Electrocochleographic frequency-following responses as a potential marker of age-related cochlear neural degeneration.

Auditory nerve (AN) fibers that innervate inner hair cells in the cochlea degenerate with advancing age. It has been proposed that age-related reductions in brainstem frequency-following responses (FFR) to the carrier of low-frequency, high-intensity pure tones may partially reflect this neural loss in the cochlea (Märcher-Rørsted et al., 2022). If the loss of AN fibers is the primary factor contributing to age-related changes in the brainstem FFR, then the FFR could serve as an indicator of cochlear neural degeneration. In this study, we employed electrocochleography (ECochG) to investigate the effects of age on frequency-following neurophonic potentials, i.e., neural responses phase-locked to the carrier frequency of the tone stimulus. We compared these findings to the brainstem-generated FFRs obtained simultaneously using the same stimulation. We conducted recordings in young and older individuals with normal hearing. Responses to pure tones (250 ms, 516 and 1086 Hz, 85 dB SPL) and clicks were recorded using both ECochG at the tympanic membrane and traditional scalp electroencephalographic (EEG) recordings of the FFR. Distortion product otoacoustic emissions (DPOAE) were also collected. In the ECochG recordings, sustained AN neurophonic (ANN) responses to tonal stimulation, as well as the click-evoked compound action potential (CAP) of the AN, were significantly reduced in the older listeners compared to young controls, despite normal audiometric thresholds. In the EEG recordings, brainstem FFRs to the same tone stimulation were also diminished in the older participants. Unlike the reduced AN CAP response, the transient-evoked wave-V remained unaffected. These findings could indicate that a decreased number of AN fibers contributes to the response in the older participants. The results suggest that the scalp-recorded FFR, as opposed to the clinical standard wave-V of the auditory brainstem response, may serve as a more reliable indicator of age-related cochlear neural degeneration.

Predicting early auditory evoked potentials using a computational model of auditory-nerve processing.

Non-invasive electrophysiological measures, such as auditory evoked potentials (AEPs), play a crucial role in diagnosing auditory pathology. However, the relationship between AEP morphology and cochlear degeneration remains complex and not well understood. Dau [J. Acoust. Soc. Am. 113, 936-950 (2003)] proposed a computational framework for modeling AEPs that utilized a nonlinear auditory-nerve (AN) model followed by a linear unitary response function. While the model captured some important features of the measured AEPs, it also exhibited several discrepancies in response patterns compared to the actual measurements. In this study, an enhanced AEP modeling framework is presented, incorporating an improved AN model, and the conclusions from the original study were reevaluated. Simulation results with transient and sustained stimuli demonstrated accurate auditory brainstem responses (ABRs) and frequency-following responses (FFRs) as a function of stimulation level, although wave-V latencies remained too short, similar to the original study. When compared to physiological responses in animals, the revised model framework showed a more accurate balance between the contributions of auditory-nerve fibers (ANFs) at on- and off-frequency regions to the predicted FFRs. These findings emphasize the importance of cochlear processing in brainstem potentials. This framework may provide a valuable tool for assessing human AN models and simulating AEPs for various subtypes of peripheral pathologies, offering opportunities for research and clinical applications.

Age-related reduction in frequency-following responses as a potential marker of cochlear neural degeneration.

Healthy aging may be associated with neural degeneration in the cochlea even before clinical hearing loss emerges. Reduction in frequency-following responses (FFRs) to tonal carriers in older clinically normal-hearing listeners has previously been reported, and has been argued to reflect an age-dependent decline in temporal processing in the central auditory system. Alternatively, age-dependent loss of auditory nerve fibers (ANFs) may have little effect on audiometric sensitivity and yet compromise the precision of neural phase-locking relying on joint activity across populations of fibers. This peripheral loss may, in turn, contribute to reduced neural synchrony in the brainstem as reflected in the FFR. Here, we combined human electrophysiology and auditory nerve (AN) modeling to investigate whether age-related changes in the FFR would be consistent with peripheral neural degeneration. FFRs elicited by pure tones and frequency sweeps at carrier frequencies between 200 and 1200 Hz were obtained in older (ages 48-76) and younger (ages 20-30) listeners, both groups having clinically normal audiometric thresholds up to 6 kHz. The same stimuli were presented to a computational model of the AN in which age-related loss of hair cells or ANFs was modelled using human histopathological data. In the older human listeners, the measured FFRs to both sweeps and pure tones were found to be reduced across the carrier frequencies examined. These FFR reductions were consistent with model simulations of age-related ANF loss. In model simulations, the phase-locked response produced by the population of remaining fibers decreased proportionally with increasing loss of the ANFs. Basal-turn loss of inner hair cells also reduced synchronous activity at lower frequencies, albeit to a lesser degree. Model simulations of age-related threshold elevation further indicated that outer hair cell dysfunction had no negative effect on phase-locked AN responses. These results are consistent with a peripheral source of the FFR reductions observed in older normal-hearing listeners, and indicate that FFRs at lower carrier frequencies may potentially be a sensitive marker of peripheral neural degeneration.

On the use of envelope following responses to estimate peripheral level compression in the auditory system.

Individual estimates of cochlear compression may provide complementary information to traditional audiometric hearing thresholds in disentangling different types of peripheral cochlear damage. Here we investigated the use of the slope of envelope following response (EFR) magnitude-level functions obtained from four simultaneously presented amplitude modulated tones with modulation frequencies of 80-100 Hz as a proxy of peripheral level compression. Compression estimates in individual normal hearing (NH) listeners were consistent with previously reported group-averaged compression estimates based on psychoacoustical and distortion-product oto-acoustic emission (DPOAE) measures in human listeners. They were also similar to basilar membrane (BM) compression values measured invasively in non-human mammals. EFR-based compression estimates in hearing-impaired listeners were less compressive than those for the NH listeners, consistent with a reduction of BM compression. Cochlear compression was also estimated using DPOAEs in the same NH listeners. DPOAE estimates were larger (less compressive) than EFRs estimates, showing no correlation. Despite the numerical concordance between EFR-based compression estimates and group-averaged estimates from other methods, simulations using an auditory nerve (AN) model revealed that compression estimates based on EFRs might be highly influenced by contributions from off-characteristic frequency (CF) neural populations. This compromises the possibility to estimate on-CF (i.e., frequency-specific or "local") peripheral level compression with EFRs.

Investigating the Effect of Cochlear Synaptopathy on Envelope Following Responses Using a Model of the Auditory Nerve.

The healthy auditory system enables communication in challenging situations with high levels of background noise. Yet, despite normal sensitivity to pure tones, many listeners complain about having difficulties in such situations. Recent animal studies demonstrated that noise overexposure that produces temporary threshold shifts can cause the loss of auditory nerve (AN) fiber synapses (i.e., cochlear synaptopathy, CS), which appears to predominantly affect medium- and low-spontaneous rate (SR) fibers. In the present study, envelope following response (EFR) magnitude-level functions were recorded in normal hearing (NH) threshold and mildly hearing-impaired (HI) listeners with thresholds elevated above 2 kHz. EFRs were elicited by sinusoidally amplitude modulated (SAM) tones presented in quiet with a carrier frequency of 2 kHz, modulated at 93 Hz, and modulation depths of 0.85 (deep) and 0.25 (shallow). While EFR magnitude-level functions for deeply modulated tones were similar for all listeners, EFR magnitudes for shallowly modulated tones were reduced at medium stimulation levels in some NH threshold listeners and saturated in all HI listeners for the whole level range. A phenomenological model of the AN was used to investigate the extent to which hair-cell dysfunction and/or CS could explain the trends observed in the EFR data. Hair-cell dysfunction alone, including postulated elevated hearing thresholds at extended high frequencies (EHF) beyond 8 kHz, could not account for the recorded EFR data. Postulated CS led to simulations generally consistent with the recorded data, but a loss of all types of AN fibers was required within the model framework. The effects of off-frequency contributions (i.e., away from the characteristic place of the stimulus) and the differential loss of different AN fiber types on EFR magnitude-level functions were analyzed. When using SAM tones in quiet as the stimulus, model simulations suggested that (1) EFRs are dominated by the activity of high-SR fibers at all stimulus intensities, and (2) EFRs at medium-to-high stimulus levels are dominated by off-frequency contributions.