Normal behavioral discrimination of envelope statistics in budgerigars with kainate-induced cochlear synaptopathy.

Cochlear synaptopathy is a common pathology in humans associated with aging and potentially sound overexposure. Synaptopathy is widely expected to cause "hidden hearing loss," including difficulty perceiving speech in noise, but support for this hypothesis is controversial. Here in budgerigars (Melopsittacus undulatus), we evaluated the impact of long-term cochlear synaptopathy on behavioral discrimination of Gaussian noise (GN) and low-noise noise (LNN) signals processed to have a flatter envelope. Stimuli had center frequencies of 1-3kHz, 100-Hz bandwidth, and were presented at sensation levels (SLs) from 10 to 30dB. We reasoned that narrowband, low-SL stimuli of this type should minimize spread of excitation across auditory-nerve fibers, and hence might reveal synaptopathy-related defects if they exist. Cochlear synaptopathy was induced without hair-cell injury using kainic acid (KA). Behavioral threshold tracking experiments characterized the minimum stimulus duration above which animals could reliably discriminate between LNN and GN. Budgerigar thresholds for LNN-GN discrimination ranged from 40 to 60ms at 30dB SL, were similar across frequencies, and increased for lower SLs. Notably, animals with long-term 39-77% estimated synaptopathy performed similarly to controls, requiring on average a ∼7.5% shorter stimulus duration (-0.7±1.0dB; mean difference ±SE) for LNN-GN discrimination. Decision-variable correlation analyses of detailed behavioral response patterns showed that individual animals relied on envelope cues to discriminate LNN and GN, with lesser roles of FM and energy cues; no difference was found between KA-exposed and control groups. These results suggest that long-term cochlear synaptopathy does not impair discrimination of low-level signals with different envelope statistics.

Sensitivity to direction and velocity of fast frequency chirps in the inferior colliculus of awake rabbit.

Neurons in the mammalian inferior colliculus (IC) are sensitive to the velocity (speed and direction) of fast frequency chirps contained in Schroeder-phase harmonic complexes (SCHR). However, IC neurons are also sensitive to stimulus periodicity, a prominent feature of SCHR stimuli. Here, to disentangle velocity sensitivity from periodicity tuning, we introduced a novel stimulus consisting of aperiodic random chirps. Extracellular, single-unit recordings were made in the IC of Dutch-belted rabbits in response to both SCHR and aperiodic chirps. Rate-velocity functions were constructed from aperiodic-chirp responses and compared to SCHR rate profiles, revealing interactions between stimulus periodicity and neural velocity sensitivity. A generalized linear model analysis demonstrated that periodicity tuning influences SCHR response rates more strongly than velocity sensitivity. Principal component analysis of rate-velocity functions revealed that neurons were more often sensitive to the direction of lower-velocity chirps and were less often sensitive to the direction of higher-velocity chirps. Overall, these results demonstrate that sensitivity to chirp velocity is common in the IC. Harmonic sounds with complex phase spectra, such as speech and music, contain chirps, and velocity sensitivity would shape IC responses to these sounds.

Limitations of the human iPSC-derived neuron model for early-onset Alzheimer's disease.

Non-familial Alzheimer's disease (AD) occurring before 65 years of age is commonly referred to as early-onset Alzheimer's disease (EOAD) and constitutes ~ 5-6% of all AD cases (Mendez et al. in Continuum 25:34-51, 2019). While EOAD exhibits the same clinicopathological changes such as amyloid plaques, neurofibrillary tangles (NFTs), brain atrophy, and cognitive decline (Sirkis et al. in Mol Psychiatry 27:2674-88, 2022; Caldwell et al. in Mol Brain 15:83, 2022) as observed in the more prevalent late-onset AD (LOAD), EOAD patients tend to have more severe cognitive deficits, including visuospatial, language, and executive dysfunction (Sirkis et al. in Mol Psychiatry 27:2674-88, 2022). Patient-derived induced pluripotent stem cells (iPSCs) have been used to model and study penetrative, familial AD (FAD) mutations in APP, PSEN1, and PSEN2 (Valdes et al. in Research Square 1-30, 2022; Caldwell et al. in Sci Adv 6:1-16, 2020) but have been seldom used for sporadic forms of AD that display more heterogeneous disease mechanisms. In this study, we sought to characterize iPSC-derived neurons from EOAD patients via RNA sequencing. A modest difference in expression profiles between EOAD patients and non-demented control (NDC) subjects resulted in a limited number of differentially expressed genes (DEGs). Based on this analysis, we provide evidence that iPSC-derived neuron model systems, likely due to the loss of EOAD-associated epigenetic signatures arising from iPSC reprogramming, may not be ideal models for studying sporadic AD.

Histological Correlates of Auditory Nerve Injury from Kainic Acid in the Budgerigar (Melopsittacus undulatus).

PURPOSE: Loss of auditory nerve afferent synapses with cochlear hair cells, called cochlear synaptopathy, is a common pathology in humans caused by aging and noise overexposure. The perceptual consequences of synaptopathy in isolation from other cochlear pathologies are still unclear. Animal models provide an effective approach to resolve uncertainty regarding the physiological and perceptual consequences of auditory nerve loss, because neural lesions can be induced and readily quantified. The budgerigar, a parakeet species, has recently emerged as an animal model for synaptopathy studies based on its capacity for vocal learning and ability to behaviorally discriminate simple and complex sounds with acuity similar to humans. Kainic acid infusions in the budgerigar produce a profound reduction of compound auditory nerve responses, including wave I of the auditory brainstem response, without impacting physiological hair cell measures. These results suggest selective auditory nerve damage. However, histological correlates of neural injury from kainic acid are still lacking. METHODS: We quantified the histological effects caused by intracochlear infusion of kainic acid (1 mM; 2.5 µL), and evaluated correlations between the histological and physiological assessments of auditory nerve status. RESULTS: Kainic acid infusion in budgerigars produced pronounced loss of neural auditory nerve soma (60% on average) in the cochlear ganglion, and of peripheral axons, at time points 2 or more months following injury. The hair cell epithelium was unaffected by kainic acid. Neural loss was significantly correlated with reduction of compound auditory nerve responses and auditory brainstem response wave I. CONCLUSION: Compound auditory nerve responses and wave I provide a useful index of cochlear synaptopathy in this animal model.

Mechanisms of masking by Schroeder-phase harmonic tone complexes in the budgerigar (Melopsittacus undulatus).

Schroeder-phase harmonic tone complexes can have a flat temporal envelope and rising or falling instantaneous-frequency sweeps within F0 periods, depending on the phase-scaling parameter C. Human tone-detection thresholds in a concurrent Schroeder masker are 10-15 dB lower for positive C values (rising frequency sweeps) compared to negative (falling sweeps), potentially due to cochlear mechanics, though this hypothesis remains controversial. Birds provide an interesting model for studies of Schroeder masking because many species produce vocalizations containing frequency sweeps. Prior behavioral studies in birds suggest less behavioral threshold difference between maskers with opposite C values than in humans, but focused on low masker F0s and did not explore neural mechanisms. We performed behavioral Schroeder-masking experiments in budgerigars (Melopsittacus undulatus) using a wide range of masker F0 and C values. Signal frequency was 2800 Hz. Neural recordings from the midbrain characterized encoding of behavioral stimuli in awake animals. Behavioral thresholds increased with increasing masker F0 and showed minimal difference between opposite C values, consistent with prior budgerigar studies. Midbrain recordings showed prominent temporal and rate-based encoding of Schroeder F0, and in many cases, marked asymmetry in Schroeder responses between C polarities. Neural thresholds for Schroeder-masked tone detection were often based on a response decrement compared to the masker alone, consistent with prominent modulation tuning in midbrain neurons, and were generally similar between opposite C values. The results highlight the likely importance of envelope cues in Schroeder masking and show that differences in supra-threshold Schroeder responses do not necessarily result in neural threshold differences.

Responses to dichotic tone-in-noise stimuli in the inferior colliculus.

Human listeners are more sensitive to tones embedded in diotic noise when the tones are out-of-phase at the two ears (N0Sπ) than when they are in-phase (N0S0). The difference between the tone-detection thresholds for these two conditions is referred to as the binaural masking level difference (BMLD) and reflects a benefit of binaural processing. Detection in the N0Sπ condition has been explained in modeling studies by changes in interaural correlation (IAC), but this model has only been directly tested physiologically for low frequencies. Here, the IAC-based hypothesis for binaural detection was examined across a wide range of frequencies and masker levels using recordings in the awake rabbit inferior colliculus (IC). IAC-based cues were strongly correlated with neural responses to N0Sπ stimuli. Additionally, average rate-based thresholds were calculated for both N0S0 and N0Sπ conditions. The rate-based neural BMLD at 500 Hz matched rabbit behavioral data, but the trend of neural BMLDs across frequency differed from that of humans.

Tone in Noise Detection in Children with a History of Temporary Conductive Hearing Loss.

Children with a history of temporary conductive hearing loss (CHL) during early development may show long-term impairments in auditory processes that persist after restoration of normal audiometric hearing thresholds. Tones in noise provide a simplified paradigm for studying hearing in noise. Prior research has shown that adults with sensorineural hearing loss may alter their listening strategy to use single-channel energy cues for tone-in-noise (TIN) detection rather than rove-resistant envelope or spectral profile cues. Our objective was to determine the effect of early CHL on TIN detection in healthy children compared to controls. Children ages 4-7 years, with and without a history of CHL due to otitis media with effusion (OME) before age 3 years, participated in a two-alternative forced choice TIN detection task. Audiometric thresholds were normal at the time of testing. Thresholds for detection of a 1000 Hz tone were measured in fixed-level noise and in roving-level noise that made single-channel energy cues unreliable. Participants included 23 controls and 23 with a history of OME-related CHL. TIN thresholds decreased with increasing age across participants. Children in both groups showed similar TIN sensitivity and little or no threshold elevation in the roving-level condition compared to fixed-level tracks, consistent with use of rove-resistant cues. In contrast to older listeners with sensorineural hearing loss, there was no detectable change in TIN sensitivity with roving level for children with a history of OME-related CHL.

Animal models of hidden hearing loss: Does auditory-nerve-fiber loss cause real-world listening difficulties?

Afferent innervation of the cochlea by the auditory nerve declines during aging and potentially after sound overexposure, producing the common pathology known as cochlear synaptopathy. Auditory-nerve-fiber loss is difficult to detect with the clinical audiogram and has been proposed to cause 'hidden hearing loss' including impaired speech-in-noise perception. While evidence that auditory-nerve-fiber loss causes hidden hearing loss in humans is controversial, behavioral animal models hold promise to rigorously test this hypothesis because neural lesions can be induced and histologically validated. Here, we review recent animal behavioral studies on the impact of auditory-nerve-fiber loss on perception in a range of species. We first consider studies of tinnitus and hyperacusis inferred from acoustic startle reflexes, followed by a review of operant-conditioning studies of the audiogram, temporal integration for tones of varying duration, temporal resolution of gaps in noise, and tone-in-noise detection. Studies quantifying the audiogram show that tone-in-quiet sensitivity is unaffected by auditory-nerve-fiber loss unless neural lesions exceed 80%, at which point large deficits are possible. Changes in other aspects of perception, which were typically investigated for moderate-to-severe auditory-nerve-fiber loss of 50-70%, appear heterogeneous across studies and might be small compared to impairment caused by hair-cell pathologies. Future studies should pursue recent findings that behavioral sensitivity to brief tones and silent gaps in noise may be particularly vulnerable to auditory-nerve-fiber loss. Furthermore, aspects of auditory perception linked to central inhibition and fine neural response timing, such as modulation masking release and spatial hearing, may be productive directions for further animal behavioral research.

Characterizing the Access of Cholinergic Antagonists to Efferent Synapses in the Inner Ear.

Stimulation of cholinergic efferent neurons innervating the inner ear has profound, well-characterized effects on vestibular and auditory physiology, after activating distinct ACh receptors (AChRs) on afferents and hair cells in peripheral endorgans. Efferent-mediated fast and slow excitation of vestibular afferents are mediated by α4ß2*-containing nicotinic AChRs (nAChRs) and muscarinic AChRs (mAChRs), respectively. On the auditory side, efferent-mediated suppression of distortion product otoacoustic emissions (DPOAEs) is mediated by α9α10nAChRs. Previous characterization of these synaptic mechanisms utilized cholinergic drugs, that when systemically administered, also reach the CNS, which may limit their utility in probing efferent function without also considering central effects. Use of peripherally-acting cholinergic drugs with local application strategies may be useful, but this approach has remained relatively unexplored. Using multiple administration routes, we performed a combination of vestibular afferent and DPOAE recordings during efferent stimulation in mouse and turtle to determine whether charged mAChR or α9α10nAChR antagonists, with little CNS entry, can still engage efferent synaptic targets in the inner ear. The charged mAChR antagonists glycopyrrolate and methscopolamine blocked efferent-mediated slow excitation of mouse vestibular afferents following intraperitoneal, middle ear, or direct perilymphatic administration. Both mAChR antagonists were effective when delivered to the middle ear, contralateral to the side of afferent recordings, suggesting they gain vascular access after first entering the perilymphatic compartment. In contrast, charged α9α10nAChR antagonists blocked efferent-mediated suppression of DPOAEs only upon direct perilymphatic application, but failed to reach efferent synapses when systemically administered. These data show that efferent mechanisms are viable targets for further characterizing drug access in the inner ear.

Responses to diotic tone-in-noise stimuli in the inferior colliculus: stimulus envelope and neural fluctuation cues.

Human detection thresholds in tone-in-noise (TIN) paradigms cannot be explained by the prevalent power-spectrum model when stimulus energy is made less reliable, e.g., in roving-level or equal-energy paradigms. Envelope-related cues provide an alternative that is more robust across level. The TIN stimulus envelope is encoded by slow fluctuations in auditory-nerve (AN) responses - a temporal representation affected by inner-hair-cell (IHC) saturation and cochlear compression. Here, envelope-related fluctuations in AN responses were hypothesized to be reflected in responses of neurons in the inferior colliculus (IC), which have average discharge rates that are sensitive to amplitude-modulation (AM) depth and frequency. Responses to tones masked by narrowband gaussian noise (GN) and low-noise noise (LNN) were recorded in the IC of awake rabbits. Fluctuation amplitudes in the stimulus envelope and in model AN responses decrease for GN maskers and increase for LNN upon addition of tones near threshold. Response rates of IC neurons that are excited by AM were expected to be positively correlated with fluctuation amplitudes, whereas rates of neurons suppressed by AM were expected to be negatively correlated. Of neurons with measurable TIN-detection thresholds, most had the predicted changes in rate with increasing tone level for both GN and LNN maskers. Changes in rate with tone level were correlated with envelope sensitivity measured with two methods, including the maximum slopes of modulation transfer functions. IC rate-based thresholds were broadly consistent with published human and rabbit behavioral data. These results highlight the importance of midbrain sensitivity to envelope cues, as represented in peripheral neural fluctuations, for detection of signals in noise.

Midbrain-Level Neural Correlates of Behavioral Tone-in-Noise Detection: Dependence on Energy and Envelope Cues.

Hearing in noise is a problem often assumed to depend on encoding of energy level by channels tuned to target frequencies, but few studies have tested this hypothesis. The present study examined neural correlates of behavioral tone-in-noise (TIN) detection in budgerigars (Melopsittacus undulatus, either sex), a parakeet species with human-like behavioral sensitivity to many simple and complex sounds. Behavioral sensitivity to tones in band-limited noise was assessed using operant-conditioning procedures. Neural recordings were made in awake animals from midbrain-level neurons in the inferior colliculus, the first processing stage of the ascending auditory pathway with pronounced rate-based encoding of stimulus amplitude modulation. Budgerigar TIN detection thresholds were similar to human thresholds across the full range of frequencies (0.5-4 kHz) and noise levels (45-85 dB SPL) tested. Also as in humans, thresholds were minimally affected by a challenging roving-level condition with random variation in background-noise level. Many midbrain neurons showed a decreasing response rate as TIN signal-to-noise ratio (SNR) was increased by elevating the tone level, a pattern attributable to amplitude-modulation tuning in these cells and the fact that higher SNR tone-plus-noise stimuli have flatter amplitude envelopes. TIN thresholds of individual neurons were as sensitive as behavioral thresholds under most conditions, perhaps surprisingly even when the unit's characteristic frequency was tuned an octave or more away from the test frequency. A model that combined responses of two cell types enhanced TIN sensitivity in the roving-level condition. These results highlight the importance of midbrain-level envelope encoding and off-frequency neural channels for hearing in noise.SIGNIFICANCE STATEMENT Detection of target sounds in noise is often assumed to depend on energy-level encoding by neural processing channels tuned to the target frequency. In contrast, we found that tone-in-noise sensitivity in budgerigars was often greatest in midbrain neurons not tuned to the test frequency, underscoring the potential importance of off-frequency channels for perception. Furthermore, the results highlight the importance of envelope processing for hearing in noise, especially under challenging conditions with random variation in background noise level over time.

Effects of Kainic Acid-Induced Auditory Nerve Damage on Envelope-Following Responses in the Budgerigar (Melopsittacus undulatus).

Sensorineural hearing loss is a prevalent problem that adversely impacts quality of life by compromising interpersonal communication. While hair cell damage is readily detectable with the clinical audiogram, this traditional diagnostic tool appears inadequate to detect lost afferent connections between inner hair cells and auditory nerve (AN) fibers, known as cochlear synaptopathy. The envelope-following response (EFR) is a scalp-recorded response to amplitude modulation, a critical acoustic feature of speech. Because EFRs can have greater amplitude than wave I of the auditory brainstem response (ABR; i.e., the AN-generated component) in humans, the EFR may provide a more sensitive way to detect cochlear synaptopathy. We explored the effects of kainate- (kainic acid) induced excitotoxic AN injury on EFRs and ABRs in the budgerigar (Melopsittacus undulatus), a parakeet species used in studies of complex sound discrimination. Kainate reduced ABR wave I by 65-75 % across animals while leaving otoacoustic emissions unaffected or mildly enhanced, consistent with substantial and selective AN synaptic loss. Compared to wave I loss, EFRs showed similar or greater percent reduction following kainate for amplitude-modulation frequencies from 380 to 940 Hz and slightly less reduction from 80 to 120 Hz. In contrast, forebrain-generated middle latency responses showed no consistent change post-kainate, potentially due to elevated "central gain" in the time period following AN damage. EFR reduction in all modulation frequency ranges was highly correlated with wave I reduction, though within-animal effect sizes were greater for higher modulation frequencies. These results suggest that even low-frequency EFRs generated primarily by central auditory nuclei might provide a useful noninvasive tool for detecting synaptic injury clinically.

Normal Tone-In-Noise Sensitivity in Trained Budgerigars despite Substantial Auditory-Nerve Injury: No Evidence of Hidden Hearing Loss.

Loss of auditory-nerve (AN) afferent cochlear innervation is a prevalent human condition that does not affect audiometric thresholds and therefore remains largely undetectable with standard clinical tests. AN loss is widely expected to cause hearing difficulties in noise, known as "hidden hearing loss," but support for this hypothesis is controversial. Here, we used operant conditioning procedures to examine the perceptual impact of AN loss on behavioral tone-in-noise (TIN) sensitivity in the budgerigar (Melopsittacus undulatus; of either sex), an avian animal model with complex hearing abilities similar to humans. Bilateral kainic acid (KA) infusions depressed compound AN responses by 40-70% without impacting otoacoustic emissions or behavioral tone sensitivity in quiet. Surprisingly, animals with AN damage showed normal thresholds for tone detection in noise (0.1 ± 1.0 dB compared to control animals; mean difference ± SE), even under a challenging roving-level condition with random stimulus variation across trials. Furthermore, decision-variable correlations (DVCs) showed no difference for AN-damaged animals in their use of energy and envelope cues to perform the task. These results show that AN damage has less impact on TIN detection than generally expected, even under a difficult roving-level condition known to impact TIN detection in individuals with sensorineural hearing loss (SNHL). Perceptual deficits could emerge for different perceptual tasks or with greater AN loss but are potentially minor compared with those caused by SNHL.SIGNIFICANCE STATEMENT Loss of auditory-nerve (AN) cochlear innervation is a common problem in humans that does not affect audiometric thresholds on a clinical hearing test. AN loss is widely expected to cause hearing problems in noise, known as "hidden hearing loss," but existing studies are controversial. Here, using an avian animal model with complex hearing abilities similar to humans, we examined for the first time the impact of an experimentally induced AN lesion on behavioral tone sensitivity in noise. Surprisingly, AN-lesioned animals showed no difference in hearing performance in noise or detection strategy compared with controls. These results show that perceptual deficits from AN damage are smaller than generally expected, and potentially minor compared with those caused by sensorineural hearing loss (SNHL).

Identifying cues for tone-in-noise detection using decision variable correlation in the budgerigar (Melopsittacus undulatus).

Previous studies evaluated cues for masked tone detection using reproducible noise waveforms. Human results founded on this approach suggest that tone detection is based on combined energy and envelope (ENV) cues, but detection cues in nonhuman species are less clear. Decision variable correlation (DVC) was used to evaluate tone-in-noise detection cues in the budgerigar, an avian species with human-like behavioral sensitivity to many complex sounds. DVC quantifies a model's ability to predict trial-by-trial variance in behavioral responses. Budgerigars were behaviorally conditioned to detect 500-Hz tones in wideband (WB; 100-3000 Hz) and narrowband (NB; 452-552 Hz) noise. Behavioral responses were obtained using a single-interval, two-alternative discrimination task and two-down, one-up adaptive tracking procedures. Tone-detection thresholds in WB noise were higher than human thresholds, putatively due to broader peripheral frequency tuning, whereas NB thresholds were within ∼1 dB of human results. Budgerigar average hit and false-alarm rates across noise waveforms were consistent, highly correlated across subjects, and correlated to human results. Trial-by-trial behavioral results in NB noise were best explained by a model combining energy and ENV cues. In contrast, WB results were better predicted by ENV-based or multiple-channel energy detector models. These results suggest that budgerigars and humans use similar cues for tone-in-noise detection.

Sensorineural Hearing Loss Diminishes Use of Temporal Envelope Cues: Evidence From Roving-Level Tone-in-Noise Detection.

OBJECTIVES: The objective of our study is to understand how listeners with and without sensorineural hearing loss (SNHL) use energy and temporal envelope cues to detect tones in noise. Previous studies of low-frequency tone-in-noise detection have shown that when energy cues are made less reliable using a roving-level paradigm, thresholds of listeners with normal hearing (NH) are only slightly increased. This result is consistent with studies demonstrating the importance of temporal envelope cues for masked detection. In contrast, roving-level detection thresholds are more elevated in listeners with SNHL at the test frequency, suggesting stronger weighting of energy cues. The present study extended these tests to a wide range of frequencies and stimulus levels. The authors hypothesized that individual listeners with SNHL use energy and temporal envelope cues differently for masked detection at different frequencies and levels, depending on the degree of hearing loss. DESIGN: Twelve listeners with mild to moderate SNHL and 12 NH listeners participated. Tone-in-noise detection thresholds at 0.5, 1, 2, and 4 kHz in 1/3 octave bands of simultaneously gated Gaussian noise were obtained using a novel, two-part tracking paradigm. A track refers to the sequence of trials in an adaptive test procedure; the signal to noise ratio was the tracked variable. Each part of the track consisted of a two-alternative, two-interval, forced-choice procedure. The initial portion of the track estimated detection threshold using a fixed masker level. When the track continued, stimulus levels were randomly varied over a 20-dB rove range (±10 dB with respect to mean masker level), and a second threshold was estimated. Rove effect (RE) was defined as the difference between thresholds for the fixed- and roving-level tests. The size of the RE indicated how strongly a listener weighted energy-based cues for masked detection. Participants were tested at one to three masker levels per frequency, depending on audibility. RESULTS: Across all stimulus frequencies and levels, NH listeners had small REs (≈1 dB), whereas listeners with SNHL typically had larger REs. Some listeners with SNHL had larger REs at higher frequencies, where pure-tone audiometric thresholds were typically elevated. RE did not vary significantly with masker level for either group. Increased RE for the SNHL group was consistent with simulations in which energy cues were more heavily weighted than envelope cues. CONCLUSIONS: Tone-in-noise detection thresholds in NH listeners were typically elevated only slightly by the roving-level paradigm at any frequency or level tested, consistent with the primary use of level-independent cues, such as temporal envelope cues that are conveyed by fluctuations in neural responses. In comparison, thresholds of listeners with SNHL were more affected by the roving-level paradigm, suggesting stronger weighting of energy cues. For listeners with SNHL, the largest RE was observed at 4000 Hz, for which pure-tone audiometric thresholds were most elevated. Specifically, RE size at 4000 Hz was significantly correlated with higher pure-tone audiometric thresholds at the same frequency, after controlling for the effect of age. Future studies will explore strategies for restoring or enhancing neural fluctuation cues that may lead to improved hearing in noise for listeners with SNHL.

Divergent Auditory Nerve Encoding Deficits Between Two Common Etiologies of Sensorineural Hearing Loss.

Speech intelligibility can vary dramatically between individuals with similar clinically defined severity of hearing loss based on the audiogram. These perceptual differences, despite equal audiometric-threshold elevation, are often assumed to reflect central-processing variations. Here, we compared peripheral-processing in auditory nerve (AN) fibers of male chinchillas between two prevalent hearing loss etiologies: metabolic hearing loss (MHL) and noise-induced hearing loss (NIHL). MHL results from age-related reduction of the endocochlear potential due to atrophy of the stria vascularis. MHL in the present study was induced using furosemide, which provides a validated model of age-related MHL in young animals by reversibly inhibiting the endocochlear potential. Effects of MHL on peripheral processing were assessed using Wiener-kernel (system identification) analyses of single AN fiber responses to broadband noise, for direct comparison to previously published AN responses from animals with NIHL. Wiener-kernel analyses show that even mild NIHL causes grossly abnormal coding of low-frequency stimulus components. In contrast, for MHL the same abnormal coding was only observed with moderate to severe loss. For equal sensitivity loss, coding impairment was substantially less severe with MHL than with NIHL, probably due to greater preservation of the tip-to-tail ratio of cochlear frequency tuning with MHL compared with NIHL rather than different intrinsic AN properties. Differences in peripheral neural coding between these two pathologies-the more severe of which, NIHL, is preventable-likely contribute to individual speech perception differences. Our results underscore the need to minimize noise overexposure and for strategies to personalize diagnosis and treatment for individuals with sensorineural hearing loss.SIGNIFICANCE STATEMENT Differences in speech perception ability between individuals with similar clinically defined severity of hearing loss are often assumed to reflect central neural-processing differences. Here, we demonstrate for the first time that peripheral neural processing of complex sounds differs dramatically between the two most common etiologies of hearing loss. Greater processing impairment with noise-induced compared with an age-related (metabolic) hearing loss etiology may explain heightened speech perception difficulties in people overexposed to loud environments. These results highlight the need for public policies to prevent noise-induced hearing loss, an entirely avoidable hearing loss etiology, and for personalized strategies to diagnose and treat sensorineural hearing loss.

Effects of selective auditory-nerve damage on the behavioral audiogram and temporal integration in the budgerigar.

Auditory-nerve fibers are lost steadily with age and as a possible consequence of noise-induced glutamate excitotoxicity. Auditory-nerve loss in the absence of other cochlear pathologies is thought to be undetectable with a pure-tone audiogram while degrading real-world speech perception (hidden hearing loss). Perceptual deficits remain unclear, however, due in part to the limited behavioral capacity of existing rodent models to discriminate complex sounds. The budgerigar is an avian vocal learner with human-like behavioral sensitivity to many simple and complex sounds and the capacity to mimic speech. Previous studies in this species show that intracochlear kainic-acid infusion reduces wave 1 of the auditory brainstem response by 40-70%, consistent with substantial excitotoxic auditory-nerve damage. The present study used operant-conditioning procedures in trained budgerigars to quantify kainic-acid effects on tone detection across frequency (0.25-8 kHz; the audiogram) and as a function of duration (20-160 ms; temporal integration). Tone thresholds in control animals were lowest from 1 to 4 kHz and decreased with increasing duration as in previous studies of the budgerigar. Behavioral results in kainic-acid-exposed animals were as sensitive as in controls, suggesting preservation of the audiogram and temporal integration despite auditory-nerve loss associated with up to 70% wave 1 reduction. Distortion-product otoacoustic emissions were also preserved in kainic-acid exposed animals, consistent with normal hair-cell function. These results highlight considerable perceptual resistance of tone-detection performance with selective auditory-nerve loss. Future behavioral studies in budgerigars with auditory-nerve damage can use complex speech-like stimuli to help clarify aspects of auditory perception impacted by this common cochlear pathology.

Amplitude Modulation Detection in Children with a History of Temporary Conductive Hearing Loss Remains Impaired for Years After Restoration of Normal Hearing.

Otitis media with effusion (OME) is considered a form of relative sensory deprivation that often occurs during a critical period of language acquisition in children. Animal studies have demonstrated that hearing loss during early development can impair behavioral sensitivity to amplitude modulation (AM), critical for speech understanding, even after restoration of normal hearing thresholds. AM detection in humans with a history of OME-associated conductive hearing loss (CHL) has not been previously investigated. Our objective was to determine whether OME-associated CHL in children ages 6 months to 3 years results in deficits in AM detection in later childhood, after restoration of normal audiometric thresholds. Children ages 4 to 7 years with and without a history of OME-associated CHL participated in an AM detection two-alternative forced-choice task at 8 and 64 Hz modulation frequencies using a noise carrier signal and an interactive touch screen interface. Thirty-four subjects were studied (17 with a history of OME-related CHL and 17 without). Modulation detection thresholds improved with age and were slightly lower (more sensitive) for the 64 Hz modulation frequency for both groups. Modulation detection thresholds of children with a history of OME-associated CHL were higher than control thresholds at 5 years, but corrected to expected levels between ages 6-7. OME-associated CHL results in impaired AM detection, even when measured years after restoration of normal audiometric thresholds. Future studies may shed light on implications for speech and language development and academic success for children affected by OME and associated conductive hearing loss.

Persistent Auditory Nerve Damage Following Kainic Acid Excitotoxicity in the Budgerigar (Melopsittacus undulatus).

Permanent loss of auditory nerve (AN) fibers occurs with increasing age and sound overexposure, sometimes without hair cell damage or associated audiometric threshold elevation. Rodent studies suggest effects of AN damage on central processing and behavior, but these species have limited capacity to discriminate low-frequency speech-like sounds. Here, we introduce a new animal model of AN damage in an avian communication specialist, the budgerigar (Melopsittacus undulatus). The budgerigar is a vocal learner and speech mimic with sensitive low-frequency hearing and human-like behavioral sensitivity to many complex signals including speech components. Excitotoxic AN damage was induced through bilateral cochlear infusions of kainic acid (KA). Acute KA effects on cochlear function were assessed using AN compound action potentials (CAPs) and hair cell cochlear microphonics (CMs). Long-term KA effects were assessed using auditory brainstem response (ABR) measurements for up to 31 weeks post-KA exposure. KA infusion immediately abolished AN CAPs while having mild impact on the CM. ABR wave I, the far-field AN response, showed a pronounced 40-75 % amplitude reduction at moderate-to-high sound levels that persisted for the duration of the study. In contrast, wave I latency and the amplitude of wave V were nearly unaffected by KA, and waves II-IV were less reduced than wave I. ABR thresholds, calculated based on complete response waveforms, showed no impairment following KA. These results demonstrate that KA exposure in the budgerigar causes irreversible AN damage, most likely through excitotoxic injury to afferent fibers or synapses as in other species, while sparing ABR thresholds. Normal wave V amplitude, assumed to originate centrally, may persist through compensatory mechanisms that restore central response amplitude by downregulating inhibition. Future studies in this new animal model of AN damage can explore effects of this neural lesion, in isolation from hair cell trauma and threshold elevation, on central processing and perception of complex sounds.

Discovery of chiral dihydropyridopyrimidinones as potent, selective and orally bioavailable inhibitors of AKT.

During the course of our research efforts to develop potent and selective AKT inhibitors, we discovered enatiomerically pure substituted dihydropyridopyrimidinones (DHP) as potent inhibitors of protein kinase B/AKT with excellent selectivity against ROCK2. A key challenge in this program was the poor physicochemical properties of the initial lead compound 5. Integration of structure-based drug design and physical properties-based design resulted in replacement of a highly hydrophobic poly fluorinated aryl ring by a simple trifluoromethyl that led to identification of compound 6 with much improved physicochemical properties. Subsequent SAR studies led to the synthesis of new pyran analog 7 with improved cell potency. Further optimization of pharmacokintetics properties by increasing permeability with appropriate fluorinated alkyl led to compound 8 as a potent, selective AKT inhibitors that blocks the phosphorylation of GSK3ß in vivo and had robust, dose and concentration dependent efficacy in the U87MG tumor xenograft model.