PP1315 - Effects of Selective Inner Hair Cell Loss on Envelope Following Response Correlates

Pure tone audiometry is the accepted metric for hearing healthcare. However, the relationship between anatomical damage and hearing deficits is complex as threshold testing can fail to detect some forms of inner ear pathology, such as the loss of afferent synapses, referred to as cochlear synaptopathy, or complete loss of inner hair cells (IHC). Here we aimed to evaluate the relationship among threshold and suprathreshold auditory brainstem response (ABR) correlates and envelope following response (EFR) magnitude-level functions before and after carboplatin, an ototoxic drug that reliably and selectively destroys IHCs in the chinchilla.


Summary:

Objectives:

Inner hair cell (IHC) pathology, such as deafferentation of IHC afferent nerve fibers, referred to as synaptopathy, or the complete loss of IHCs, has been speculated to contribute to functional auditory deficits such as poorer hearing-in-noise. However, suprathreshold outcomes are often not well correlated with hearing sensitivity, suggesting a need for additional diagnostic tools that are sensitive to various auditory lesions. Thus far, pre-clinical physiological studies measuring auditory brainstem response (ABR) outcomes after IHC pathology have shown little to no change in thresholds. Yet, ABR wave-I amplitudes are typically reduced at suprathreshold levels, suggesting a reduction in cochlear output despite an absence of elevated thresholds. Suprathreshold ABR wave-I amplitude reductions have been established as the hallmark of afferent synapse loss, but wave-I amplitudes are known to vary greatly across individuals, limiting their use as a physiological biomarker of IHC lesions among patients with auditory complaints without threshold elevations. The envelope following response (EFR) has been suggested as a potential assay that may be sensitive to IHC lesions. The EFR is a steady-state evoked potential that can assess the auditory system’s ability to phase-lock to the stimulus envelope. For the current investigation, we evaluated the relationship among EFR magnitude-level functions before and after carboplatin-induced selective IHC loss in the chinchilla. We hypothesized that IHC loss would reduce EFR amplitudes and these response magnitudes would show a greater degree of sensitivity as a function of stimulus presentation rate and amplitude modulation (AM) depth.

Design:

Free-feeding, young-adult chinchillas (1 – 3 years-of-age), were used to evaluate effects of selective IHC loss on suprathreshold EFR measures before and after carboplatin-treatment. Distortion product otoacoustic emissions (DPOAE) and ABR thresholds were obtained to assess the status of cochlear nonlinearity and as a measure of overall hearing sensitivity. Steady-state stimuli were presented with carrier frequencies of 1, 2, 4, and 8 kHz modulated around 88 Hz (fast-rate) or 50 Hz (slow-rate) across three AM depths, 100% (deep AM), 40% (moderate AM), and 20% (shallow AM). Simultaneous EFR response magnitudes were recorded for bilateral presentations at suprathreshold intensities of 90, 80, and 70 dB SPL for each experimental condition (rate and AM depth). Following baseline measures, animals were treated with a single dose of 75 mg/kg of the anticancer drug carboplatin, a dose known to reliably produce 50 – 80% IHC loss with minimal outer hair cell (OHC) loss. Post-carboplatin assessments were performed three weeks following treatment to allow for recovery time. 

Results:

As expected, carboplatin-treatment had no significant effect on ABR thresholds and DPAEs, suggesting survival and function of OHCs. EFR magnitude-level functions showed differences following carboplatin, even in the absence of elevated thresholds. Specifically, magnitude and phase locking values for shallow AM tones were significantly reduced.

Conclusions:

Findings suggest that suprathreshold EFR measures may be used as a sensitive assay of selective IHC loss and could potentially be used clinically to better classify patient auditory deficits.

Research reported in this abstract was supported by the NIDCD of the National Institute of Health under award number R01DC014088.