Abstract
Auditory de-afferentation, a permanent reduction in the number of inner-hair-cells and auditory-nerve synapses due to cochlear synaptopathy or damage, can reliably be quantified using temporal bone histology and immunostaining. There is, however, 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) based markers for synaptopathy, their interpretation in humans has suffered from translational issues related to neural generator differences, unknown hearing-damage histopathologies or measurement sensitivity. To render AEP-based markers of synaptopathy more robust 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 physiology, we optimized the stimulus envelope for envelope-following-responses (EFRs) to optimally and synchronously stimulate the available auditory-nerve population and consequently generate a strong AEP. We additionally used model simulations to explore which stimuli evoked a response which was sensitive to synaptopathy, while being insensitive to possible co-existing outer-hair-cell pathologies. We compared the model-predicted trends to AEPs recorded in younger and older listeners (N=44, 24f) who either had normal or impaired audiograms. We conclude that optimal stimulation paradigms for EFR-based quantification of synaptopathy should have sharply rising envelope shapes, a minimal plateau duration of 1.7-2.1 ms for a 120 Hz modulation rate, and inter-peak intervals which contain near-zero amplitudes. From our recorded conditions, the optimal EFR-evoking stimulus had a rectangular envelope shape with a 25% duty cycle and a 95% modulation depth.
Significance Statement Even though cochlear synaptopathy is since 2009 identified as a form of sensorineural hearing loss (SNHL) which also affect primates and humans, clinical practice does not routinely screen for it and the role of synaptopathy for sound and speech perception is presently unclear. Consequently, cochlear synaptopathy may be underdiagnosed in the ageing population with self-reported hearing difficulties and its perceptual impact underestimated. To enable a differential EEG-based diagnosis of synaptopathy in humans, it is crucial to adopt a stimulation and analysis method which yields a robust response which shows large inter-individual differences which are sensitive to synaptopathy but not affected by other SNHL aspects. Our study uniquely combines computational modeling with experiments in normal and hearing-impaired listeners to design a EFR stimulus which can be used for the differential diagnosis of synaptopathy in humans.
Competing Interest Statement
Ghent University filed a patent application (PCTEP2020053192) which covers some of the ideas presented in this paper. Sarah Verhulst and Viacheslav Vasilkov are inventors.
Abbreviations
- ABR
- auditory brainstem response
- AEP
- auditory evoked potentials
- AM
- amplitude modulation
- ANF
- auditory-nerve fiber
- BB
- broadband
- BM
- basilar membrane
- CF
- characteristic frequency
- CN
- cochlear nucleus
- EFR
- envelope following response
- H/M/LSR
- high/medium/low spontaneous rate
- HI
- hearing-impaired
- IC
- inferior colliculus
- IHC
- inner-hair-cell
- MD
- modulation depth
- NH
- normal-hearing
- OAE
- otoacoustic emission
- OHC
- outer hair cell
- peSPL
- peak-equivalent sound pressure level
- RAM
- rectangular-wave amplitude-modulated
- RMS
- root mean square
- SAM
- sinusoidal amplitude-modulated
- SNHL
- sensorineural hearing loss