, they will be applied in conjunction with or instead of cochlear implants. An understanding of the current state-of-the-art of this technology, including its advantages, disadvantages, and its potential for delivering and interacting with biomolecular hearing restoration approaches, is helpful for designing modern hearing-restoration strategies. Cochlear implants (CI) have evolved over the last four decades to restore hearing more effectively, in more people, with diverse indications. This evolution has been driven by advances in technology, surgery, and healthcare delivery. Here, we offer a practical treatise on the state of cochlear implantation directed towards developing the next generation of inner ear therapeutics. We aim to capture and distill conversations ongoing in CI research, development, and clinical management. In this review, we discuss successes and physiological constraints of hearing with an implant, common surgical approaches and electrode arrays, new indications and outcome measures for implantation, and barriers to CI utilization. Additionally, we compare cochlear implantation with biomolecular and pharmacological approaches, consider strategies to combine these approaches, and identify unmet medical needs with cochlear implants. The strengths and weaknesses of modern implantation highlighted here can mark opportunities for continued progress or improvement in the design and delivery of the next generation of inner ear therapeutics.

Differences in Auditory Perception Between Young and Older Adults When Controlling for Differences in Hearing Loss and Cognition.

This study was designed to examine age effects on various auditory perceptual skills using a large group of listeners (155 adults, 121 aged 60-88 years and 34 aged 18-30 years), while controlling for the factors of hearing loss and working memory (WM). All subjects completed 3 measures of WM, 7 psychoacoustic tasks (24 conditions) and a hearing assessment. Psychophysical measures were selected to tap phenomena thought to be mediated by higher-level auditory function and included modulation detection, modulation detection interference, informational masking (IM), masking level difference (MLD), anisochrony detection, harmonic mistuning, and stream segregation. Principal-components analysis (PCA) was applied to each psychoacoustic test. For 6 of the 7 tasks, a single component represented performance across the multiple stimulus conditions well, whereas the modulation-detection interference (MDI) task required two components to do so. The effect of age was analyzed using a general linear model applied to each psychoacoustic component. Once hearing loss and WM were accounted for as covariates in the analyses, estimated marginal mean thresholds were lower for older adults on tasks based on temporal processing. When evaluated separately, hearing loss led to poorer performance on roughly 1/2 the tasks and declines in WM accounted for poorer performance on 6 of the 8 psychoacoustic components. These results make clear the need to interpret age-group differences in performance on psychoacoustic tasks in light of cognitive declines commonly associated with aging, and point to hearing loss and cognitive declines as negatively influencing auditory perceptual skills.

Differences Between Young and Older Adults in Working Memory and Performance on the Test of Basic Auditory Capabilities†.

The Test of Basic Auditory Capabilities (TBAC) is a battery of auditory-discrimination tasks and speech-identification tasks that has been normed on several hundred young normal-hearing adults. Previous research with the TBAC suggested that cognitive function may impact the performance of older adults. Here, we examined differences in performance on several TBAC tasks between a group of 34 young adults with a mean age of 22.5 years (SD = 3.1 years) and a group of 115 older adults with a mean age of 69.2 years (SD = 6.2 years) recruited from the local community. Performance of the young adults was consistent with prior norms for this age group. Not surprisingly, the two groups differed significantly in hearing loss and working memory with the older adults having more hearing loss and poorer working memory than the young adults. The two age groups also differed significantly in performance on six of the nine measures extracted from the TBAC (eight test scores and one average test score) with the older adults consistently performing worse than the young adults. However, when these age-group comparisons were repeated with working memory and hearing loss as covariates, the groups differed in performance on only one of the nine auditory measures from the TBAC. For eight of the nine TBAC measures, working memory was a significant covariate and hearing loss never emerged as a significant factor. Thus, the age-group deficits observed initially on the TBAC most often appeared to be mediated by age-related differences in working memory rather than deficits in auditory processing. The results of these analyses of age-group differences were supported further by linear-regression analyses with each of the 9 TBAC scores serving as the dependent measure and age, hearing loss, and working memory as the predictors. Regression analyses were conducted for the full set of 149 adults and for just the 115 older adults. Working memory again emerged as the predominant factor impacting TBAC performance. It is concluded that working memory should be considered when comparing the performance of young and older adults on auditory tasks, including the TBAC.

Perceptual Dimensions Underlying Tinnitus-Like Sounds.

Purpose The goal of this study was to establish the perceptual underpinnings of the terms that are commonly used by patients when describing the quality of their tinnitus. Method Using a free-classification method, 15 subjects with normal hearing placed 60 different tinnitus-like sounds into similarity clusters on a grid. Multidimensional scaling, hierarchical clustering, and acoustic analyses were used to determine the acoustic underpinnings of the perceptual dimensions and perceptual similarity. Results Multidimensional scaling revealed three different perceptual dimensions (pitch, modulation depth + spectral elements, and envelope rate). Hierarchical clustering revealed five explicit similarity clusters: tonal, steady noise, pulsatile, low-frequency fluctuating noise, and high-frequency fluctuating. Conclusions Results are consistent with tinnitus perceptions falling into a small set of categories that can be characterized by their acoustics. As a result, there is the potential to develop different tools to assess tinnitus using a variety of different sounds.

Does a pitch rating method converge on the frequencies within tonal stimuli?

This study determined how well the "perceived spectrum," estimated using a pitch similarity rating method, reflected the spectrum and pitch of seven different tonal sounds. The perceived spectrum well-matched the acoustic spectrum for pure tones ranging from 1 to 12 kHz, it also matched the broad frequency range for two complex tones with periodicity pitches of 1 and 2 kHz, but it did not reflect the pitch of the complex tones. These results suggest that while this method may not measure the pitch of sounds, it may be useful for measuring the general perceived frequency range of sounds.

Direct Delivery of Antisense Oligonucleotides to the Middle and Inner Ear Improves Hearing and Balance in Usher Mice.

Usher syndrome is a syndromic form of hereditary hearing impairment that includes sensorineural hearing loss and delayed-onset retinitis pigmentosa (RP). Type 1 Usher syndrome (USH1) is characterized by congenital profound sensorineural hearing impairment and vestibular areflexia, with adolescent-onset RP. Systemic treatment with antisense oligonucleotides (ASOs) targeting the human USH1C c.216G>A splicing mutation in a knockin mouse model of USH1 restores hearing and balance. Herein, we explore the effect of delivering ASOs locally to the ear to treat hearing and vestibular dysfunction associated with Usher syndrome. Three localized delivery strategies were investigated in USH1C mice: inner ear injection, trans-tympanic membrane injection, and topical tympanic membrane application. We demonstrate, for the first time, that ASOs delivered directly to the ear correct Ush1c expression in inner ear tissue, improve cochlear hair cell transduction currents, restore vestibular afferent irregularity, spontaneous firing rate, and sensitivity to head rotation, and successfully recover hearing thresholds and balance behaviors in USH1C mice. We conclude that local delivery of ASOs to the middle and inner ear reach hair cells and can rescue both hearing and balance. These results also demonstrate the therapeutic potential of ASOs to treat hearing and balance deficits associated with Usher syndrome and other ear diseases.

Fetal antisense oligonucleotide therapy for congenital deafness and vestibular dysfunction.

Disabling hearing loss impacts ∼466 million individuals worldwide with 34 million children affected. Gene and pharmacotherapeutic strategies to rescue auditory function in mouse models of human deafness are most effective when administered before hearing onset, after which therapeutic efficacy is significantly diminished or lost. We hypothesize that preemptive correction of a mutation in the fetal inner ear prior to maturation of the sensory epithelium will optimally restore sensory function. We previously demonstrated that transuterine microinjection of a splice-switching antisense oligonucleotide (ASO) into the amniotic cavity immediately surrounding the embryo on embryonic day 13-13.5 (E13-13.5) corrected pre-mRNA splicing in the juvenile Usher syndrome type 1c (Ush1c) mouse mutant. Here, we show that this strategy only marginally rescues hearing and partially rescues vestibular function. To improve therapeutic outcomes, we microinjected ASO directly into the E12.5 inner ear. A single intra-otic dose of ASO corrects harmonin RNA splicing, restores harmonin protein expression in sensory hair cell bundles, prevents hair cell loss, improves hearing sensitivity, and ameliorates vestibular dysfunction. Improvements in auditory and vestibular function were sustained well into adulthood. Our results demonstrate that an ASO pharmacotherapeutic administered to a developing organ system in utero preemptively corrects pre-mRNA splicing to abrogate the disease phenotype.

Hearing Protection Success: Musicians Have a Favorable Response to Hearing Protection and Listeners Are Unable to Identify Music Produced by Musicians Wearing Hearing Protection.

BACKGROUND: Musicians are known to be at risk for developing hearing sensitivity and hearing-related problems given their occupational exposure to high-level sound. Among options for hearing conservation, earplugs are an effective and inexpensive choice. Adoption rates for musicians' earplugs remains consistently low, however, given concerns about the impact of hearing protection on their own performance as well as concerns that the resultant music will be a negative experience for listeners. In fact, few studies have (1) examined musicians' attitudes about using hearing protection while performing themselves and (2) determined whether music played by musicians wearing hearing protection sounds different to listeners. PURPOSE: The purposes of this study were (1) to evaluate how wearing musicians' earplugs affected musicians' perception of their performance while they were playing, and (2) to examine whether listeners can distinguish a difference between music recorded by musicians playing with and without earplugs. RESEARCH DESIGN: Experiment 1: student musicians were recorded playing under two conditions (with and without wearing earplugs) and then were surveyed about their experience. Experiment 2: musically experienced and naïve listeners were presented with musical samples played by musicians with and without earplugs in an ABX format. Listeners responded by indicating whether the third stimulus (X) was conditionally identical to the first (A) or second stimulus (B). RESULTS: Experiment 1: while performing, musicians always preferred the no earplugs condition. The majority, however, rated the overall experience of playing with earplugs as generally positive. Experiment 2: listeners were unable to hear a difference between the two recordings. DISCUSSION: In this experiment, musicians rated their experience playing without hearing protection more favorably than their experience playing with hearing protection, but most musicians rated their experience with hearing protection as generally positive. The inability of listeners to distinguish a difference in music played with and without hearing protection suggests that the listening experience may not be adversely impacted by hearing protection worn by the performers. CONCLUSION: Earplugs are an inexpensive, noninvasive strategy for hearing conservation for musicians, and this study indicates that barriers to wearing hearing protection might be less problematic than previously reported.

Platelet-Activating Factor (PAF) Receptor Antagonism Modulates Inflammatory Signaling in Experimental Uveitis.

BACKGROUND: The phospholipid mediator platelet-activating factor (PAF) activates an inflammatory response that includes arachidonic acid release and prostaglandin production in the eye, increasing vascular permeability and inflammation. The purpose of this study is to investigate the action of LAU-0901, a novel PAF receptor antagonist, on experimental uveitis. METHODS: Uveitis was induced in Lewis rats by lipopolysaccharide treatment. LAU-0901 was then delivered systemically in different concentrations at plus 4 and 16 hours, or vehicle injected as controls. Additional animals were used for histological analyses of untreated, uveitis, and uveitis-plus-LAU-0901 retinas. Conventional histological and immunohistochemical methods were employed. A slit lamp and Spectral Domain-Ocular Coherence Tomography (SD-OCT) retinal imager was used for anterior segment photography and posterior pole OCT. Rats were euthanized 4 hours after the second LAU-0901 injection in this 24-hour model. Aqueous humor was collected and quantified, and also analyzed for tumor necrosis factor alpha (TNF-α). RESULTS: Uveitic eyes demonstrated hypopyon formation, leukocyte infiltration, and an increase in aqueous protein and TNF-α levels. LAU-0901 treatment resulted in a dose-dependent reduction in inflammation, reflected by reduced total protein levels (up to a 64% reduction). Moreover, hypopyon was prevented, leukocytes were absent in vitreous and aqueous humor, and TNF-α levels were reduced by 91%. CONCLUSIONS: The PAF receptor antagonist LAU-0901 decreases ocular inflammation in a rat model of anterior uveitis in a dose-dependent manner, suggesting that use of this molecule may provide a means to attenuate inflammation onset and offer a future alternative or adjunctive treatment for ocular inflammation.

Rescue of Outer Hair Cells with Antisense Oligonucleotides in Usher Mice Is Dependent on Age of Treatment.

The absence of functional outer hair cells is a component of several forms of hereditary hearing impairment, including Usher syndrome, the most common cause of concurrent hearing and vision loss. Antisense oligonucleotide (ASO) treatment of mice with the human Usher mutation, Ush1c c.216G>A, corrects gene expression and significantly improves hearing, as measured by auditory-evoked brainstem responses (ABRs), as well as inner and outer hair cell (IHC and OHC) bundle morphology. However, it is not clear whether the improvement in hearing achieved by ASO treatment involves the functional rescue of outer hair cells. Here, we show that Ush1c c.216AA mice lack OHC function as evidenced by the absence of distortion product otoacoustic emissions (DPOAEs) in response to low-, mid-, and high-frequency tone pairs. This OHC deficit is rescued by treatment with an ASO that corrects expression of Ush1c c.216G>A. Interestingly, although rescue of inner hairs cells, as measured by ABR, is achieved by ASO treatment as late as 7 days after birth, rescue of outer hair cells, measured by DPOAE, requires treatment before post-natal day 5. These results suggest that ASO-mediated rescue of both IHC and OHC function is age dependent and that the treatment window is different for the different cell types. The timing of treatment for congenital hearing disorders is of critical importance for the development of drugs such ASO-29 for hearing rescue.

Audiometric Testing With Pulsed, Steady, and Warble Tones in Listeners With Tinnitus and Hearing Loss.

PURPOSE: This study evaluated the American Speech-Language-Hearing Association's recommendation that audiometric testing for patients with tinnitus should use pulsed or warble tones. Using listeners with varied audiometric configurations and tinnitus statuses, we asked whether steady, pulsed, and warble tones yielded similar audiometric thresholds, and which tone type was preferred. METHOD: Audiometric thresholds (octave frequencies from 0.25-16 kHz) were measured using steady, pulsed, and warble tones in 61 listeners, who were divided into 4 groups on the basis of hearing and tinnitus status. Participants rated the appeal and difficulty of each tone type on a 1-5 scale and selected a preferred type. RESULTS: For all groups, thresholds were lower for warble than for pulsed and steady tones, with the largest effects above 4 kHz. Appeal ratings did not differ across tone type, but the steady tone was rated as more difficult than the warble and pulsed tones. Participants generally preferred pulsed and warble tones. CONCLUSIONS: Pulsed tones provide advantages over steady and warble tones for patients regardless of hearing or tinnitus status. Although listeners preferred pulsed and warble tones to steady tones, pulsed tones are not susceptible to the effects of off-frequency listening, a consideration when testing listeners with sloping audiograms.

Rescue of peripheral vestibular function in Usher syndrome mice using a splice-switching antisense oligonucleotide.

Usher syndrome type 1C (USH1C/harmonin) is associated with profound retinal, auditory and vestibular dysfunction. We have previously reported on an antisense oligonucleotide (ASO-29) that dramatically improves auditory function and balance behavior in mice homozygous for the harmonin mutation Ush1c c.216G > A following a single systemic administration. The findings were suggestive of improved vestibular function; however, no direct vestibular assessment was made. Here, we measured vestibular sensory evoked potentials (VsEPs) to directly assess vestibular function in Usher mice. We report that VsEPs are absent or abnormal in Usher mice, indicating profound loss of vestibular function. Strikingly, Usher mice receiving ASO-29 treatment have normal or elevated vestibular response thresholds when treated during a critical period between postnatal day 1 and 5, respectively. In contrast, treatment of mice with ASO-29 treatment at P15 was minimally effective at rescuing vestibular function. Interestingly, ASO-29 treatment at P1, P5 or P15 resulted in sufficient vestibular recovery to support normal balance behaviors, suggesting a therapeutic benefit to balance with ASO-29 treatment at P15 despite the profound vestibular functional deficits that persist with treatment at this later time. These findings provide the first direct evidence of an effective treatment of peripheral vestibular function in a mouse model of USH1C and reveal the potential for using antisense technology to treat vestibular dysfunction.

Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c.

Because there are currently no biological treatments for hearing loss, we sought to advance gene therapy approaches to treat genetic deafness. We focused on Usher syndrome, a devastating genetic disorder that causes blindness, balance disorders and profound deafness, and studied a knock-in mouse model, Ush1c c.216G>A, for Usher syndrome type IC (USH1C). As restoration of complex auditory and balance function is likely to require gene delivery systems that target auditory and vestibular sensory cells with high efficiency, we delivered wild-type Ush1c into the inner ear of Ush1c c.216G>A mice using a synthetic adeno-associated viral vector, Anc80L65, shown to transduce 80-90% of sensory hair cells. We demonstrate recovery of gene and protein expression, restoration of sensory cell function, rescue of complex auditory function and recovery of hearing and balance behavior to near wild-type levels. The data represent unprecedented recovery of inner ear function and suggest that biological therapies to treat deafness may be suitable for translation to humans with genetic inner ear disorders.

Corrigendum: Auditory and cognitive factors underlying individual differences in aided speech-understanding among older adults.

[This corrects the article on p. 55 in vol. 7, PMID: 24098273.].

Antisense oligonucleotides delivered to the amniotic cavity in utero modulate gene expression in the postnatal mouse.

Congenital diseases account for a large portion of pediatric illness. Prenatal screening and diagnosis permit early detection of many genetic diseases. Fetal therapeutic strategies to manage disease processes in utero represent a powerful new approach for clinical care. A safe and effective fetal pharmacotherapy designed to modulate gene expression ideally would avoid direct mechanical engagement of the fetus and present an external reservoir of drug. The amniotic cavity surrounding the fetus could serve as an ideal drug reservoir. Antisense oligonucleotides (ASOs) are an established tool for the therapeutic modulation of gene expression. We hypothesize that ASOs administered to the amniotic cavity will gain entry to the fetus and modulate gene expression. Here, we show that an ASO targeting MALAT1 RNA, delivered by transuterine microinjection into the mouse amniotic cavity at embryonic day 13-13.5, reduces target RNA expression for up to 4 weeks after birth. A similarly delivered ASO targeting a causal splice site mutation for Usher syndrome corrects gene expression in the inner ear, a therapeutically relevant target tissue. We conclude that intra-amniotic delivery of ASOs is well tolerated and produces a sustained effect on postnatal gene expression. Transuterine delivery of ASOs is an innovative platform for developing fetal therapeutics to efficaciously treat congenital disease.

The McGurk effect: An investigation of attentional capacity employing response times.

This paper proposes a novel approach to assess audiovisual integration for both congruent and incongruent speech stimuli using reaction times (RT). The experiments are based on the McGurk effect, in which a listener is presented with incongruent audiovisual speech signals. A typical example involves the auditory consonant/b/combined with a visually articulated/g/, often yielding a perception of/d/. We quantify the amount of integration relative to the predictions of a parallel independent model as a function of attention and congruency between auditory and visual signals. We assessed RT distributions for congruent and incongruent auditory and visual signals in a within-subjects signal detection paradigm under conditions of divided versus focused attention. Results showed that listeners often received only minimal benefit from congruent auditory visual stimuli, even when such information could have improved performance. Incongruent stimuli adversely affected performance in divided and focused attention conditions. Our findings support a parallel model of auditory-visual integration with interactions between auditory and visual channels.

Across-frequency processing of modulation phase differences in hearing-impaired listeners.

Two experiments tested the influence of hearing impairment (HI) on representing across-frequency temporal coherence. In one experiment, HI listeners demonstrated similar abilities to normal-hearing listeners in detecting across-frequency differences in modulation phase. In another, spectral-shape discrimination was detrimentally affected by modulation phase disparities imposed on spectral components. Spectral-shape discrimination by HI listeners was less influenced by the disparities, suggesting that hearing loss alters the representation of envelope phase. Results suggest that multiple approaches may be necessary to determine alterations associated with hearing loss­detection tasks may not be sufficient to elucidate distortions to temporal envelope associated with hearing loss.