Biomedical subjects

Sharon G Kujawa

Publications and source records attributed to Sharon G Kujawa.

10 recordsLinked to original sources

PubMed2006

Acceleration of age-related hearing loss by early noise exposure: evidence of a misspent youth.

Age-related and noise-induced hearing losses in humans are multifactorial, with contributions from, and potential interactions among, numerous variables that can shape final outcome. A recent retrospective clinical study suggests an age-noise interaction that exacerbates age-related hearing loss in previously noise-damaged ears (Gates et al., 2000). Here, we address the issue in an animal model by comparing noise-induced and age-related hearing loss (NIHL; AHL) in groups of CBA/CaJ mice exposed identically (8-16 kHz noise band at 100 dB sound pressure level for 2 h) but at different ages (4-124 weeks) and held with unexposed cohorts for different postexposure times (2-96 weeks). When evaluated 2 weeks after exposure, maximum threshold shifts in young-exposed animals (4-8 weeks) were 40-50 dB; older-exposed animals (> or =16 weeks) showed essentially no shift at the same postexposure time. However, when held for long postexposure times, animals with previous exposure demonstrated AHL and histopathology fundamentally unlike unexposed, aging animals or old-exposed animals held for 2 weeks only. Specifically, they showed substantial, ongoing deterioration of cochlear neural responses, without additional change in preneural responses, and corresponding histologic evidence of primary neural degeneration throughout the cochlea. This was true particularly for young-exposed animals; however, delayed neuropathy was observed in all noise-exposed animals held 96 weeks after exposure, even those that showed no NIHL 2 weeks after exposure. Data suggest that pathologic but sublethal changes initiated by early noise exposure render the inner ears significantly more vulnerable to aging.

Aging↗

PubMed2006

Osteoprotegrin knockout mice demonstrate abnormal remodeling of the otic capsule and progressive hearing loss.

OBJECTIVES: The otic capsule, when compared with other bones in the body, is unique in that it undergoes no significant remodeling of bone after development. We previously demonstrated that osteoprotegerin (OPG), which inhibits formation and function of osteoclasts, is produced at high levels in the inner ear of normal mice and secreted into the perilymph from where it diffuses into the surrounding otic capsule bone through a lacunocanalicular system. To test our hypothesis that the high level of OPG may be important in the inhibition of otic capsule remodeling, we studied the light microscopic histology of the otic capsule in OPG knockout mice for evidence of abnormal remodeling of bone. We also tested the hearing in OPG knockout mice to determine whether OPG and its influence on surrounding bone is important for auditory function. METHODS: Temporal bone histopathology and pathophysiology were compared in homozygous OPG knockout mice and C57BL/6 (B6) mice, the background strain for the knockouts. Auditory function in age-matched animals from each group was evaluated at approximately 4-week intervals from 8 to 21 weeks using frequency-specific auditory brainstem responses (ABR) and distortion product otoacoustic emissions (DPOAE). After each of the last three evaluations, the cochleae from one mouse of each group were harvested, processed, and examined by light microscopy. RESULTS: Osteoprotegerin knockout mice demonstrated abnormal remodeling of bone within the otic capsule with multiple foci showing osteoclastic bone resorption and formation of new bone. Such changes were not seen in the age-matched B6 controls. The active bone remodeling process in the knockout animals showed many similarities to otosclerosis seen in human temporal bones. Over the time period that we monitored, auditory function was significantly and progressively compromised in the knockout animals relative to B6 controls. At the earliest age of test (8 wk), the loss was apparent as a mild, high-frequency reduction in sensitivity by ABR. In contrast, DPOAE losses in the knockouts were substantial even at 8 weeks, and by 21 weeks, these losses exceeded our equipment limits. Results of ABR testing showed hearing sensitivity changes in the animals of the background strain were confined largely to the high frequencies, whereas OPG knockouts demonstrated substantial low-frequency shifts in addition to those at high frequencies. CONCLUSIONS: The histopathological and pathophysiological findings in OPG knockout mice support the hypothesis that OPG is important in the inhibition of bone remodeling within the otic capsule and the maintenance of normal auditory function. This mouse may provide a valuable animal model of human otosclerosis.

Acoustic Stimulation↗

PubMed2006

Vestibular evoked myogenic potential (VEMP) in patients with Ménière's disease with drop attacks.

OBJECTIVE: In this retrospective study, we tested the hypothesis that vestibular evoked myogenic potential (VEMP) thresholds are more often elevated or absent in patients with Ménière's disease experiencing Tumarkin drop attacks than in other patients with Ménière's disease. METHODS: Subjects included normal subjects (n = 14) and patients with unilateral Ménière's disease by AAO-HNS (1995) diagnostic criteria with (n = 12) and without (n = 82) Tumarkin drop attacks at a large specialty hospital otology service. VEMP threshold testing was conducted using 250, 500, and 1,000 Hz tone burst stimuli. RESULTS: VEMP responses were present in at all frequencies in both ears of all normal subjects. In unaffected ears of patients with unilateral Ménière's disease, VEMPs were undetectable in 13% of measurements attempted. This number rose to 18% in affected ears of patients with unilateral Ménière's disease and to 41% in Meniere ears with Tumarkin drop attacks. Frequency tuning of the VEMP response in normal subjects showed lowest thresholds at 500 Hz. In Meniere ears, the tuning was altered such that the 500-Hz thresholds were higher than the 1,000-Hz thresholds. There was a gradient of threshold elevation and altered tuning that corresponded to the gradient of worsening disease. CONCLUSION: Our findings support the hypothesis that Tumarkin drop attacks arise from advanced disease involving the saccule and that VEMP may be a clinically valuable metric of disease severity or progression in patients with Ménière's disease.

Acoustic Stimulation↗

PubMed2006

Vestibular evoked myogenic potentials (VEMP) can detect asymptomatic saccular hydrops.

OBJECTIVE: The objective of this study was to explore the useful of vestibular evoked myogenic potential (VEMP) testing for detecting endolymphatic hydrops, especially in the second ear of patients with unilateral Ménière disease (MD). METHODS: This study was performed at a tertiary care academic medical center. Part I consisted of postmortem temporal bone specimens from the temporal bone collection of the Massachusetts Eye & Ear Infirmary; part II consisted of consecutive consenting adult patients (n = 82) with unilateral MD by American Academy of Otolaryngology-Head and Neck Surgery criteria case histories. Outcome measures consisted of VEMP thresholds in patients and histologic saccular endolymphatic hydrops in postmortem temporal bones. RESULTS: Saccular hydrops was observed in the asymptomatic ear in six of 17 (35%) of temporal bones from donors with unilateral MD. Clinic patients with unilateral MD showed elevated mean VEMP thresholds and altered VEMP tuning in their symptomatic ears and, to a lesser degree, in their asymptomatic ears. Specific VEMP frequency and tuning criteria were used to define a "Ménière-like" response. This "Ménière-like" response was seen in 27% of asymptomatic ears of our patients with unilateral MD. CONCLUSIONS: Bilateral involvement is seen in approximately one third of MD cases. Saccular hydrops appears to precede symptoms in bilateral MD. Changes in VEMP threshold and tuning appear to be sensitive to these structural changes in the saccule. If so, then VEMP may be useful as a detector of asymptomatic saccular hydrops and as a predictor of evolving bilateral MD.

Acoustic Stimulation↗

PubMed2006

Modeling distortion product otoacoustic emission input/output functions using segmented regression.

Distortion product otoacoustic emissions (DPOAEs) are low-level acoustic signals, the detection of which involves extraction from a background of noise. Boege and Janssen [J. Acoust. Soc. Am. 111, 1810-1818 (2002)] described a method for modeling the presence and growth of these responses. While improving growth function parameter estimation, this technique excludes a significant fraction of the data (especially low-level responses), and relies on ad hoc model fit acceptance criteria. The statistical difficulties associated with these limitations are described, and a weighted segmented linear regression model that avoids them is proposed. A simple test is presented for the presence of DPOAE growth. This technique is compared to that of Boege and Janssen in a dataset of 9 556 input/output (I/O) functions collected over 4 years on 866 ears from 379 construction apprentices and 63 age-matched controls. Comparisons are made on the entire dataset and within audiometric hearing loss categories. Segmented regression avoids the statistical pitfalls of the previous method, allows estimation of the threshold and slope of auditory response on a far greater number of I/O functions, and improves estimation of these parameters in this dataset. The potential for this method to yield more sensitive metrics of hearing function and compromise is discussed.

Acoustic Impedance Tests↗

PubMed2005

Inner ear drug delivery via a reciprocating perfusion system in the guinea pig.

Rapid progress in understanding the molecular mechanisms associated with cochlear and auditory nerve degenerative processes offers hope for the development of gene-transfer and molecular approaches to treat these diseases in patients. For therapies based on these discoveries to become clinically useful, it will be necessary to develop safe and reliable mechanisms for the delivery of drugs into the inner ear, bypassing the blood-labyrinthine barrier. Toward the goal of developing an inner ear perfusion device for human use, a reciprocating microfluidic system that allows perfusion of drugs into the cochlear perilymph through a single inlet hole in scala tympani of the basal turn was developed. The performance of a prototype, extracorporeal reciprocating perfusion system in guinea pigs is described. Analysis of the cochlear distribution of compounds after perfusion took advantage of the place-dependent generation of responses to tones along the length of the cochlea. Perfusion with a control artificial perilymph solution had no effect. Two drugs with well-characterized effects on cochlear physiology, salicylate (5 mM) and DNQX (6,7-Dinitroquinoxaline-2,3-dione; 100 and 300 microM), reversibly altered responses. The magnitude of drug effect decreased with distance from the perfusion pipette for up to 10 mm, and increased with dose and length of application.

Animals↗

PubMed2005

A method for intracochlear drug delivery in the mouse.

The confluence of two rapidly emerging research arenas - development of mouse models of human deafness and inner ear drug therapy for treatment and prevention of hearing loss - provides an opportunity for unprecedented approaches to study and treat deafness. Toward such goals, we have developed a method for intracochlear drug delivery in the mouse. The bulla was exposed using a ventral approach and the stapedial artery cauterized. An opening made into the inferior-medial aspect of the bulla, where the basal cochlear wall fuses with tympanic bulla, provided direct access to the scala tympani without separately opening the bulla or elevating auditory response thresholds. Cochlear responses, assayed by frequency-specific effects on ABRs and DPOAEs, were stable with infusion (1 microl/h) of an artificial perilymph solution (80 min). The glutamate receptor antagonist, CNQX (100 microM; 175 min), reduced ABR responses without affecting DPOAEs. Salicylate (5mM; 165 min) altered both. Both drugs had greatest effects at high frequencies, but distributed throughout the cochlea and were reversible. The safe delivery of drugs into the cochlea by this approach has immediate application in the study and treatment of various forms of human hearing loss that can be modeled in the mouse.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed2004

Vestibular evoked myogenic potentials show altered tuning in patients with Ménière's disease.

OBJECTIVE: Acoustic stimulation of the saccule gives rise to a vestibulocollic reflex, the output of which can be measured in the neck as inhibition of activity in the ipsilateral sternocleidomastoid muscle. This vestibular evoked myogenic potential has been promoted as a means of assessing integrity of saccular function. In this study, we test the hypothesis that the cochleosaccular hydrops of Ménière's syndrome leads to alterations in saccular motion that change the dynamics of the vestibular evoked myogenic potential. STUDY DESIGN: Prospective cohort study. SETTING: Large specialty hospital, department of otolaryngology. SUBJECTS: Fourteen normal adult volunteers and 34 consecutive consenting adult patients with unilateral Ménière's disease by American Academy of Otolaryngology-Head and Neck Surgery diagnostic criteria. INTERVENTIONS: All subjects underwent vestibular evoked myogenic potential testing using ipsilateral broadband click and short tone-burst stimuli at 250, 500, 1,000, 2,000, and 4,000 Hz. MAIN OUTCOME MEASURES: Threshold, amplitude, and latency of vestibular evoked myogenic potential responses in normal and Ménière's affected and unaffected ears. RESULTS: Vestibular evoked myogenic potential was present in all ears tested. Normal subjects show a frequency-dependent vestibular evoked myogenic potential threshold, with best response ("frequency tuning") at 500 Hz. Compared with normal subjects and unaffected ears of Ménière's subjects, affected Ménière's ears had significantly increased vestibular evoked myogenic potential thresholds. Affected Ménière's ears showed threshold shifts at all frequencies and there was less tuning apparent at 500 Hz. Unaffected ears of Ménière's subjects also showed significantly elevated vestibular evoked myogenic potential thresholds compared with normal subjects. Analyses of vestibular evoked myogenic potential thresholds for effects of age, hearing loss, and audiometric configuration showed no significant differences. CONCLUSIONS: Ménière's ears display alterations in vestibular evoked myogenic potential threshold and tuning, supporting our hypothesis of altered saccular motion mechanics arising from hydropic distention. Unaffected ears of unilateral Ménière's subjects show similar changes, though to a lesser degree. This finding may be because of occult saccular hydrops in the asymptomatic ear or binaural interactions in the vestibular evoked myogenic potential otolith-cervical reflex arc.

Acoustic Stimulation↗

PubMed2004

Vestibular evoked myogenic potentials versus vestibular test battery in patients with Meniere's disease.

OBJECTIVE: The present study was undertaken to assess the sensitivity of vestibular evoked myogenic potentials testing to side-of-disease in Meniere's disease patients and to test the hypothesis that information supplied by vestibular evoked myogenic potentials is complementary to that provided by a conventional vestibular test battery. STUDY DESIGN: Prospective cohort study. SETTING: Large specialty hospital, department of otolaryngology. SUBJECTS: Twenty consenting adults (9 men and 11 women) with unilateral Meniere's disease by American Academy of Otolaryngology-Head and Neck Surgery diagnostic criteria. INTERVENTIONS: All subjects underwent bilateral vestibular evoked myogenic potentials testing using ipsilateral broadband click and short-toneburst stimuli at 250, 500, and 1,000 Hz. All subjects also underwent electronystagmography and sinusoidal vertical axis rotation testing. MAIN OUTCOME MEASURES: Accuracy of side-of-disease assignment by vestibular evoked myogenic potentials, caloric asymmetry, and multivariate analysis. RESULTS: Side-of-disease assignment was most accurate using caloric asymmetry with a 5% interaural difference criterion, achieving 85% correct assignment. The next best method was vestibular evoked myogenic potentials using 250-Hz toneburst stimuli, achieving 80% correct assignment. The least accurate method was caloric asymmetry using a traditional 30% interaural difference limen, achieving 55% correct assignment. Comparison of 5% interaural difference criterion and vestibular evoked myogenic potentials using 250-Hz toneburst stimuli showed discordant results, but in no case did both 5% interaural difference criterion and vestibular evoked myogenic potentials using 250-Hz toneburst stimuli make an incorrect assignment. CONCLUSION: Vestibular evoked myogenic potentials threshold was shown to be highly sensitive to side-of-disease in unilateral Meniere's disease. We observed instances of discordance in side-of-disease assignment by caloric asymmetry and vestibular evoked myogenic potential methods but no case in which both methods were incorrect. This supports the hypothesis that vestibular evoked myogenic potentials supplies information complementary to that provided by other components of the vestibular test battery.

Adult↗

PubMed2003

The aging of the middle ear in 129S6/SvEvTac and CBA/CaJ mice: measurements of umbo velocity, hearing function, and the incidence of pathology.

Measurements of umbo velocity and auditory brainstem response (ABR) were made on two different strains of mice, 129S6/SvEvTac (129S6) and CBA/CaJ (CB), within three different age ranges. The velocity measurements were made with a laser Doppler vibrometer using a semiclosed sound delivery system; the frequency range of accurate velocity measurements is from 1 to 21 kHz. The visual detection threshold of the ABR was determined at selected frequencies between 2 and 32 kHz. The velocity results suggest a small but significant change in umbo velocity with age in both strains, between the youngest (1.5-3 months) and mid-aged (12-14 months) groups. There is also a clear difference in the umbo velocity in the youngest animals of the two strains, with the 129S6 having more sensitive middle-ear function than the CB. These results support the existence of a small age-related loss in middle-ear sensitivity in the mouse that was first described in the BALB/6J strain. The age-related changes in middle-ear function observed in both CB and 129S6 are much smaller than the age-related decreases in ABR. Our results also describe a statistically significant increase in the incidence of middle-ear pathology with age in the 129S6.

Aging↗