Relationships between click-evoked otoacoustic emissions (CEOAEs) and behavioral thresholds have not been explored above 5 kHz due to limitations in CEOAE measurement procedures. New techniques were used to measure behavioral thresholds and CEOAEs up to 16 kHz. A long cylindrical tube of 8-mm diameter, serving as a reflection-less termination, was used to calibrate audiometric stimuli and design a wideband CEOAE stimulus. A second click was presented 15 dB above a probe click level that varied over a 44 dB range, and a nonlinear residual procedure extracted a CEOAE from these click responses. In some subjects (age 14-29 years) with normal hearing up to 8 kHz, CEOAE spectral energy and latency were measured up to 16 kHz. Audiometric thresholds were measured using an adaptive yes-no procedure. Comparison of CEOAE and behavioral thresholds suggested a clinical potential of using CEOAEs to screen for high-frequency hearing loss. CEOAE latencies determined from the peak of averaged, filtered, temporal envelopes decreased to 1 ms with increasing frequency up to 16 kHz. Individual CEOAE envelopes included both compressively-growing, longer-delay components consistent with a coherent-reflection source, and linearly- or expansively-growing, shorter-delay components consistent with a distortion source. Envelope delays of both components were approximately invariant with level.

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Activation of the medial olivocochlear reflex (MOCR) can be assessed indirectly using transient-evoked otoacoustic emissions (TEOAEs). The change in TEOAE amplitudes when the MOCR is activated (medial olivocochlear (MOC) shift) has most often been quantified as the mean value in groups of subjects. The usefulness of MOC shift measurements may be increased by the ability to quantify significant shifts in individuals. This study used statistical resampling to quantify significant MOC shifts in 16 subjects. TEOAEs were obtained using transient stimuli containing energy from 1 to 10 kHz. A nonlinear paradigm was used to extract TEOAEs. Transient stimuli were presented at 30 dB sensation level (SL) with suppressor stimuli presented 12 dB higher. Contralateral white noise, used to activate the MOCR, was presented at 30 dB SL and was interleaved on and off in 30-s intervals during a 7-min recording period. Confounding factors of middle ear muscle reflex and slow amplitude drifts were accounted for. TEOAEs were analyzed in 11 1/3-octave frequency bands. The statistical significance of each individual MOC shift was determined using a bootstrap procedure. The minimum detectable MOC shifts ranged from 0.10 to 3.25 dB and were highly dependent on signal-to-noise ratio at each frequency. Subjects exhibited a wide range of magnitudes of significant MOC shifts in the 1.0-3.2-kHz region (median=1.94 dB, range=0.34-6.51 dB). There was considerable overlap between the magnitudes of significant and nonsignificant shifts. While most subjects had significant MOC shifts in one or more frequency bands below 4 kHz, few had significant shifts in all of these bands. Above 4 kHz, few significant shifts were seen, but this may have been due to lower signal-to-noise ratios. The specific frequency bands containing significant shifts were variable across individuals. Further work is needed to determine the clinical usefulness of examining MOC shifts in individuals.

Hearing impairment is the most common sensory deficit. It is frequently caused by the expression of an allele carrying a single dominant missense mutation. Herein, we show that a single intracochlear injection of an artificial microRNA carried in a viral vector can slow progression of hearing loss for up to 35 weeks in the Beethoven mouse, a murine model of non-syndromic human deafness caused by a dominant gain-of-function mutation in Tmc1 (transmembrane channel-like 1). This outcome is noteworthy because it demonstrates the feasibility of RNA-interference-mediated suppression of an endogenous deafness-causing allele to slow progression of hearing loss. Given that most autosomal-dominant non-syndromic hearing loss in humans is caused by this mechanism of action, microRNA-based therapeutics might be broadly applicable as a therapy for this type of deafness.

Results indicated that a wide range of within- and across-subject variability of MOC shifts was present in a group of young normal-hearing individuals. In some cases, very large changes in MOC shifts (e.g., 1.5 to 2 dB) would need to occur before one could attribute the change to either an intervention or pathology, rather than to measurement variability. It appears that MOC shifts, as analyzed in the present study, may be too variable for clinical use, at least in some individuals. Further study is needed to determine the extent to which changes in MOC shifts can be reliably measured across time for clinical purposes.