Kourosh Parham

Cisplatin-Induced Ototoxicity: Effect of Intratympanic Dexamethasone Injections

Hypothesis: Intratympanic (IT) application of dexamethasone will reduce ototoxicity associated with systemic cisplatin therapy. Background: Cisplatin is a common chemotherapeutic drug often dose-limited by ototoxicity attributed to the formation of reactive oxygen and nitrogen species damaging critical inner ear structures. Steroids have been shown to reduce formation of reactive oxygen species and thus may reduce ototoxicity. In the present pilot study, we test this hypothesis by IT administration of dexamethasone in a novel murine model of cisplatin ototoxicity. Methods: Click- and pure-tone-evoked auditory brainstem responses (ABRs) in young CBA/J mice were measured. The first phase consisted of a dosing study to identify the optimal cisplatin dose for ototoxicity. In the next phase, ABR thresholds were measured in cisplatin-treated mice after 5 days of IT injection of 24 mg/ml of dexamethasone in 1 ear and normal saline in the opposite ear to serve as controls. Results: Intraperitoneal injection of 14 mg/kg of cisplatin induces significant hearing loss (click-evoked ABR threshold elevation = 12 ± 7 dB, &mgr; ± standard error of the mean) with acceptable mortality (20%). The ears that received IT dexamethasone in cisplatin-treated mice had minimal ABR threshold shifts with the click, 8 and 16 kHz of stimuli. There was no significant difference between IT dexamethasone and IT saline ears at 32 kHz. Conclusion: IT dexamethasone protected the mouse ear against cisplatin-induced ototoxicity in a frequency-dependent manner. The present results suggest that IT dexamethasone may be a safe, simple, and effective intervention that minimizes cisplatin ototoxicity without interfering with the chemotherapeutic actions of cisplatin.

Stimulus-frequency otoacoustic emission: Measurements in humans and simulations with an active cochlear model

An efficient method for measuring stimulus-frequency otoacoustic emissions (SFOAEs) was developed incorporating (1) stimulus with swept frequency or level and (2) the digital heterodyne analysis. SFOAEs were measured for 550-1450 Hz and stimulus levels of 32-62 dB sound pressure level in eight normal human adults. The mean level, number of peaks, frequency spacing between peaks, phase change, and energy-weighted group delays of SFOAEs were determined. Salient features of the human SFOAEs were stimulated with an active cochlear model containing spatially low-pass filtered irregularity in the impedance. An objective fitting procedure yielded an optimal set of model parameters where, with decreasing stimulus level, the amount of cochlear amplification and the base amplitude of the irregularity increased while the spatial low-pass cutoff and the slope of the spatial low-pass filter decreased. The characteristics of the human cochlea were inferred with the model. In the model, an SFOAE consisted of a long-delay component originating from irregularity in a traveling-wave peak region and a short-delay component originating from irregularity in regions remote from the peak. The results of this study should be useful both for understanding cochlear function and for developing a clinical method of assessing cochlear status.

Prospective clinical investigation of the relationship between idiopathic benign paroxysmal positional vertigo and bone turnover: a pilot study.

Idiopathic benign paroxysmal positional vertigo (BPPV) is a strong indicator of decreased bone density (osteopenia/osteoporosis) in postmenopausal women, and there is a correlation between BPPV and serum levels of biochemical markers of bone turnover.

Distortion product otoacoustic emissions in the CBA/J mouse model of presbycusis.

CBA mice do not exhibit age-related loss of auditory sensitivity or cochlear pathology until relatively late in life. Therefore, this strain is believed to be an excellent animal model for the examination of the effects of age on the cochlea. To evaluate the effects of age on outer hair cell function, 2f1-f2 distortion product otoacoustic emissions (DPOAEs) were measured for f2 between 8 and 16 kHz in CBA/J mice between 1 and 25 months of age. CBA mice exhibited mild age-related changes in DPOAE level and detection threshold at 17 months of age, and changes of 20-40 dB by 25 months of age. The DPOAE level decreased and detection threshold increased with age in a frequency-dependent manner, starting at high frequencies and eventually extending to low frequencies. The range of frequencies in which notches were observed in the DPOAE input/output (I/O) functions extended toward lower frequencies by 17 months of age. Notches were absent in the I/O functions of 25-month-old mice. The present results for a frequency range of 8-16 kHz suggest that age has modest effects on outer hair cell function in CBA mice.

Comprehensive Management of Presbycusis Central and Peripheral

The prevailing otolaryngologic approach to treatment of age-related hearing loss (ARHL), presbycusis, emphasizes compensation of peripheral functional deficits (ie, hearing aids and cochlear implants). This approach does not address adequately the needs of the geriatric population, 1 in 5 of whom is expected to consist of the “old old” in the coming decades. Aging affects both the peripheral and central auditory systems, and disorders of executive function become more prevalent with advancing age. Growing evidence supports an association between age-related hearing loss and cognitive decline. Thus, to facilitate optimal functional capacity in our geriatric patients, a more comprehensive management strategy of ARHL is needed. Diagnostic evaluation should go beyond standard audiometric testing and include measures of central auditory function, including dichotic tasks and speech-in-noise testing. Treatment should include not only appropriate means of peripheral compensation but also auditory rehabilitative training and counseling.

Small neurons in the vestibular nerve root project to the marginal shell of the anteroventral cochlear nucleus in the cat

We injected biotinylated dextran amine (BDA) into marginal shell regions of the anteroventral cochlear nucleus (AVCN) of the cat. These injections led to retrograde labeling of cells including small cells (median some area = 111 micron2, equivalent diameter = 11.9 microns) in the vestibular nerve root (VNR), just ventral to an anterior part of the AVCN. This is an unexpected new finding. The cells were scattered among BDA-labeled fibers and were oriented parallel to the course of the VNR fibers. We suggest that the small neurons of the VNR might serve as second-order vestibular neurons conveying information from vestibular end organs to the cochlear nucleus (CN) and/or act as interneurons between the olivocochlear fibers in the VNR and the CN.

Challenges and Opportunities in Presbycusis

The population aged 65 years and older is increasing at a faster rate than the total population, with predictions that by 2030, 20% of the population will be 65 years or older. In 2006, between 35% and 50% of those aged 65 years or older reportedly had presbycusis, a sensory impairment that contributes to social isolation and loss of autonomy and is associated with anxiety, depression, and cognitive decline. To address these concerns, the Geriatric Committee of the American Academy of Otolaryngology, in conjunction with the Hearing Committee, focused on 3 challenges and opportunities in the management of presbycusis: (1) the financial burden of caring for patients with presbycusis in the face of increasing costs and declining reimbursements; (2) future treatment options arising from improved understanding of the molecular mechanisms underlying presbycusis, and (3) recognition of central presbycusis as a condition commonly superimposed on peripheral age-related hearing loss whose diagnosis and management can improve outcomes.

Spatial response profiles of posteroventral cochlear nucleus neurons and auditory-nerve fibers in unanesthetized decerebrate cats: Response to pure tones

Encoding of 1- and 5-kHz pure tones by auditory-nerve (AN) fibers and choppers of the posteroventral cochlear nucleus (PVCN) was investigated. Neuronal responses were analyzed as the discharge rate, rate change, and the mean and standard deviation (or sigma) of spike counts. The major findings are: (1) Sideband inhibitory areas were observed in spatial profiles of rate changes of PVCN choppers whereas they were absent in those of AN fibers; (2) spatial profiles of rate changes and mean discharge rates of PVCN choppers were sharper than those of high spontaneous-rate (HSR) AN fibers and were comparable to those of low and medium SR (LMSR) AN fibers for 1 kHz at 50 and 70 dB SPL re: 20 microPa; (3) to 5 kHz, 30 dB SPL, PVCN choppers were strongly driven comparable to HSR AN fibers whereas LMSR AN fibers were weakly driven (implying higher thresholds); (4) PVCN choppers exhibited higher maximum discharge rates (300-600 spikes/s) than either LMSR AN fibers (200-250 spikes/s) or HSR AN fibers (150-250 spikes/s); (5) mean-to-sigma ratios of PVCN choppers, particularly at 70 dB SPL, were much higher than those of LMSR or HSR AN fibers; (6) rate-change profiles of LMSR AN fibers were distinct from those of HSR AN fibers, more conspicuously for 1 kHz than for 5 kHz; (7) the neural response profiles to 5 kHz were sharper than those to 1 kHz; and (8) 45% of PVCN choppers in the present study exhibited SR greater than 20 spikes/s whereas only 11%-12% of AVCN choppers in previous studies of anesthetized cats exhibited the same SR, which may represent an effect of anesthesia. The observations support a hypothesis that the transformation of the discharge-rate signal from AN fibers to PVCN choppers leads to an amplification of the mean discharge-rate signal with an increase in the signal-to-noise ratio. The observations suggest that PVCN choppers can encode pure-tone frequency in a spatial profile more accurately than HSR or LMSR AN fibers. The present data on AN and PVCN spatial profiles should be valuable to CN modeling studies by providing the input to the CN and the output of a class of physiologically characterized CN neurons for an identical set of stimuli.

Purkinje cell degeneration and control mice: responses of single units in the dorsal cochlear nucleus and the acoustic startle response

The cartwheel cell is the most numerous inhibitory interneuron of the dorsal cochlear nucleus (DCN). It is expected to be an important determinant of DCN function. To assess the contribution of the cartwheel cell, we examined the discharge characteristics of DCN neurons and behavioral measures in the Purkinje cell degeneration (pcd) mice, which lack cartwheel cells, and compared them to those of the control mice. Distortion product otoacoustic emissions and auditory brainstem-evoked response thresholds were similar between the two groups. Extracellularly recorded DCN single units in ketamine/xylazine-anesthetized mice were classified according to post-stimulus time histogram (PSTH) and excitatory-inhibitory response area (EI-area) schemes. PSTHs recorded in mouse DCN included chopper, pauser/buildup, onset, inhibited and nondescript types. EI-areas recorded included Types I, II, III, I/III, IV and V. There were no significant differences in the proportions of various unit types between the pcd and control mice. The pcd units had slightly lower thresholds to characteristic frequency tones; however, they had spontaneous rates, thresholds to noise, and maximum driven rates to noise that were similar to those of the control units. Pcd mice had smaller startle amplitudes, but startle latency, prepulse inhibition/augmentation and facilitation by a background tone were comparable between the two groups. From these results, we conclude that DCN function in response to relatively simple acoustic stimuli is minimally affected by the absence of the cartwheel cells. Future studies employing more complex and/or multimodal stimuli should help assess the role of the cartwheel cells.

Inner Ear Protein as a Biomarker in Circulation

Serum biomarkers detect the earliest events in disease, monitor management, and provide insight into disease pathogenesis. At this time, there are no biomarkers available for otologic disorders. Otolin-1 is a scaffolding protein exclusively expressed in otoconia and cells of the vestibule and the cochlea; therefore, it may be a biomarker candidate for assessing the health of the inner ear. As a proof of concept, we used serum samples from controls without otologic history and subjects with a history of benign paroxysmal positional vertigo (BPPV), performed enzyme-linked immunosorbent assay for otolin-1, and measured the optical density of the substrate. Otolin-1 was detectable and quantifiable in all subjects, indicating that this inner ear protein crosses the blood-labyrinthine barrier. Furthermore, subjects with BPPV had significantly higher levels, with about one-third being above the control range. This promising preliminary result suggests that inner ear–specific proteins have the potential to serve as biomarkers for otologic disease processes.