Alfred L. Nuttall

Aminoglycoside (AG) antibiotic safety is limited by ototoxicity, the mitigation of which is vital considering bacterial resistance mediated erosion of our antibiotic arsenal. Previously, we observed tectorial membrane (TM) sequestration of Ca ²⁺ . We hypothesized that the TM sequesters other cations, including the AG gentamicin. We proposed to test the effect of TM genetic ablation on ototoxicity and TM-AG sequestration. After intraperitoneal AG-furosemide, TM-lacking Tecta ^ΔENT/ΔENT mice showed limited outer hair cell loss, unlike wildtype littermates. Spectroscopy measurements of gentamicin-Texas red (GTTR) were made in isolated wildtype and Tecta ^Y1870C TMs and guinea pig cochleae following direct or intraperitoneal GTTR administration. TM-GTTR sequestration was observed in all cases, while negatively correlated with Tecta ^Y1870C zygosity. In summary, we discovered a novel TM component in the AG ototoxicity pathway. Intact TM structure is necessary for sequestration, and the TM modulates AG ototoxicity. TM-GTTR sequestration following systemic injection indicates that this phenomenon occurs during AG therapy. Single sentence summary: Ototoxic aminoglycosides collect inside the acellular tectorial membrane of the inner ear, likely due to electrostatic interactions, and the structural status of that membrane modulates the toxic effect of those aminoglycosides on sensory hair cells.

Upon acoustic stimulation of the mammalian cochlea, a travelling wave will move in a base-to-apex direction, peaking close to the resonant place of the basilar membrane. A gradient of different resonances along the basilar membrane gives rise to frequency-place coding, or tonotopicity, throughout the majority of the cochlea. Per our previous findings, the organ of Corti in the guinea pig cochlear apex does not display tonotopicity. The behavior of the basilar membrane has not been explored throughout the cochlear apex, and so hypothetically tonotopicity is conserved at the level of this structure. Outer hair cells, which influence organ of Corti and basilar membrane mechanics, provide amplification throughout the cochlea. The mechanism for this process in the region close to the helicotrema, which is important for speech and music perception, is not fully described. Here, we describe the acoustically evoked vibrations measured using optical coherence tomography (OCT) at three locations within the guinea pig cochlear apex. We note a decline in the ratio of organ of Corti and basilar membrane gain with proximity to the helicotrema and show that distinct nonlinear behaviors are associated with each location. Phase differences between the cellular portion of the organ of Corti and basilar membrane were present and remained after furosemide treatment. We report that the frequency tuning of the apical basilar membrane is inconsistent with standard models. The analysis of nonlinearity indicates that the mechanisms governing sensory transduction, while still not elucidated, change rapidly within the apical turn—findings that are important for understanding how communication-relevant sounds are encoded by the cochlea.

The auditory physicist stimulated innovation in clinical audiology.

The cochlea maps tones with different frequencies to distinct anatomical locations. For instance, a faint 5000-hertz tone produces brisk responses at a place approximately 8 millimeters into the 18-millimeter-long guinea pig cochlea, but little response elsewhere. This place code pervades the auditory pathways, where neurons have “best frequencies” determined by their connections to the sensory cells in the hearing organ. However, frequency selectivity in cochlear regions encoding low-frequency sounds has not been systematically studied. Here, we show that low-frequency hearing works according to a unique principle that does not involve a place code. Instead, sound-evoked responses and temporal delays are similar across the low-frequency regions of the cochlea. These findings are a break from theories considered proven for 100 years and have broad implications for understanding information processing in the brainstem and cortex and for optimizing the stimulus delivery in auditory implants.

The mammalian cochlea possesses unique acoustic sensitivity due to a mechanoelectrical ‘amplifier’, which requires the metabolic support of the cochlear lateral wall. Loud sound exposure sufficient to induce permanent hearing damage causes cochlear blood flow reduction, which may contribute to hearing loss. However, sensory epithelium involvement in the cochlear blood flow regulation pathway is not fully described. We hypothesize that genetic manipulation of the mechanoelectrical transducer complex will abolish sound induced cochlear blood flow regulation. We used salsa mice, a Chd23 mutant with no mechanoelectrical transduction, and deafness before p56. Using optical coherence tomography angiography, we measured the cochlear blood flow of salsa and wild-type mice in response to loud sound (120 dB SPL, 30 minutes low-pass filtered noise). An expected sound induced decrease in cochlear blood flow occurred in CBA/CaJ mice, but surprisingly the same sound protocol induced cochlear blood flow increases in salsa mice. Blood flow did not change in the contralateral ear. Disruption of the sympathetic nervous system partially abolished the observed wild-type blood flow decrease but not the salsa increase. Therefore sympathetic activation contributes to sound induced reduction of cochlear blood flow. Additionally a local, non-sensory pathway, potentially therapeutically targetable, must exist for cochlear blood flow regulation.

Optical coherence tomography (OCT) has revolutionized physiological studies of the hearing organ, the vibration and morphology of which can now be measured without opening the surrounding bone. In this review, we provide an overview of OCT as used in the otological research, describing advances and different techniques in vibrometry, angiography, and structural imaging.

To understand speech, the slowly varying outline, or envelope, of the acoustic stimulus is used to distinguish words. A small amount of information about the envelope is sufficient for speech recognition, but the mechanism used by the auditory system to extract the envelope is not known. Several different theories have been proposed, including envelope detection by auditory nerve dendrites as well as various mechanisms involving the sensory hair cells. We used recordings from human and animal inner ears to show that the dominant mechanism for envelope detection is distortion introduced by mechanoelectrical transduction channels. This electrical distortion, which is not apparent in the sound-evoked vibrations of the basilar membrane, tracks the envelope, excites the auditory nerve, and transmits information about the shape of the envelope to the brain.

All With the advent of Optical Coherence Tomography (OCT), a variation of the standard laser-interferometer technique, vibrations of various points inside the cochlea can be measured separately and concurrently. In this work we measured vibrations of the basilar membrane (BM) and the Reticular Lamina (RL) in the cochlea of the guinea pig. Stimulus tones had frequencies in the range from 10 to 25 kHz, they were generated and measured with a spacing of 250 Hz. By smoothing and interpolation the spacing was reduced to 50 Hz. We confirmed earlier findings in that in viable animals the responses at the RL are generally larger than those of the BM, and have smaller phase delays. Moreover, these differences are little dependent of the level of stimulation. Our main hypothesis is: stimulation of the stapes primarily excites the structures in the upper (RL) part of the Organ of Corti (OoC) channel. Subsequently, movements of the RL cause movements of the fluid in the OoC channel, which in turn moves the BM. Computation of the sound field generated by the RL yielded results that agree very well with the data. These results thus confirm the hypothesis.

Significance: To perceive speech, the brain relies on inputs from sensory cells located near the top of the spiral-shaped cochlea. This low-frequency region of the inner ear is anatomically difficult to access, and it has not previously been possible to study its mechanical response to sound in intact preparations. Here, we used optical coherence tomography to image sound-evoked vibration inside the intact cochlea. We show that low-frequency sound moves a small portion of the basilar membrane, and that the motion declines in an exponential manner across the basilar membrane. Hence, the response of the hearing organ to speech-frequency sounds is different from the one evident in high-frequency cochlear regions.