Auditory-evoked Brainstem Response Thresholds Research Articles

Alpha-1-antitrypsin single dose adjuvant therapy for acute otitis media

Problem: Proteases are thought to contribute to the pathogenesis of otitis media (OM). The serine protease inhibitor, recombinant alpha-1-antitrypsin (rAAT) has been shown to effectively inhibit human neutrophil elastase in a wide range of human OM. The purpose of this study was to determine whether resolution of antibiotic-treated, acute, pneumococcal OM could be facilitated by intratympanic administration of a single dose of rAAT in the chinchilla. Methods: Pneumococcus was injected into both middle ears of 12 chinchillas. After 3 to 4 days, OM was confirmed, middle ears were cultured, systemic antibiotics were initiated, and rAAT or its vehicle was administered into one middle ear of all animals. Serial tympanic membrane (TM) scoring, tympanometry, and auditory-evoked brainstem response (ABR) testing were performed. The animals were euthanized at varying timepoints and temporal bones were studied for objective measures of OM. Results: OM was induced in all ears. Pneumococcus was recovered from 18 of 24 ears. OM resolved more quickly in rAAT-treated ears, but did not reach statistical significance ( P = 0.5). Tympanometry, ABR thresholds, and quantitative histologic parameters did not differ between rAAT- and vehicle-treated ears. Conclusion: A single dose of intratympanic rAAT does not facilitate the resolution of antibiotic-treated pneumococcal OM in the chinchilla model. Small sample size and use of a single administration of study drug may have contributed to the lack of statistical significance. Significance: The value of protease inhibitor therapy in the treatment of human OM remains to be determined. Support: Supported by a grant from Arriva Pharmaceuticals.

Brain-stem auditory impairment during the neonatal period in term infants after asphyxia: dynamic changes in brain-stem auditory evoked response to clicks of different rates

Objective To explore dynamic changes in brain-stem auditory electrophysiology during the neonatal period in term infants after perinatal asphyxia. Methods Sixty-eight term newborn infants who suffered asphyxia were studied on days 1, 3, 5, 7, 14 and 30 after birth. Brain-stem auditory evoked response (BAER) was recorded with clicks, delivered at 21, 51 and 91 s −1 and ≥40 dB above BAER threshold of each subject. Results During the neonatal period wave I latency in the infants after asphyxia increased slightly while later BAER components changed more significantly. On the first day after birth wave III and V latencies and I–V and III–V intervals increased significantly at all rates of clicks (ANOVA P<0.01–0.001). On day 3, the latencies and intervals increased further. III–V/I–III interval ratio increased at 51 and 91 s −1, suggesting a relatively more significant increase in III–V interval than in I–III interval at higher rates. Thereafter, wave III and V latencies and all intervals decreased progressively, although these BAER variables were still significantly longer than in normal controls on days 5 and 7 ( P<0.05–0.001). On day 30, all latencies and intervals approached near normal values, with a slight increase in wave V latency and I–V and III–V intervals at 51 and 91 s −1. Conclusions Perinatal asphyxia has a major effect on central auditory function, resulting in acute impairment. The impairment progresses during the first 3 days and then tends towards recovery. By 1 month the impaired auditory function has largely returned to normal. Significant increase in click rates can moderately improve the detection of auditory impairment. Significance After perinatal asphyxia early detection of hypoxic-ischaemic damage to the central auditory system and initialisation of neuroprotective and therapeutic measures during the first hours after birth are critical to prevent or reduce deterioration of central impairment.

Aminoguanidine reduces cisplatin ototoxicity

Cisplatin is known to cause high-frequency neurosensory hearing loss. While reactive oxygen species have been shown to play a role, reactive nitrogen species have been implicated, but not proven to be involved, in cisplatin ototoxicity. The purpose of the present study was to investigate the role of nitric oxide ( NO) in cisplatin ototoxicity by administering aminoguanidine (AG), a relatively specific inhibitor of inducible nitric oxide synthase (iNOS), in conjunction with cisplatin. Rats were injected with cisplatin, AG, or both. Auditory brainstem evoked responses (ABR) were measured before and 3 days after cisplatin administration. The cochlear tissue was then assayed for NO and malondialdehyde. Cisplatin alone caused significant ABR threshold shifts at all stimuli tested, whereas AG alone caused no shifts. There was a significant reduction in threshold shift for clicks and 16 kHz tone bursts (but not 32 kHz) when AG was given with cisplatin. The malondialdehyde concentration (but not the NO concentration) in the AG/cisplatin group was significantly lower than that of the cisplatin group. This suggests that AG reduces cisplatin ototoxicity by directly scavenging hydroxyl radicals. The iNOS pathway may play a role in the generation of free radicals and hearing loss resulting from cisplatin administration, but this conclusion was not supported by our data.

Separate forms of pathology in the cochlea of congenitally deaf white cats

Congenital deafness due to cochlear pathology can have an immediate or progressive onset. The timing of this onset could have a significant impact on the development of structures in the central auditory system, depending on the animal’s hearing status during its critical period. In order to determine whether cats in our deaf white cat colony suffered from progressive hearing loss, they were tested repeatedly in 30-day intervals using standard auditory evoked brainstem response (ABR) methodology. ABR thresholds did not change over time, indicating that deafness in our colony was not progressive. Moreover, different forms of cochlear pathology were associated with deafness. One form (67% of the deaf ears) had a collapsed Reissner’s membrane that obliterated the scala media, resembling what is called the Scheibe deformity in humans. A second form (18%) exhibited excessive epithelial growth within the bony labyrinth. A third form (15%) combined excessive epithelial growth in the apex and a collapsed Reissner’s membrane in the base. Cochleae having an abnormally thin tectorial membrane and an outward bulging Reissner’s membrane were associated with elevated thresholds (poor hearing).

Blockage of immune-mediated inner ear damage by etanercept.

Etanercept will be able to reduce the inflammation and hearing loss associated with experimentally induced labyrinthitis. Inner ear immune responses cause hearing loss that may be reversible with pharmacologic treatment. Etanercept, tumor necrosis factor receptor blocker, was investigated in a guinea pig model of immune-mediated hearing loss. Sterile labyrinthitis was created by injection of keyhole limpet hemocyanin into the inner ear after systemic sensitization to keyhole limpet hemocyanin with adjuvant. Labyrinthitis involves infiltration of inflammatory cells and hearing loss detectable 3 to 5 days after challenge with keyhole limpet hemocyanin. Etanercept was administered either systemically (2.5 mg) 30 minutes before intracochlear challenge with keyhole limpet hemocyanin, with a second intraperitoneal dose (2.5 mg) 3 days later or locally by long-term infusion into the scala tympani with an osmotic pump (5.0 microg/h for 7 days). Auditory evoked brainstem response thresholds were measured before and after treatment to determine hearing loss. Cochleas were evaluated for the amount of inflammation. Hearing loss in the untreated systemic group averaged 71 +/- 21 dB versus 37 +/- 32 dB in the etanercept-treated animals (t test, P < 0.001). There was also less inflammation in the cochleas from etanercept-treated animals (t test, P < 0.01). Hearing loss with local administration of etanercept was 59 +/- 31 dB in the nontreated ears and 18 +/- 8 dB in the treated ears (t test, P < 0.02). Inflammation was also less (t test, P < 0.01). Etanercept was not ototoxic. Prompt intervention with the anti-inflammatory drug etanercept significantly reduces inflammation sufficient for substantive hearing preservation.

A Major Gene Affecting Age-Related Hearing Loss Is Common to at Least Ten Inbred Strains of Mice

Inbred strains of mice offer promising models for understanding the genetic basis of human presbycusis or age-related hearing loss (AHL). We previously mapped a major gene affecting AHL in C57BL/6J mice. Here, we show that the same Chromosome 10 gene (Ahl) is a major contributor to AHL in nine other inbred mouse strains—129P1/ReJ, A/J, BALB/cByJ, BUB/BnJ, C57BR/cdJ, DBA/2J, NOD/LtJ, SKH2/J, and STOCK760. F1 hybrids between each of these inbred strains and the normal-hearing inbred strain CAST/Ei retain good hearing, indicating that inheritance of AHL is recessive. To follow segregation of hearing loss, F1 hybrids were backcrossed to the parental strains with AHL. Auditory-evoked brain-stem response thresholds were used to assess hearing in more than 1500 N2 mice and analyzed as quantitative traits for linkage associations with Chromosome 10 markers. Highly significant linkage was found in all nine strain backcrosses, with the highest probability (LOD > 70) near the marker D10Mit112. This map position for Ahl is near the waltzer mutation (v) and the modifier of deaf waddler locus (mdfw), suggesting the possibility of allelism. Results from an intercross of C57BL/6J and NOD/LtJ mice indicate that the 6- to 10-month difference in AHL onset between these two strains is not due to allelic heterogeneity of the Ahl gene.

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 non-descript 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.

Blood-Perilymph Barrier and Ototoxicity: An In Vivo Study in the Rat

Cisplatin and gentamicin are two ototoxicants that are supposed to be transported by the paracellar route, i.e. via cellular junctions, to the perilymphatic compartment. This study was initiated to test the hypothesis that susceptive variation of individuals to ototoxic drugs may be explained by variability in transport properties. The transport of radioactive mannitol through the blood-perilymph barrier was correlated in vivo with the acute effect of cisplatin and gentamicin on auditory function. Transport of radioactive mannitol across the blood-perilymph barrier was monitored by sampling of scala vestibuli perilymph at 60 and 120 min after an intravenous infusion of the tracer to nephrectomized Long Evans rats. Counting of hair cell loss was performed in the animals receiving 16 mg/kg body weight cisplatin. The transport of radioactive mannitol across the blood-perilymph barrier did not correlate with the ototoxic effect of cisplatin, evaluated as changes in the auditory-evoked brainstem response thresholds or loss of outer hair cells. The results provide evidence that the barrier function is not involved in the interindividual variability of the ototoxic effect of cisplatin. Furthermore, it can be postulated that neither cisplatin nor gentamicin induce a disruption of endothelial cell junction stability in the inner ear.

Otoacoustic emission, evoked potential, and behavioral auditory thresholds in the rhesus monkey ( Macaca mulatta)

Distortion product otoacoustic emission (DPOAE), auditory brainstem evoked response (ABR), and behavioral thresholds were recorded in a group of 15 adult rhesus monkeys with normal auditory function. DPOAE thresholds were recorded with stimulus parameters selected to maximize signal-to-noise ratio. Additional averaging at the lowest frequencies ensured comparable noise levels across frequencies. DPOAE thresholds decreased with increasing frequency ( f 2=0.5–16 kHz) and at 16 kHz were close to 0 dB SPL. ABR thresholds were best from 1 through 16 kHz (32–38 dB peSPL); higher at 0.5 (45 dB peSPL), 24 (39 dB peSPL), and 30 kHz (49 dB peSPL). At all levels including threshold, the early ABR waves (II and I) were more prominent at the high frequencies while the later waves (IV and V) were more prominent at the low frequencies. The behavioral thresholds recorded were similar to those reported by other researchers although elevated by about 10 dB presumably because of the complexity of the threshold task. DPOAE and ABR thresholds can be reliably and efficiently recorded in the rhesus monkey and provide information concerning site of processing in the auditory pathway not directly available from behavioral data.

Dose dependent protection by lipoic acid against cisplatin-induced ototoxicity in rats: antioxidant defense system.

This study investigated the alterations that occur in auditory brainstem-evoked responses (ABRs) concurrent with changes in cochlear concentrations of glutathione (GSH), lipid peroxidation, and antioxidant enzyme activity in cisplatin-induced ototoxicity and in dose-dependent otoprotection by an antioxidant lipoate. Male Wistar rats were divided into different groups and were treated as follows, with: (1) vehicle (saline) control; (2) cisplatin (16 mg/kg, i.p.); (3) lipoate (100 mg/kg, i.p.) plus saline; (4) cisplatin plus lipoate (25 mg/kg); (5) cisplatin plus lipoate (50 mg/kg), and (6) cisplatin plus lipoate (100 mg/kg). Post-treatment ABRs were evaluated after three days, the rats were sacrificed, and cochleae were harvested and analyzed. The cisplatin-injected rats showed ABR threshold elevations above the pre-treatment thresholds. Rats treated with lipoate plus cisplatin did not show significant elevation of hearing thresholds. Cisplatin administration resulted in a depletion of cochlear GSH concentration (69% of control), whereas, cisplatin-plus-lipoate treatment increased GSH concentration close to control value. Cisplatin-treated rats showed a decrease in cochlear superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activities (57, 78, 59, and 58% of control, respectively), and an increase in malondialdehyde (MDA) concentration (196% of control). Cochlear SOD, CAT, GSH-Px, and GR activities and MDA concentrations were restored in the rats injected with cisplatin plus graded doses of lipoate than those with cisplatin alone. It is concluded that cisplatin-induced ototoxicity is related to impairment of the cochlear antioxidant defense system, and the dose-dependent otoprotection conferred by an antioxidant lipoate against cisplatin ototoxicity is associated with sparing of the cochlear antioxidant defense system.

Absence of thyroid hormone receptor beta-retinoid X receptor interactions in auditory function and in the pituitary-thyroid axis.

THYROID hormone receptor beta-deficient (TRbeta-/-) mice have defective auditory-evoked brain stem responses (ABR). Since in vitro, TRbeta binds to DNA as homodimers or as heterodimers with retinoid X receptors (RXRs), we investigated whether the TRbeta-/- phenotype may reflect loss of RXR-TRbeta heterodimer or TRbeta homodimer function. Normal ABR thresholds were recorded in RXRbeta-/-, RXRgamma-/-, RXRalpha-/+ and RXR compound mutant mice. When RXR mutations were introduced onto TRbeta-/+ or TRbeta-/- backgrounds, thresholds were dictated solely by TRbeta and not RXR genotype. TRbeta-/-mice also over-produce thyroid hormones and thyroid stimulating hormone; however, levels of these hormones were unaltered by RXR mutations. This suggests that, contrary to in vitro models, RXRs may be dispensable and that TRbeta may function in vivo by an RXR-independent mechanism in the auditory system and pituitary-thyroid axis.

CD1 hearing-impaired mice. I: Distortion product otoacoustic emission levels, cochlear function and morphology

The levels of distortion product otoacoustic emissions (DPOAEs) were measured in a strain of hearing-impaired mutant mice (CD1) at various stages of outer hair cell impairment and compared to those of a control inbred strain (CBA/J). Parallel measurements of cochlear potentials and auditory brainstem evoked responses (ABRs) were performed and surface preparations of organs of Corti were observed using phalloidin staining of filamentous actin. Comparison of DPOAEs (elicited by stimulus levels of 60 and 70 dB SPL) with standard functional tests allowed the categorization of CD1 ears into two groups on the basis of the presence or absence of DPOAE, which corresponded to mean ABR thresholds greater or less than 40 dB nHL respectively. When adopting ABR threshold as the gold standard, this procedure yielded rates of false-positives and -negatives ranging from 5 to 16%. However, individual predictions of electrophysiological function from DPOAE levels were not accurate, owing to their large variance, and attempts to optimize stimulus levels did not reduce this variance. In contrast, the profiles of DPOAE level vs. f 2 exhibited large correlations with ABR threshold profiles as a function of f 2. It was also noteworthy that the mean levels of DPOAEs in CD1 mice recorded in frequency intervals with normal ABR thresholds were significantly smaller than those of CBA/J mice. Although hearing loss was revealed early both by DPOAEs and by other functional tests, surface preparations often remained normal until about 3–4 months of age.

CD1 hearing-impaired mice. II: Group latencies and optimal f 2/f 1 ratios of distortion product otoacoustic emissions, and scanning electron microscopy

In our companion paper (Le Calvez et al., 1998), the levels of distortion product otoacoustic emissions (DPOAE) were collected in the ears of CD1 mice with progressive degeneration of cochlear outer hair cells (OHC). Their comparison to standard functional measurements such as auditory-evoked brainstem responses (ABR) showed that CD1 ears could be classified as normal or impaired in a frequency-specific manner using DPOAE levels. The present work reports how DPOAE phases and levels of young CD1 mice were affected by varying the frequency ratio of eliciting stimuli at frequencies f 1 and f 2. Normally hearing CBA/J mice served as controls. The rate of phase change of DPOAE when f 1 was varied and f 2 was fixed allowed the group delay of DPOAE to be derived. The changes of DPOAE levels during this procedure disclosed bandpass characteristics that several reports (Fahey and Allen, 1986; Brown and Gaskill, 1990) assumed to be the reflection of important features of cochlear micromechanics, possibly in relation to the coupling of OHCs to the tectorial membrane. Group delays became significantly shorter when ABR thresholds exceeded 40 dB elevation. The bandpass filter characteristics strikingly depended on auditory function so that the optimal ratio f 2/f 1 progressively shifted from 1.24 to 1.50 or more when hearing loss increased. A difference was also noted between CD1 ears whose ABR thresholds were not yet increased and control CBA/J (optimal ratio 1.20). Scanning electron microscopy disclosed a variety of often minor OHC lesions that were only roughly correlated with cochlear function. However, the presence of abnormalities in the reticular lamina associated with early changes of DPOAE fine structure as a function of f 2/f 1 supported the hypothesis of some involvement of micromechanical features in the bandpass filter characteristics of DPOAE. The sensitivity of their measurement in pathological situations is potentially interesting.

Changes in otoacoustic emissions and auditory brain stem response after cis-platinum exposure in gerbils

Ototoxicity associated with cis -platinum administration commonly presents as hearing loss and tinnitus. The hearing loss is usually an irreversible, high-frequency sensorineural loss. Histologic studies in humans and animals suggest that the outer hair cells (OHCs) are most susceptible to cis -platinum. Evoked otoacoustic emissions (EOAE), as a measure of outer hair cell function, are potentially useful in following ototoxic insults involving OHCs. Distortion-product otoacoustic emission (DPOAE) test frequency-specific regions of the cochlea and therefore may be particularly well suited for monitoring ototoxic injuries. We measured distortion product otoacoustic emissions, at f2 = 2, 4, 6, 8, 10, and 12 kHz, in gerbils after a single large dose of cis -platinum. Animals treated with saline served as controls. The findings were compared to auditory brain stem evoked response (ABR) thresholds, using tone pipe of the same frequencies. The DPOAE and ABR thresholds were measured before treatment and again 2, 5, and 14 days after drug administration. The changes in DPOAE were compared with the changes in ABR. No treatment effect was noted in the 2-day group. Animals treated with cis -platinum demonstrated significant elevation of DPOAE and ABR thresholds compared with control animals at 5 and 14 days. There was no significant difference between the threshold changes in the 5-and 14-day groups. (Otolaryngol Head Neck Surg 1997; 116:585-92.)

Kangaroo rats exhibit spongiform degeneration of the central auditory system similar to that found in gerbils

Kangaroo rats develop spongiform degeneration of the central auditory system similar to that seen in the gerbil. Light microscopic and transmission electron microscopic study of the cochlear nucleus and auditory nerve root (ANR) of Dipodomys deserti and D. merriami show that spongiform lesions develop in dendrites and oligodendrocytes of the cochlear nucleus and in oligodendrocytes of the ANR that are morphologically indistinguishable from those extensively described in the Mongolian gerbil, Meriones unguiculatus. As in Mongolian gerbils, the spongiform degeneration in Dipodomys were much more numerous in animals continually exposed to modest levels of low-frequency noise ( < 75 dB SPL). The kangaroo rats with extensive spongiform degeneration also show slightly, but significantly, elevated auditory brainstem evoked response (ABR) thresholds to low-frequency stimuli, a result also found in Mongolian gerbils. These results suggest that the elevated ABR thresholds may be the result of spongiform degeneration. Because low-frequency noise-induced spongiform degeneration has now been shown in the cochlear nucleus of animals from separate families of Rodentia (Heteromyidae and Muridae), the possibility should be investigated that similar noise-induced degenerative changes occur in the central auditory system of other mammals with good low-frequency hearing.

Syngeneic Bone Marrow Transplantation Reduces the Hearing Loss Associated With Murine Mucopolysaccharidosis Type VII

MPS VII mice are deficient in beta-glucuronidase and share many clinical, biochemical, and pathologic characteristics with human mucopolysaccharidosis type VII (MPS VII). We have shown that syngeneic bone marrow transplantation (BMT) prolongs survival and reduces lysosomal storage in many organs of the MPS VII mouse. In this report, we quantify the hearing loss and determine the impact of syngeneic BMT on the development of deafness and the associated pathology in the MPS VII mouse. Eleven weeks after syngeneic BMT performed at birth, treated MPS VII mice had normal auditory-evoked brainstem responses (ABR), whereas untreated MPS VII mice had ABR thresholds 43 dB higher than normal. Treated MPS VII mice had beta-glucuronidase-positive cells in the temporal bone and in the subepithelial connective tissue of the external auditory canal. There was less thickening of the tympanic membrane and middle ear mucosa and decreased distortion of the ossicles and the cochlear bone. Although transplanted MPS VII mice had increased ABR thresholds by 33 weeks of age, four of the six had thresholds 12 to 32 dB lower than untreated mutants. These data indicate that syngeneic BMT in newborn MPS VII mice prevents early hearing loss and, in some animals, results in long-term improved auditory function.

Auditory brainstem responses in children with Cornelia de Lange syndrome

Auditory brainstem evoked responses (ABRs) were recorded in 10 Japanese infants and children with Cornelia de Lange syndrome to determine the level of the lesion causing their poor response to sound. Behavioral audiometry showed severe threshold elevation compared to an age-matched control group. ABR thresholds, peak latencies of wave I and IV and the peak interval latency of waves I–V were measured. ABR abnormalities of 4 types: no ABRs following 85 dB clicks in both ears (4 cases), no ABRs in one ear but normal ABR in the other (2 cases), mild wave V threshold elevation of ABR with a markedly prolonged wave V (2 cases) and normal ABR pattern in the one side and abnormal ABR pattern in the opposite side suggesting brainstem immaturity for age (2 cases). Our results demonstrate a high prevalence of peripheral sensorineural hearing loss in Cornelia de Lange syndrome, but brainstem immaturity was not ruled out in 2 cases.

The effects of rate and forward masking on human adult and newborn auditory evoked brainstem response thresholds

Several investigators have reported that human newborn auditory brainstem evoked response (ABR) thresholds to clicks are about 10-20 dB higher than human adult thresholds to the same stimuli (Galambos & Hecox, 1978; Shulman-Galambos & Galambos, 1979; Lasky, Rupert, & Waller, 1987). The present study replicated these results, but, in addition, addressed developmental differences in ABR thresholds due to forward masking and changes in stimulus repetition rate. Eight human newborns and seven human adults served as subjects. Newborn ABR thresholds to a 100 microseconds click which followed a 82 db(A) SPL 50 ms broadband forward masker by 10 ms were significantly more elevated relative to their unmasked ABR thresholds than were those of the adults. Relatively loud sounds seem to have a greater effect on the newborn's ability to process subsequently presented soft sounds than they do on adult processing. In contrast, changes in repetition rate of 100 microseconds clicks from 10/s to 50/s had no greater effect on newborn than adult ABR thresholds. At near threshold stimulus levels, rate effects on the ABR are not apparent in newborns nor adults.

Trimethyltin effects on auditory function and cochlear morphology

Trimethyltin (TMT) is a neurotoxicant known to alter auditory function. The present study was designed to compare TMT-induced auditory dysfunction using behavioral, electrophysiological, and anatomical techniques. Adult male Long-Evans hooded rats ( n = 9–12/group) were acutely exposed to saline, 3, 5, or 7 mg/kg TMT. Auditory thresholds were determined 11 weeks postdosing for 5- and 40-kHz tones using reflex modification of the auditory startle response (ASR). Brainstem auditory evoked response (BAER) thresholds were determined for 5-, 40-, and 80-kHz tonal stimuli 9 weeks postdosing. Cochlear histology was assessed at 13 weeks postdosing. Functional endpoints demonstrated a high-frequency hearing loss. ASR thresholds for 40-kHz tones were elevated 25–35 dB in all dosage groups. BAER thresholds for 40- and 80-kHz tones were elevated 30–50 dB in the 5 and 7 mg/kg groups. Organ of Corti surface preparations revealed a pattern of damage suggesting classical ototoxicity. That is, outer hair cells died preferentially in regions associated with high-frequency hearing, in a dosage-dependent manner from base to apex. These data demonstrate the utility of the ASR and BAER in detecting functional alterations in audition and indicate that TMT-induced high-frequency hearing loss is associated with cochlear damage.

AUDITORY ACUITY IN ADRENOCORTICOID INSUFFICIENCY

Studies in man have proposed that individuals with adrenocorticoid insufficiency show a heightened auditory detection threshold. This hyperacuity was shown to be specific for deficits in carbohydrate-active steroids, with threshold levels improved at least 13 dB between 1,000 Hz and 4,000 Hz. These reversible changes in auditory detection have been related to specific influences of glucocorticoids on the metabolism of neural tissue. The present study was designed to examine the hypothesis that glucocorticoid deficiencies cause decreased electrocochleographically measured auditory thresholds with interference in the central conduction of these impulses. A rat model was employed in an attempt to demonstrate the mechanism for a state of increased neural excitability in the absence of carbohydrate-active steroid influence. Electrocochleographic and auditory brain-stem evoked response threshold and latency determinations were made in eight experimental rats. Adrenalectomies were then performed in all animals with postoperative electrocochleographic and auditory brain stem responses being made at 3, 7, and 21 days. Threshold recordings for all experimental animals showed no significant changes following the cessation of glucocorticoid production. Latency measurements revealed impaired central neural transmission of the first and second order neurons. The possible mechanisms for these findings are discussed.