Neil J. Ingham1, Clarisse H. Panganiban1, Navid Banafshe1, Christopher J. Plack2, Karen P. Steel1
Wolfson Centre for Age-Related Diseases, King’s College London, London SE1 1UL, UK
2Manchester Centre for Audiology and Deafness, The University of Manchester, Manchester M13 9PL, UK

Any clinical trial for hearing treatments would benefit from improved stratification of the participants according to the pathophysiology underlying their hearing loss, but this need becomes more acute as molecular or small molecule approaches are developed. Three major categories of cochlear pathology in age-related hearing loss were proposed by Schuknecht & Gacek (1993): sensory (hair cell dysfunction), metabolic (stria vascularis dysfunction) and neural (auditory neuron defects). Non-invasive methods for distinguishing hair cell from synaptic/neural defects have been proposed, although there are concerns regarding sensitivity and specificity. However, methods for identifying a strial defect are not well-established beyond audiogram shapes (Dubno et al 2013), yet these are important to detect because they will require different treatment approaches, and there is little point in treating a hair cell or a synaptic defect if the primary pathology is a dysfunctional stria. In the mouse we have the advantage of a better understanding of the underlying pathology compared with humans. We are using a set of mouse mutants with known initial sites of lesion to search for diagnostic tools based on objective electrophysiological measures. The mutants have a primary strial dysfunction and reduced endocochlear potential (S1pr2stdf), a primary inner hair cell defect (Klhl18lowf), a primary outer hair cell defect (Slc26a5tm1(EGFP/cre/ERT2)Wtsi) and a primary synaptic abnormality with swelling of synaptic boutons under inner hair cells (Wbp2tm1a). So far, we have used features of ABRs and DPOAEs to distinguish between inner and outer hair cell defects but not strial dysfunction (Ingham et al. 2020). We continue investigating ABR waveform features, frequency tuning, forward masking responses, increasing click repetition rates, tone-in-noise responses and inter-trial coherence tests as non-invasive objectives measures that have potential to be translated into a human diagnostic test.

Schuknecht HF & Gacek MR (1993). Ann. Otol. Rhinol. Laryngol. 102:1-16.
Dubno JR et al (2013) JARO 14:687-701.
Ingham NJ et al (2020). ARO abstracts 43:92.

Acknowledgements: Supported by RNID.