Debra L. Park

Central nervous system plasticity during hair cell loss and regeneration

Following cochlear ablation, auditory neurons in the central nervous system (CNS) undergo alterations in morphology and function, including neuronal cell death. The trigger for these CNS changes is the abrupt cessation of afferent input via eighth nerve fiber activity. Gentamicin can cause ototoxic damage to cochlear hair cells responsible for high frequency hearing, which seems likely to cause a frequency-specific loss of input into the CNS. In birds, these hair cells can regenerate, presumably restoring input into the CNS. This review summarizes current knowledge of how CNS auditory neurons respond to this transient, frequency-specific loss of cochlear function. A single systemic injection of a high dose of gentamicin results in the complete loss of high frequency hair cells by 5 days, followed by the regeneration of new hair cells. Both hair cell-specific functional measures and estimates of CNS afferent activity suggest that newly regenerated hair cells restore afferent input to brainstem auditory neurons. Frequency-specific neuronal cell death and shrinkage occur following gentamicin damage to hair cells, with an unexpected recovery of neuronal cell number at longer survival times. A newly-developed method for topical, unilateral gentamicin application will allow future studies to compare neuronal changes within a given animal.

Evidence for loss and recovery of chick brainstem auditory neurons during gentamicin-induced cochlear damage and regeneration.

It is well documented that damage to the chick cochlea caused by acoustic overstimulation or ototoxic drugs is reversible. Second-order auditory neurons in nucleus magnocellularis (NM) are sensitive to changes in input from the cochlea. However, few experiments studying changes in NM during cochlear hair cell loss and regeneration have been reported. Chicks were given a single systemic dose of gentamicin, which results in maximal hair cell loss in the base of the cochlea after 5 days. Many new hair cells are present by 9 days. These new hair cells are mature but not completely recovered in organization by 70 days. We counted neurons in Nissl-stained sections of the brainstem within specific tonotopic regions of NM, comparing absolute cell number between gentamicin- and saline-treated animals at both short and long survival times. Our data suggest that neuronal number in rostral NM parallels hair cell number in the base of the cochlea. That is, after a single dose of gentamicin, we see a loss of both cochlear hair cells and NM neurons early, followed by a recovery of both cochlear hair cells and NM neurons later. These results suggest that neurons, like cochlear hair cells, can recover following gentamicin-induced damage.

Tonotopic changes in 2-deoxyglucose activity in chick cochlear nucleus during hair cell loss and regeneration

Following cochlear ablation, auditory neurons in the central nervous system (CNS) undergo alterations in morphology and function, including neuronal cell death. The trigger for these CNS changes is the abrupt cessation of eighth nerve fiber activity. Gentamicin can cause ototoxic damage to cochlear hair cells responsible for high frequency hearing. In birds, these hair cells can regenerate. Therefore, gentamicin causes a partial, yet reversible insult to the ear. It is not known how this partial hair cell damage affects excitatory input to the cochlear nucleus. We examined chick cochlear nucleus activity during hair cell loss and regeneration by measuring 2-deoxyglucose (2DG) uptake. Normal animals showed a rostral to caudal gradient of 2DG activity, with higher activity in caudal regions. When hair cells are damaged (2, 5 days), 2DG uptake is decreased in cochlear nucleus. When hair cells regenerate (9, 16, 28 days), 2DG uptake returns to control levels. This decrease and subsequent return of activity only occurs in the rostral, high frequency region of the cochlear nucleus. No changes are seen in the caudal, low frequency region. These results suggest that changes in activity of cochlear nucleus occur at a similar time course to anatomical changes in the cochlea.

Breed differences in cochlear integrity in adult, commercially raised chickens.

Two types of chickens are commercially available. Broiler birds are bred to develop quickly for meat production, while egg layers are bred to attain a smaller adult size. Because we have observed breed differences in the response of central auditory neurons to cochlear ablation in adult birds [Edmonds et al. (1999) Hear. Res. 127, 62-76], we examined cochleae from the two breeds for differences in integrity. We evaluated cochlear hair cell structure using scanning electron microscopy and cochlear hair cell function using distortion product otoacoustic emissions (DPOAEs) and the auditory brainstem response. We observed striking breed differences in cochlear integrity in adult but not hatchling birds. In adult broiler birds, all cochleae showed damage, encompassing at least the basal 29% of the cochlea. In 15 of 18 broiler ears, damage was observed throughout the basal 60% of the cochlea. In contrast, cochleae from egg layer adults were largely normal. Two thirds of egg layer ears showed no anatomical abnormalities, while in the remainder cochlear damage was seen within the basal 48% of the cochlea. DPOAEs recorded from egg layer birds showed loss of high frequency emissions in every ear for which the cochlea displayed anatomical damage. Average sound pressure levels in both commercial facilities were 90 dB, suggesting these two breeds may exhibit differential susceptibility to noise damage.

Time course and quantification of changes in cochlear integrity observed in commercially raised broiler chickens.

Extensive cochlear hair cell damage and loss occurs in aged broiler chickens. We describe the time course and several characteristics of this decline in cochlear integrity in 19-, 30-, 38- and 66-week-old commercially raised broiler chickens. The 19-week-old group is normal and serves as a baseline for comparison. Generally, cochlear damage increases in severity and percent length of the cochlea with age. Hair cell density increases from the base to the apex. Density is similar across the groups in regions of the cochlea that sustained little or no damage, and decreases in regions of extreme damage. Counts of normal and abnormal hair cells are inversely related. A subset of 66-week-old birds has higher density measurements and increased hair cell counts in the apical region of the cochlea. The progressive damage found in these commercially raised birds is described in the context of both the effects of age and noise exposure on the auditory system. Two additional groups of birds were raised at the University of Kansas Medical Center in a quieter environment to determine the cause of the damage seen in age-matched commercially raised birds. These cochleae are largely normal; a small number displayed damage. This suggests that noise exposure exacerbates naturally occurring cochlear degradation.

Does successful segmental tracheal resection require releasing maneuvers

OBJECTIVES: Tracheal resection is a well-established option for the management of airway stenosis. Releasing maneuvers have been described to reduce anastomotic tension. The aim of this study is to report on a series of tracheal resections performed without the use of these maneuvers. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary hospital. METHODS: All patients undergoing tracheal resection by the first author over a 6-year period were reviewed. RESULTS: Patients (n = 17; 7 men and 10 women, ages 23-76) were managed with tracheal resection and anastomosis without stenting or postoperative tracheotomy. 16/17 (94%) patients had successful treatment of their stenosis. 1/17 (6%) failed and 1/17 (6%) required dilation. There was no postoperative swallowing dysfunction. CONCLUSIONS: Segmental tracheal resection without releasing maneuvers was successful in 16/17 (94%) patients. SIGNIFICANCE: Though extrapolation from this series may be limited, future practitioners may consider forgoing additional releasing maneuvers for tracheal resection in many cases.

Effects of age and cochlear damage on the metabolic activity of the avian cochlear nucleus.

Most aging commercially raised broiler chickens display a progressive loss of cochlear hair cells in a pattern similar to the cochlear degeneration found in aging humans: basal (high frequency) hair cells are affected first, followed by apical (low frequency) hair cells [Durham et al., Hear. Res. 166 (2002) 82-95]. Here, cochlear anatomy was assessed from scanning electron micrographs. Then, the metabolic activity of cochlear nucleus (nucleus magnocellularis, NM) neurons in 15-19, 30, 39, 40, and 65-66 week old broiler chickens was examined using cytochrome oxidase histochemistry and compared to the degree of cochlear abnormality. Cochleae of 15-19 week old birds are largely normal; therefore the level of NM metabolic activity is considered the baseline. Cochleae of the 30 week old group display mild damage and hair cell regeneration in the base. Metabolic activity in rostral (high frequency) NM is increased relative to the baseline, while activity remains unchanged in caudal (low frequency) NM. The 39 and 65-66 week old groups display severe and total damage extending into the apex of the cochlea. Metabolic activity is decreased in rostral and caudal NM at these ages. These results suggest that auditory central nervous system metabolism (cytochrome oxidase activity) is affected by changes in the aging chicken cochlea.

Avian brainstem neurogenesis is stimulated during cochlear hair cell regeneration.

Unlike mammals, adult avians are able to regenerate cochlear sensory hair cells following injury. Brainstem auditory neurons in chicken nucleus magnocellularis (NM), which receive their sole excitatory afferent input from the cochlea, were examined for evidence of mitosis during ototoxin-induced loss and regeneration of cochlear hair cells. Using tritiated thymidine as a mitotic marker in tissue processed for autoradiography and counterstained with thionin, labeled NM neurons and glia were counted from chickens killed 16 days after gentamicin or saline injections. Newly generated NM neurons were observed during cochlear hair cell regeneration. More labeled neurons were observed in the experimental chickens, but a few were also seen in the control chickens. We predicted labeled NM neurons would be found solely in the rostral high frequency region, given the gentamicin-induced high frequency cochlear hair cell loss and regeneration. However, the labeled NM neurons were located throughout the tonotopic axis of the nucleus. The total number of labeled neurons was lower than predicted. Many labeled NM glia were observed in experimental and control chickens. Labeled cells were also observed throughout the chicken brainstem and cerebellum in both experimental and control chickens, indicating great potential for CNS plasticity. Results in NM indicate the avian auditory system is capable of regenerating brainstem auditory neurons in addition to the previously well-established capability of regenerating cochlear hair cells in response to ototoxic injury. Recovery of both central and peripheral auditory components will be necessary to restore hearing damaged by noise or ototoxic drugs.

Allergy Symptom Response to Intradermal Testing-Based Immunotherapy: A Retrospective Study of Clinical Practice

OBJECTIVE: Evaluate the multiple end-organ targets affected by intradermal testing (IDT)-based immunotherapy. STUDY DESIGN AND SETTING: We conducted a retrospective medical record review of 139 patients, as well as a follow-up questionnaire in a university setting. RESULTS: Statistically significant differences (t-tests, P < 0.05) were observed in the prevalence of symptoms after IDT-based immunotherapy for each category (ear, eye, nasal, and throat). When divided into treatment time groups, the reduction was less in the first group (0–6 months therapy), than the subsequent groups (6–24 months and >24 months). The reduction leveled off after 6 months of therapy, with no difference seen between the 6- to 24-month and >24-month groups. CONCLUSIONS: IDT-based immunotherapy has a broad response on otolaryngic allergy symptoms that appears to be consistent over time. SIGNIFICANCE: IDT-based immunotherapy is an effective form of treatment for allergy-induced diseases of the head and neck.