Gain-sensitive cochlear microphonics - a diagnostic test of functional and physiological effects of sensory hearing loss

PROJECT SUMMARY
According to the Centers for Disease Control, hearing loss is the third most common chronic physical condition
in the US, surpassing diabetes, and cancer in prevalence. Most cases of hearing loss occur due to damage to
the cochlear amplifier. The term "cochlear amplifier" refers to the chain of processes that amplify low-level vibra-
tions within the cochlea, thereby enhancing the sensitivity and dynamic range of hearing. While many details of
the amplifier's mechanisms remain unclear, it is well-established that electromotility, the voltage-activated length
changes of cochlear outer hair cells (OHCs), plays a crucial role. The OHC-driven amplification is vulnerable to
common factors such as excessive noise, ototoxic drugs, aging, and congenital defects. Various insults can
affect distinct stages of the amplification process, inhibiting electromotility or reducing OHC stimulation, leading
to sensory hearing loss. However, current diagnostic tests, such as recordings of otoacoustic emissions (OAEs),
have limited ability to provide precise information on the site of damage within the cochlea and its functional
consequences. My research aims to address this gap by developing a diagnostic test of cochlear amplification.
We propose that recordings of cochlear microphonics (CM), which represent the summed electrical fields of
stimulated OHCs, can assess the functional state of local cochlear amplification and identify the site of damage
within the amplifier. The proposed test combines the place-specific properties of cochlear two-tone suppression
with recent findings on intracochlear motions that reveal broad regions of excitation and suppression in OHC
vibrations. We hypothesize that the suppression of CM responses is controlled by local gain changes in cochlear
motions; hence, we named it gain-sensitive CM (gCM). Thus, the gCM test should be capable of detecting coch-
lear regions with dysfunctional OHCs and evaluating the dynamic range of the amplifier at a specific cochlear
location. Furthermore, we predict that gCM, when measured in low- vs. high-intensity regimes, will exhibit differ-
ential sensitivity to cochlear amplification loss caused solely by dysfunctional electromotility vs. by disruptions in
the processes driving it. Currently, no other hearing test can achieve this level of diagnostic precision, which is
essential for developing and testing individualized treatment options. In the short term, we aim to validate the
gCM in mice by comparing it to direct, albeit invasive, measures of cochlear gain in the organ of Corti vibrations
as well as to more established OAE tests. To evaluate the hypothesized site- and place-specificity of gCM, we
will use both healthy and hearing-impaired mice where damage is either limited to a specific stage of the ampli-
fication process or to a specific cochlear region. The results of this study have the potential to revolutionize the
treatment of sensory hearing loss by providing an objective and noninvasive test to identify the nature and loca-
tion of cellular damage responsible for amplification loss that outperforms OAE tests. Consequently, this project
could enhance the precision of diagnosing sensory hearing loss in humans and facilitate the development and
implementation of targeted intervention strategies in both research and clinical settings.

Grant Number: 1R21DC021794-01A1
NIH Institute/Center: NIH
Principal Investigator: Karolina Charaziak