Theodore J. Glattke

A nicotinic-like receptor mediates suppression of distortion product otoacoustic emissions by contralateral sound.

The purpose of this investigation was to provide in vivo pharmacologic characterization of a cholinergic receptor mediating the suppressive effects of medial olivocochlear (MOC) efferent activation. MOC neurons were activated by contralateral sound and the resulting suppression of ipsilateral distortion product otoacoustic emissions (DPOAEs) was monitored before and after intracochlear perfusions of cholinergic antagonists. Results revealed a dose-dependent blockade of contralateral suppression of DPOAEs by a wide variety of nicotinic and muscarinic cholinergic receptor antagonists, as well as by non-traditional antagonists of cholinergic activity. The nicotinic antagonists, alpha-bungarotoxin, curare and kappa-bungarotoxin, and the glycine antagonist, strychnine, blocked contralateral suppression at nanomolar concentrations and demonstrated similar potencies. IC50 values were 2.38 x 10(-7), 2.79 x 10(-7), 3.81 x 10(-7) and 2.96 x 10(-7) M, respectively. These agents were followed in potency by the nicotinic antagonist, trimethaphan (1.75 x 10(-6) M), the M3 muscarinic antagonist, 4-DAMP (1.88 x 10(-6) M) and the GABAA antagonist, bicuculline (2.39 x 10(-6) M). Increasingly greater concentrations of the muscarinic antagonists, atropine (9.52 x 10(-6) M), AF-DX 116 (2.72 x 10(-5) M) and pirenzepine (8.24 x 10(-4) M) were necessary to block contralateral suppression of DPOAEs. The in vivo pharmacology of this putative outer hair cell cholinergic receptor suggests that it may be a member of the nicotinic family of receptors.

Contralateral sound suppresses distortion product otoacoustic emissions through cholinergic mechanisms

Presentation of an acoustic signal to one ear can suppress sound-evoked activity recorded at the opposite ear. The suppression appears to be mediated by medial olivocochlear (MOC) efferent neurons synapsing with outer hair cells (OHCs) and acting through the MOC neurotransmitter, acetylcholine (ACh). The purpose of the present investigation was to study the suppression of distortion product otoacoustic emissions (DPOAEs) by contralateral sound and to examine whether the suppression could be blocked by known antagonists of olivocochlear (OC) efferent activity. Urethane-anesthetized guinea pigs were used. Perilymph spaces of ipsilateral cochleae were alternately perfused with artificial perilymph and drugs at 2.5 microliters/min for 10 min. After each period of perfusion, DPOAEs were measured before, during and after contralateral wideband noise (WBN) stimulation. Pre-perfusion, contralateral WBN attenuated the ipsilateral DPOAEs between 1-3 dB. This suppression was blocked reversibly by strychnine (10 microM), curare (10 microM) and atropine (20 microM), known antagonists of OC efferent activity. These results confirm the findings of Puel and Rebillard (1990) that contralateral WBN can suppress DPOAEs in anesthetized guinea pigs. Furthermore, results suggest that this efferent control of the cochlear mechanical response can either be mediated by both nicotinic and muscarinic cholinergic receptors, or that a single receptor with as yet undescribed structure and pharmacology mediates effects seen.

A phase II study of α-difluoromethylornithine (DFMO) for the treatment of metastatic melanoma

Difluoromethylornithine (DFMO) is an irreversible enzyme-activated inhibitor of ornithine decarboxylase, a key enzyme in polyamine synthesis. We have screened for potential anti-cancer activity of DFMO using a clonogenic assay, which suggested that melanoma might have sensitivity to this agent. Accordingly, we have performed a phase II trial of DFMO (2 g/m2 po q 8 h) in 24 patients, 21 of whom were evaluable for response. One patient achieved a complete response of a large subcutaneous mass for 11 months. Although stabilization is frequently difficult to measure, seven patients appeared to stabilize previously active disease, with a median duration of response of eight weeks. Toxicity was significant and DFMO was discontinued in five patients due to side effects — hearing loss alone in four and hearing loss associated with thrombocytopenia in the fifth patient. Hearing changes occurred in ten patients. Other side effects were mild. These data indicate that DFMO as a single agent may be an effective therapy for melanoma. A phase II trial of DFMO in previously untreated patients using a different schedule to decrease hearing loss is warranted. Additionally, several in vitro and animal models suggest that DFMO plus interferon are synergistic, and this combination might be used for a clinical trial as well.

Intracochlear application of acetylcholine alters sound-induced mechanical events within the cochlear partition

Activation of olivocochlear (OC) efferent fibers has been suggested to alter micromechanical events occurring within the cochlear partition, possibly through an effect of the efferent neurotransmitter (acetylcholine; ACh) on outer hair cells (OHCs). Based on the widely-accepted assumption that otoacoustic emissions reflect OHC activity, we investigated the in vivo influence of ACh on OHCs by studying alterations in emission amplitude with local ACh application. Distortion product otoacoustic emissions (DPOAEs) were measured in anesthetized guinea pigs before, during, and after intracochlear application of ACh (250 microM) with the cholinesterase inhibitor, eserine (20 microM). Perfusion of ACh/eserine was associated with a desensitizing reduction in DPOAE amplitude of approximately 4.4 dB. This reduction was intensity-dependent, with greater and more consistent reductions observed for DPOAEs elicited by low- than by moderate-intensity primaries. The response reduction was not seen during consecutive ACh perfusions performed without an intervening artificial perilymph wash, and was effectively blocked in the presence of pharmacologic antagonists of OC efferent activity (curare, 50 microM; strychnine, 50 microM). Finally, a similar alteration in DPOAE amplitude was never seen during perfusion of the control (artificial perilymph) solution alone. It is argued that these results support the hypothesis that OC efferent activation can alter sound-induced cochlear mechanical events.

Unit Responses of the Cat Cochlear Nucleus to Amplitude‐Modulated Stimuli

Psychoacoustic studies have indicated that the pitch corresponding to the fundamental frequency of certain complex stimuli may be mediated through the temporal pattern of neural discharges. To evaluate this proposal, two populations of units from the cochlear nucleus were examined for their responses to modulated stimuli: (1) Those units with maximum sensitivity for sinusoidal stimuli of 800 Hz or less were presented with modulated stimuli having a low‐frequency fundamental, but with spectrum controlled to reduce the contribution of low‐frequency energy; (2) units with maximum sensitivity in higher‐frequency regions were studied using the stimulus frequency to which each was most sensitive and modulating it at low rates. The results suggests that units were not sensitive to the periodicity characteristics of a stimulus, per se, but that they also require certain spectral information. Once a unit is driven to respond , however, it is likely to reflect the periodicity of the stimulus in its discharge patterns.

The effect of noise bandwidth on the contralateral suppression of transient evoked otoacoustic emissions

The purpose of this study was to determine whether the bandwidth or loudness of a contralateral stimulus is the most important factor in evoking suppression of transient evoked otoacoustic emissions (TEOAEs). TEOAEs were measured in both ears of 10 women in quiet and in the presence of one of three contralateral noise bands; narrow band (NB), wide band (WB) and equalized (EQ), all centered at 2000 Hz. The NB (100 Hz bandwidth) and WB (2200 Hz bandwidth) noises were presented at 60 dB SPL. The SPL of the EQ (100 Hz bandwidth) noise was adjusted such that it was equal in loudness to the WB noise as determined using a psychoacoustic procedure. Only the WB noise was associated with a significant reduction of TEOAE levels. It is believed that this effect occurred because the WB noise has greater effective energy representation across frequency on the basilar membrane as it may receive more gain from the action of the cochlear amplifier. Results of the present study indicate that noise bandwidth is the most important factor in the contralateral suppression of TEOAEs.

Identification of Hearing Loss in Children and Young Adults Using Measures of Transient Otoacoustic Emission Reproducibility.

Measures of transient evoked otoacoustic emission (TEOAE) reproducibility were obtained for 506 ears of 260 children and young adults. Frequency-specific and whole reproducibility (WR) data were ob...

TEOAE suppression in adults with learning disabilities

The presentation of contralateral noise during the recording of transient evoked otoacoustic emissions (TEOAEs) reduces the amplitude of the TEOAE in normally-hearing adults. This is known as TEOAE suppression. The present study investigated TEOAE suppression in 18 adults with learning disabilities (LDs) compared to 18 adults without LDs. TEOAEs were elicited by 60 dB p.e. SPL clicks and were suppressed by the presentation of 60 dB SPL contralateral broadband noise. Suppression was measured as a change in the overall TEOAE response amplitude, and also analysed in 2-ms epochs representing different TEOAE frequency-response bands. A significant interaction was evident between group type and ear tested. Participants in the control group had right ear dominance for the suppression effect, whereas the left ear was found to be dominant for the LD group. These findings suggest a mechanism of the medial olivary cochlear bundle and efferent auditory pathway that differs in those with LD compared to those with typical learning abilities.

Waveform Preservation in the Cochlea

Past measurements and observations appear to give equivocal evidence on whether waves of different frequency travel down the cochlea at the same rate. If different frequencies travel at different rates, then steady‐state waveforms will show changes in addition to those attributable to relative amplitude change of the components. Sinusoids of simple (octave) ratio were fed into guinea‐pig cochleas, and the waveforms were observed with paired electrodes at two well‐separated points. Comparative phase shifts for the two components indicate that, on the stapes side of a given observation point along the membrane, all frequencies lower than the frequency of maximum amplitude for that point travel at the same rate.

DISTORTION PRODUCT OTOACOUSTIC EMISSIONS CREATED THROUGH THE INTERACTION OF SPONTANEOUS OTOACOUSTIC EMISSIONS AND EXTERNALLY GENERATED TONES

An SOAE (f2) and one XT (f1) were used to create 2 f1−f2 DPOAEs. External tones were applied to the ear canal at SOAE/f1 ratios between 1.08 and 1.22 XT/SOAE intensity differences varied from 0 to approximately 50 dB SPL. DPOAE amplitude and SOAE suppression characteristics were variable across subjects. However, the following trends were noted: (1) At larger frequency ratios, DPOAE generation and SOAE suppression were associated with greater XT SPLs; (2) DPOAE growth functions were characterized by slopes <1 dB/dB, a maximum, rollover and disappearance into the noise floor; (3) maximum DPOAEs were observed at frequencies approximately 1/2 oct below the SOAEs; (4) DPOAE maximums were associated with a significant amount of SOAE suppression. The results are consistent with DPOAEs created using two low‐level tones [Brown and Gaskill, in Mechanics and Biophysics of Hearing (Springer‐Verlag, Berlin, 1990)] and can be interpreted by considering suppression in a nonlinear cochlear model [Zwicker, 163–176 (1986)...