John Carey, M.D., Ph.D. - US grants

The goals of this project are: (1) to determine the minimum dose of intratympanic gentamicin necessary to control vertigo in unilateral Meniere's disease, and (2) to determine what effects this dose has on the structure and function of the vestibular organs of the inner ear. Multiple intratympanic injections, if spaced 1 week apart and halted at the first signs of loss of vestibular function, can control vertigo in >90% of patients with no greater hearing loss than the disease itself causes. We will conduct a clinical trial in which gentamicin will be given every 2 weeks until vertigo is controlled. We wish to determine if lower total doses can control vertigo yet preserve some vestibular function as measured by 3-dimensional vestibulo-ocular reflexes, vestibular-evoked myogenic potentials, subjective visual vertical, and caloric tests. By following patients for one year we can also determine if some vestibular function returns over time. We also want to know what these doses of gentamicin do to the vestibular part of the inner ear and the vestibular nerve afferents. Are all or most of the hair cells destroyed? Do the vestibular nerve afferents stop responding? Is there some return of some function over time? If so, why? Do hair cells recover, do afferents become more sensitive, or does the brain adjust its responses to make up for the peripheral loss. These questions will be answered in an animal model. The candidate has a background in vestibular physiology and now seeks a long-term career in academic otolaryngology, focusing physiologic principles on clinical vestibular problems. The short-term goals are to master the fundamentals of clinical trial design and analysis, 3D eye movements, and afferent neurophysiology. Johns Hopkins is uniquely suited to this training because it has a core group devoted to vestibular research, and the mentor's laboratory has successfully used all of the techniques required.

DESCRIPTION (provided by applicant): This project will expand on the work of my NIDCD K23 Project, "Vestibular Effects of Intratympanic Gentamicin." We have found that human subjects who have intratympanic gentamicin treatment for Meniere's disease have a decline in the angular vestibulo-ocular (AVOR) reflex gain for rapid head rotations that excite the treated labyrinth. Some of these subjects have shown increased gains on the same test at later times, suggesting either recovery of peripheral vestibular function or central augmentation of gain. We have also recorded the responses of vestibular afferents in chinchillas after the identical intratympanic gentamicin treatment. This causes a profound loss of sensitivity to vestibular stimulation, but spontaneous afferent discharge is preserved. This suggests that hair cells may be only partially damaged, such that they can release neuro-transmitter to elicit the baseline activity of afferents but that their apical structures cannot transduce head acceleration. These findings correlate well with recent histologic evidence that mammalian hair cells exposed to gentamicin may shed their apical structures but maintain their basal ones (Zheng et al., 1999). The first goal of this project is to determine if the afferent processes contacting vestibular hair cells and the synaptic specializations of these hair cells are preserved after intratympanic gentamicin treatment in chinchillas using light and transmission electron microscopy. If such structural preservation is seen, it may provide a basis for the recovery of vestibular function noted in our human subjects. The second goal is to determine if central augmentation of gain occurs after intratympanic gentamicin treatment. This will be accomplished using direct galvanic stimulation of the VIIIth nerve after intratympanic gentamicin treatment. The nystagmus elicited by excitation of the nerve on the treated side should show an increased velocity compared to the control side if there is a central augmentation of gain. Understanding whether vestibular function partially recovers after intratympanic gentamicin treatment has important implications for the treatment of Meniere's disease, as preservation of function may become an important goal if vertigo remains controlled. Furthermore, the mechanisms of vestibular recovery may help us understand the potential for the inner ear to recover from a variety of injuries.

DESCRIPTION (provided by applicant): Meniere's disease causes considerable morbidity and lost productivity because of its devastating attacks of vertigo and hearing loss. This study aims to characterize how Meniere's disease affects the function of the balance organs of the inner ear and how the human inner ear responds to the increasingly common use of intratympanic gentamicin for the treatment of Meniere's disease. Minimizing the risk of hearing loss with this treatment while achieving vertigo control is the ideal goal. Quantitative testing of the angular and translational vestibulo-ocular reflexes (VOR) in response to high-frequency, high-acceleration stimuli and measures of subjective visual vertical and horizontal provide physiologic measures of the function of the semicircular canals and utricle. These data will be correlated with clinical outcomes in hopes of providing clear guidelines as to how much ablation of vestibular function is necessary to control vertigo in Meniere's disease. In particular, comparisons will be made to data from subjects who underwent surgical destruction of the labyrinth or vestibular nerve in order to determine if complete ablation is necessary or not. Findings from animal models suggest that the key difference between these treatments is that spontaneous vestibular afferent firing is maintained after intratympanic gentamicin but not after surgical vestibular ablation. Differences in the vestibular responses between these treatments may further illuminate the role of spontaneous firing in the vestibular system. Likewise, differences between the eye movements that correct for vestibular reflex deficits after intratympanic gentamicin versus surgical vestibular destruction will be examined to illuminate the role that retained spontaneous firing plays in vestibular compensation and sensorimotor substitution strategies. Long-term follow-up testing in subjects treated with intratympanic gentamicin will show whether or not the lesion is permanent and, if it is not, whether recovery of vestibular function predicts recurrence of vertigo. Comparisons of angular and translational VOR deficits after intratympanic gentamicin should demonstrate whether or not the utricle is less susceptible than the semicircular canals to intratympanic gentamicin.

Our program aims to train and develop physician-scientists who will advance the field of otolaryngology-head and neck surgery. Our subspecialty requires a wide variety of expertise and scientific strategies for understanding and treating communication disorders and diseases of the head and neck. These diseases can limit survival, and more broadly affect the ability to relate to family, workplace and society at large. We aim to provide the scientific training, as well as communication and administrative skills that will enable our graduates to become creative contributors to the future of otolaryngology and the treatment of associated communication disorders. One significant indicator of success, and a point of great pride, is the number of trainees who have gone on to academic careers at Hopkins and elsewhere, including several who are now among the faculty of this training grant. Two residents per year enter into 2 years of research training in their third year of residency. These trainees can choose from a wide, and deep, selection of research programs both within the department, and in associated laboratories at Hopkins and elsewhere. The topics include, but are not limited to: basic mechanisms of, and therapeutic innovation for dizziness and balance; studies of the auditory nervous system; pathogenesis of sinusitis, laryngotracheal stenosis and respiratory papillomatosis; molecular biology and epidemiology of head and neck cancers; surgical robotics; and public health studies in otolaryngology-head and neck surgery. We aim to educate enthusiastic, inquisitive, critical, and knowledgeable young investigators who can pose and then answer significant questions and who will be able to conduct successful, independent research careers in academic medicine.

DESCRIPTION (provided by applicant): The Association for Research in Otolaryngology (ARO) is requesting continued support from of an NIDCD Conference Grant for its annual Midwinter Research Meeting (MWM). The MWM is a unique meeting where current basic and clinical research related to otolaryngology is presented. In addition to poster presentations and podium sessions where cutting edge research is presented, the meeting includes symposia and workshops that allow presentation of up-to-date summaries of broad scientific issues that extend beyond the field of otolaryngology. These symposia typically include invited scientists and clinician- scientists from related fields whose work may be relevant to emerging areas of research in otolaryngology. The symposia have been supported by the Conference Grant for more than 25 years and have contributed to the success of the meeting, as evidence by its growth over the years. The growth and development of otolaryngology research depends on bringing young investigators into the field. Travel awards for young investigators, including residents, medical students, and minority pre-doctoral and postdoctoral fellows have been supported by the NIDCD Conference Grant. We request support to continue these activities. In addition, the NIDCD Conference Grant would continue to enhance accessibility of the MWM for individuals with disabilities, particularly those with hearing impairments.