Auditory de-afferentation, a permanent reduction in the number of innerhair-cells and auditory-nerve synapses due to cochlear damage or synaptopathy, can reliably be quantified using temporal bone histology and immunostaining. However, there is an urgent need for non-invasive markers of synaptopathy to study its perceptual consequences in live humans and to develop effective therapeutic interventions. While animal studies have identified candidate auditory-evoked-potential (AEP) markers for synaptopathy, their interpretation in humans has suffered from translational issues related to neural generator differences, unknown hearing-damage histopathologies or lack of measurement sensitivity. To render AEP-based markers of synaptopathy more sensitive and differential to the synaptopathy aspect of sensorineural hearing loss, we followed a combined computational and experimental approach. Starting from the known characteristics of auditory-nerve

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. Here, 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 vs. 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.

4The perceptual consequences of cochlear synaptopathy are presently not well understood as a direct 5 quantification of synaptopathy is not possible in humans. To study its role for human hearing, recent studies 6 have instead correlated changes in basic supra-threshold psychoacoustic tasks with individual differences in 7 subcortical EEG responses, as a proxy measure for synaptopathy. It is not clear whether the reported 8 missing relationships between the psychoacoustic quantities and the EEG are due to the adopted methods, 9 or to a minor role of synaptopathy for sound perception. We address this topic by studying the theoretical 10 relationship between subcortical EEG and psychoacoustic methods for different sensorineural hearing deficits. 11 1 Introduction 12The role of cochlear synaptopathy (i.e., the loss of inner-hair-cell auditory-nerve fiber synapses due to noise 13 exposure or aging; or hidden hearing loss) for supra-threshold hearing has been heavily contested in recent 14 human studies [1, 2, 3, 4] even though animal studies show clear histological evidence for synaptopathy [5, 6, 7]. 15It is not clear whether the cause of the missing correlations between subcortical EEG measures, as a non-16 invasive tool to quantify synaptopathy, and the suprathreshold psychoacoustic tasks stems from methodological 17 confounds. It might be that the adopted subcortical EEG methods (e.g. the envelope-following response, EFR 18 and auditory brainstem response, ABR) are not sensitive markers of synaptopathy in humans, or, that the EEG 19 methods are not targeting the same mechanisms involved in the psychoacoustic task, resulting in differential 20 effects of synaptopathy on both measures. To address these issues, we study the theoretical relationship between 21 the EFR and two common supra-threshold hearing tasks: tone-in-noise (TiN) and amplitude-modulation (AM) 22 detection for different degrees of sensorineural hearing loss. We employ a computational model of the human 23 auditory periphery that simulates neural responses to quantify psychoacoustic detection cues and subcortical 24 EEG metrics [8]. We simulate how different aspects of sensorineural hearing loss (synaptopathy, cochlear gain 25 loss and combinations) affect the theoretical relationship between the EFR and psychoacoustic metrics to assess 26 their sensitivity in quantifying synaptopathy in humans. 27Verhulst et al., p. 2 2 Methods 28Participants were informed according to the ethical guidelines at Oldenburg University and paid for participa-29 tion. TiN detection: 11 normal-hearing (NH; 24±4.4 yrs, 9 females) subjects with normal audiograms (Auritec 30 AT900) and 9 hearing-impaired (HI; 63 ± 6, 7 females) participants with a high-frequency sloping hearing loss 31 (≤40 dB HL up to 6 kHz, with a 20 to 25 dB HL loss at 4 kHz). AM detection: 12 NH listeners (26±4, 7 32 females) with flat audiograms and a max. 15 dB HL threshold at 4 kHz. 8 HI listeners (70±5, 5 females) with 33 sloping audiograms and a 4-kHz threshold between 20 and 40 dB HL. 34Psycho...