# Predicting Cochlear Synaptopathy in Mice with Varying Degrees of Outer Hair Cell Dysfunction Using Auditory Evoked Potentials

## TL;DR

This study evaluates how well different auditory tests can predict cochlear synapse loss in mice, finding that a specific type of sound test is most effective.

## Contribution

The study validates RAM EFR as a superior predictor of synaptopathy in mice with varying outer hair cell dysfunction.

## Key findings

- RAM EFR at 1000 Hz best predicts synapse numbers in broad synapse loss.
- Combining RAM EFR with ABR improves synapse prediction accuracy.
- ABR is most effective for predicting focal synaptopathy.

## Abstract

Although human temporal bones suggest that cochlear synapse numbers decline with age and noise exposure, no validated diagnostic method exists. In animal models, 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, measuring SAM EFR at the optimal modulation frequency (1000 Hz) is difficult in humans. A rectangular amplitude modulated (RAM) tone may be more sensitive to synaptopathy, but this has not been validated in animals. In addition, because synaptopathy likely co-occurs with outer hair cell dysfunction (OHC), a diagnostic assay needs to be robust to abnormal auditory thresholds. The objective of this study was to evaluate the relative ability of ABR and EFR measures to predict synapse numbers in mice with varying degrees of synaptopathy and OHC dysfunction.

Distortion product otoacoustic emissions (DPOAEs), ABR, SAM EFR, and RAM EFR were recorded from 57 mice with a range of auditory thresholds and degrees of synaptopathy. Cross-validation was used to compare the relative ability of linear regression models incorporating different measures to predict synapse numbers. Predictions were confirmed histologically.

RAM EFR modulated at 1000 Hz was the single best predictor of synapse numbers for broad synapse loss across frequency, while combining RAM EFR with ABR further improved predictions. In contrast, ABR best predicted focal synaptopathy. Incorporating DPOAEs improved predictions for EFR, but not ABR.

RAM EFR, ABR, and DPOAEs should be used in the future when predicting synapse numbers.

The online version contains supplementary material available at 10.1007/s10162-025-01015-x.