Envelope following responses for hearing diagnosis: Robustness and methodological considerations.

Recent studies have found that envelope following responses (EFRs) are a marker of age-related and noise- or ototoxic-induced cochlear synaptopathy (CS) in research animals. Whereas the cochlear injury can be well controlled in animal research studies, humans may have an unknown mixture of sensorineural hearing loss [SNHL; e.g., inner- or outer-hair-cell (OHC) damage or CS] that cannot be teased apart in a standard hearing evaluation. Hence, a direct translation of EFR markers of CS to a differential CS diagnosis in humans might be compromised by the influence of SNHL subtypes and differences in recording modalities between research animals and humans. To quantify the robustness of EFR markers for use in human studies, this study investigates the impact of methodological considerations related to electrode montage, stimulus characteristics, and presentation, as well as analysis method on human-recorded EFR markers. The main focus is on rectangularly modulated pure-tone stimuli to evoke the EFR based on a recent auditory modelling study that showed that the EFR was least affected by OHC damage and most sensitive to CS in this stimulus configuration. The outcomes of this study can help guide future clinical implementations of electroencephalography-based SNHL diagnostic tests.

Envelope following responses predict speech-in-noise performance in normal-hearing listeners.

Permanent threshold elevation after noise exposure or aging is caused by loss of sensory cells; however, animal studies show that hair cell loss is often preceded by degeneration of the synapses between sensory cells and auditory nerve fibers. Silencing these neurons is likely to degrade auditory processing and may contribute to difficulties understanding speech in noisy backgrounds. Reduction of suprathreshold ABR amplitudes can be used to quantify synaptopathy in inbred mice. However, ABR amplitudes are highly variable in humans, and thus more challenging to use. Since noise-induced neuropathy preferentially targets fibers with high thresholds and low spontaneous rate and because phase locking to temporal envelopes is particularly strong in these fibers, measuring envelope following responses (EFRs) might be a more robust measure of cochlear synaptopathy. A recent auditory model further suggests that modulation of carrier tones with rectangular envelopes should be less sensitive to cochlear amplifier dysfunction and, therefore, a better metric of cochlear neural damage than sinusoidal amplitude modulation. In this study, we measure performance scores on a variety of difficult word-recognition tasks among listeners with normal audiograms and assess correlations with EFR magnitudes to rectangular versus sinusoidal modulation. Higher harmonics of EFR magnitudes evoked by a rectangular-envelope stimulus were significantly correlated with word scores, whereas those evoked by sinusoidally modulated tones did not. These results support previous reports that individual differences in synaptopathy may be a source of speech recognition variability despite the presence of normal thresholds at standard audiometric frequencies.NEW & NOTEWORTHY Recent studies suggest that millions of people may be at risk of permanent impairment from cochlear synaptopathy, the age-related and noise-induced degeneration of neural connections in the inner ear. This study examines electrophysiological responses to stimuli designed to improve detection of neural damage in subjects with normal hearing sensitivity. The resultant correlations with word recognition performance are consistent with a contribution of cochlear neural damage to deficits in hearing in noise abilities.

The derived-band envelope following response and its sensitivity to sensorineural hearing deficits.

The envelope following response (EFR) has been proposed as a non-invasive marker of synaptopathy in animal models. However, its amplitude is affected by the spread of basilar-membrane excitation and other coexisting sensorineural hearing deficits. This study aims to (i) improve frequency specificity of the EFR by introducing a derived-band EFR (DBEFR) technique and (ii) investigate the effect of lifetime noise exposure, age and outer-hair-cell (OHC) damage on DBEFR magnitudes. Additionally, we adopt a modelling approach to validate the frequency-specificity of the DBEFR and test how different aspects of sensorineural hearing loss affect peripheral generators. The combined analysis of simulations and experimental data proposes that the DBEFRs extracted from the [2-6]-kHz frequency band is a sensitive and frequency-specific measure of synaptopathy in humans. Individual variability in DBEFR magnitudes among listeners with normal audiograms was explained by their self-reported amount of experienced lifetime noise-exposure and corresponded to amplitude variability predicted by synaptopathy. Older listeners consistently had reduced DBEFR magnitudes in comparison to young normal-hearing listeners, in correspondence to how age-induced synaptopathy affects EFRs and compromises temporal envelope encoding. To a lesser degree, OHC damage was also seen to affect the DBEFR magnitude, hence the DBEFR metric should ideally be combined with a sensitive marker of OHC damage to offer a differential diagnosis of synaptopathy in listeners with impaired audiograms.

Applicability of subcortical EEG metrics of synaptopathy to older listeners with impaired audiograms.

Emerging evidence suggests that cochlear synaptopathy is a common feature of sensorineural hearing loss, but it is not known to what extent electrophysiological metrics targeting synaptopathy in animals can be applied to people, such as those with impaired audiograms. This study investigates the applicability of subcortical electrophysiological measures associated with synaptopathy, i.e., auditory brainstem responses (ABRs) and envelope following responses (EFRs), to older participants with high-frequency sloping audiograms. The outcomes of this study are important for the development of reliable and sensitive synaptopathy diagnostics in people with normal or impaired outer-hair-cell function. Click-ABRs at different sound pressure levels and EFRs to amplitude-modulated stimuli were recorded, as well as relative EFR and ABR metrics which reduce the influence of individual factors such as head size and noise floor level on the measures. Most tested metrics showed significant differences between the groups and did not always follow the trends expected from synaptopathy. Age was not a reliable predictor for the electrophysiological metrics in the older hearing-impaired group or young normal-hearing control group. This study contributes to a better understanding of how electrophysiological synaptopathy metrics differ in ears with healthy and impaired audiograms, which is an important first step towards unravelling the perceptual consequences of synaptopathy.

Otoacoustic emission estimates of human basilar membrane impulse response duration and cochlear filter tuning.

This study describes a method based on temporal suppression of click-evoked otoacoustic emissions (CEOAEs) to estimate the time course and duration of human basilar membrane impulse responses (BM IRs). This was achieved by tracing the suppression of dominant peaks in the CEOAE spectrum as a function of the temporal separation between two equal-level stimulus clicks. The relationship between the suppression pattern and underlying BM IR duration near the generation site of the CEOAE frequency was established using model simulations. To relate BM IR duration estimates to cochlear filter tuning (QERB), a tuning ratio was derived from available BM IR measurements in animals. Results for 11 normal-hearing subjects yielded BM IR duration estimates of 37.4/F ms at 65 dB peSPL and 36.4/F ms at 71 dB peSPL, with F in kHz. Corresponding QERB estimates were 14.2F[in kHz]0.22 at 65 dB peSPL and 13.8F[in kHz]0.22 at 71 dB peSPL. Because the proposed temporal suppression method relies on cochlear nonlinearity, the method is applicable for stimulus levels above 30-40 dB SPL and complements existing OAE methods to assess human cochlear filter tuning.

A comparative study of seven human cochlear filter models.

Auditory models have been developed for decades to simulate characteristics of the human auditory system, but it is often unknown how well auditory models compare to each other or perform in tasks they were not primarily designed for. This study systematically analyzes predictions of seven publicly-available cochlear filter models in response to a fixed set of stimuli to assess their capabilities of reproducing key aspects of human cochlear mechanics. The following features were assessed at frequencies of 0.5, 1, 2, 4, and 8 kHz: cochlear excitation patterns, nonlinear response growth, frequency selectivity, group delays, signal-in-noise processing, and amplitude modulation representation. For each task, the simulations were compared to available physiological data recorded in guinea pigs and gerbils as well as to human psychoacoustics data. The presented results provide application-oriented users with comprehensive information on the advantages, limitations and computation costs of these seven mainstream cochlear filter models.

Auditory Brainstem Response Latency in Noise as a Marker of Cochlear Synaptopathy.

Evidence from animal and human studies suggests that moderate acoustic exposure, causing only transient threshold elevation, can nonetheless cause "hidden hearing loss" that interferes with coding of suprathreshold sound. Such noise exposure destroys synaptic connections between cochlear hair cells and auditory nerve fibers; however, there is no clinical test of this synaptopathy in humans. In animals, synaptopathy reduces the amplitude of auditory brainstem response (ABR) wave-I. Unfortunately, ABR wave-I is difficult to measure in humans, limiting its clinical use. Here, using analogous measurements in humans and mice, we show that the effect of masking noise on the latency of the more robust ABR wave-V mirrors changes in ABR wave-I amplitude. Furthermore, in our human cohort, the effect of noise on wave-V latency predicts perceptual temporal sensitivity. Our results suggest that measures of the effects of noise on ABR wave-V latency can be used to diagnose cochlear synaptopathy in humans. SIGNIFICANCE STATEMENT: Although there are suspicions that cochlear synaptopathy affects humans with normal hearing thresholds, no one has yet reported a clinical measure that is a reliable marker of such loss. By combining human and animal data, we demonstrate that the latency of auditory brainstem response wave-V in noise reflects auditory nerve loss. This is the first study of human listeners with normal hearing thresholds that links individual differences observed in behavior and auditory brainstem response timing to cochlear synaptopathy. These results can guide development of a clinical test to reveal this previously unknown form of noise-induced hearing loss in humans.

Functional modeling of the human auditory brainstem response to broadband stimulation.

Population responses such as the auditory brainstem response (ABR) are commonly used for hearing screening, but the relationship between single-unit physiology and scalp-recorded population responses are not well understood. Computational models that integrate physiologically realistic models of single-unit auditory-nerve (AN), cochlear nucleus (CN) and inferior colliculus (IC) cells with models of broadband peripheral excitation can be used to simulate ABRs and thereby link detailed knowledge of animal physiology to human applications. Existing functional ABR models fail to capture the empirically observed 1.2-2 ms ABR wave-V latency-vs-intensity decrease that is thought to arise from level-dependent changes in cochlear excitation and firing synchrony across different tonotopic sections. This paper proposes an approach where level-dependent cochlear excitation patterns, which reflect human cochlear filter tuning parameters, drive AN fibers to yield realistic level-dependent properties of the ABR wave-V. The number of free model parameters is minimal, producing a model in which various sources of hearing-impairment can easily be simulated on an individualized and frequency-dependent basis. The model fits latency-vs-intensity functions observed in human ABRs and otoacoustic emissions while maintaining rate-level and threshold characteristics of single-unit AN fibers. The simulations help to reveal which tonotopic regions dominate ABR waveform peaks at different stimulus intensities.

Experimental evidence for a cochlear source of the precedence effect.

The precedence effect (PE) refers to the dominance of directional information carried by a direct sound (lead) over the spatial information contained in its multiple reflections (lags) in sound localization. Although the processes underlying the PE have been largely investigated, the extent to which peripheral versus central auditory processes contribute to this perceptual phenomenon has remained unclear. The present study investigated the contribution of peripheral processing to the PE through a comparison of physiological and psychoacoustical data in the same human listeners. The psychoacoustical experiments, comprising a fusion task, an interaural time difference detection task and a lateralization task, demonstrated a time range from 1 to 4.6-5 ms, in which the PE operated (precedence window). Click-evoked otoacoustic emissions (CEOAEs) were recorded in both ears to investigate the lead-lag interactions at the level of the basilar membrane (BM) in the cochlea. The CEOAE-derived peripheral and monaural lag suppression was largest for ICIs of 1-4 ms. Auditory-evoked brainstem responses (ABRs) were used to investigate monaural and binaural lag suppression at the brainstem level. The responses to monaural stimulation reflected the peripheral lag suppression observed in the CEOAE results, while the binaural brainstem responses did not show any substantial contribution of binaural processes to monaural lag suppression. The results demonstrated that the lag suppression occurring at the BM in a time range from 1 to 4 ms, as indicated by the suppression of the lag-CEOAE, was the source of the reduction in the lag-ABRs and a possible peripheral contributor to the PE for click stimuli.

Nonlinear time-domain cochlear model for transient stimulation and human otoacoustic emission.

This paper describes the implementation and performance of a nonlinear time-domain model of the cochlea for transient stimulation and human otoacoustic emission generation. The nonlinearity simulates compressive growth of measured basilar-membrane impulse responses. The model accounts for reflection and distortion-source otoacoustic emissions (OAEs) and simulates spontaneous OAEs through manipulation of the middle-ear reflectance. The model was calibrated using human psychoacoustical and otoacoustic tuning parameters. It can be used to investigate time-dependent properties of cochlear mechanics and the generator mechanisms of otoacoustic emissions. Furthermore, the model provides a suitable preprocessor for human auditory perception models where realistic cochlear excitation patterns are desired.

Temporal suppression of the click-evoked otoacoustic emission level-curve.

The click-evoked otoacoustic emission (CEOAE) level-curve grows linearly for clicks below 40-60 dB and saturates for higher inputs. This study investigates dynamic (i.e., time-dependent) features of the CEOAE level-curve by presenting a suppressor-click less than 8 ms before the test-click. An alteration of the CEOAE level-curve, designated here as temporal suppression, was observed within this time period, and was shown to depend on the levels and the temporal separation of the two clicks. Temporal suppression occurred for all four subjects tested, and resulted in a vertical offset from the unsuppressed level-curve for test-click levels greater than 50 dB peak-equivalent level (peSPL). Temporal suppression was greatest for suppressors presented 1-4 ms before the test click, and the magnitude and time scale of the effect were subject dependent. Temporal suppression was furthermore observed for the short- (i.e., 6-18 ms) and long-latency (i.e., 24-36 ms) regions of the CEOAE, indicating that temporal suppression similarly affects synchronized spontaneous otoacoustic emissions (SSOAEs) and purely evoked CEOAE components. Overall, this study demonstrates that temporal suppression of the CEOAE level-curve reflects a dynamic process in human cochlear processing that works on a time scale of 0-10 ms.