Predicting cochlear synaptopathy in mice with varying degrees of outer hair cell dysfunction using auditory evoked potentials

Abstract

Human temporal bones suggest a steady decline of cochlear synapses with age and greater synapse loss in adults with a history of military or occupational noise exposure. However, there is currently no validated method of diagnosing this type of cochlear deafferentation in living humans. Animal models indicate that cochlear synaptopathy is associated with reduced auditory brainstem response (ABR) wave 1 amplitude and envelope following response (EFR) magnitude for a sinusoidally amplitude modulated (SAM) tone. However, translating the SAM EFR to humans is complicated because it is difficult to obtain this measurement in humans using the same modulation frequency that showed the strongest relationship with synaptopathy in mice (1000 Hz). Computational modeling suggests that EFR magnitude measured with a rectangular amplitude modulated (RAM) tone may be a more sensitive measure of synaptopathy than the SAM EFR. In addition, because synaptopathy likely co-occurs with outer hair cell dysfunction, a diagnostic assay for synaptopathy needs to be robust even when auditory thresholds are abnormal. This study compared the relative ability of the ABR, SAM EFR, and RAM EFR to predict synapse numbers in mice with a large range of auditory thresholds and degrees of synaptopathy. The results indicate that the RAM EFR modulated at 1000 Hz is the single best predictor of synapse number when there is a broad loss of synapses across frequency, while combining RAM EFR and ABR further improves synapse prediction. In contrast, focal synaptopathy is best predicted by ABR wave 1 amplitude. Significance StatementThis study assessed the relative ability of two auditory evoked potentials to identify cochlear synaptopathy, a type of cochlear deafferentation that occurs with age and noise exposure, in mice. Performance of these measures in the presence of outer hair cell (OHC) damage was also evaluated because synaptopathy is expected to often co-occur with OHC dysfunction. Concrete recommendations of measurements to use for non-invasive diagnosis of synaptopathy in humans are provided. This represents a significant advance toward diagnosis of a condition that is thought to have a high prevalence in humans. The ability to identify individuals with cochlear synaptopathy is vital for furthering our understanding of how this auditory deficit impairs auditory perception and the future development of treatment options.