Mutant beta-spectrin 4 causes auditory and motor neuropathies in quivering mice.

The autosomal recessive mouse mutation quivering (qv), which arose spontaneously in 1953, produces progressive ataxia with hind limb paralysis, deafness and tremor. Six additional spontaneous alleles, qvJ, qv2J, qv3J, qv4J, qvlnd and qvlnd2J, have been identified. Ear twitch responses (Preyer's reflex) to sound are absent in homozygous qv/qv mice, although cochlear morphology seems normal and cochlear potentials recorded at the round window are no different from those of control mice. However, responses from brainstem auditory nuclei show abnormal transmission of auditory information, indicating that, in contrast to the many known mutations causing deafness originating in the cochlea, deafness in qv is central in origin. Here we report that quivering mice carry loss-of-function mutations in the mouse beta-spectrin 4 gene (Spnb4) that cause alterations in ion channel localization in myelinated nerves; this provides a rationale for the auditory and motor neuropathies of these mice.

Local drug delivery with a self-contained, programmable, microfluidic system.

The development and optimization of many new drug therapies requires long-term local delivery with controlled, but variable dosage. Current methods for chronic drug delivery have limited utility because they either cannot deliver drugs locally to a specific organ or tissue, do not permit changes in delivery rate in situ, or cannot be used in clinical trials in an untethered, wearable configuration. Here, we describe a small, self-contained system for liquid-phase drug delivery. This system enables studies lasting several months and infusion rates can be programmed and modified remotely. A commercial miniature pump is integrated with microfabricated components to generate ultralow flow rates and stroke volumes. Solutions are delivered in pulses as small as 370 nL, with pulses delivered at any interval of 1 min or longer. A unique feature of the system is the ability to infuse and immediately withdraw liquid, resulting in zero net volume transfer while compounds are exchanged by mixing and diffusion with endogenous fluid. We present in vitro results demonstrating repeatability of the delivered pulse volume for nearly 3 months. Furthermore, we present in vivo results in an otology application, infusing into the cochlea of a guinea pig a glutamate receptor antagonist, which causes localized and reversible changes in auditory sensitivity.

Prospective noise induced changes to hearing among construction industry apprentices.

AIMS: To characterise the development of noise induced damage to hearing. METHODS: Hearing and noise exposure were prospectively monitored among a cohort of newly enrolled construction industry apprentices and a comparison group of graduate students, using standard pure tone audiometry and distortion product otoacoustic emissions (DPOAEs). A total of 328 subjects (632 ears) were monitored annually an average of 3.4 times. In parallel to these measures, noise exposure and hearing protection device (HPD) use were extensively monitored during construction work tasks. Recreational/non-occupational exposures also were queried and monitored in subgroups of subjects. Trade specific mean exposure L(eq) levels, with and without accounting for the variable use of hearing protection in each trade, were calculated and used to group subjects by trade specific exposure level. Mixed effects models were used to estimate the change in hearing outcomes over time for each exposure group. RESULTS: Small but significant exposure related changes in DPOAEs over time were observed, especially at 4 kHz with stimulus levels (L1) between 50 and 75 dB, with less clear but similar patterns observed at 3 kHz. After controlling for covariates, the high exposure group had annual changes in 4 kHz emissions of about 0.5 dB per year. Pure tone audiometric thresholds displayed only slight trends towards increased threshold levels with increasing exposure groups. Some unexpected results were observed, including an apparent increase in DPOAEs among controls over time, and improvement in behavioural thresholds among controls at 6 kHz only. CONCLUSIONS: Results indicate that construction apprentices in their first three years of work, with average noise exposures under 90 dBA, have measurable losses of hearing function. Despite numerous challenges in using DPOAEs for hearing surveillance in an industrial setting, they appear somewhat more sensitive to these early changes than is evident with standard pure tone audiometry.

Effects of olivocochlear feedback on distortion product otoacoustic emissions in guinea pig.

Activation of ipsilaterally responsive olivocochlear (OC) neurons by sound produces rapid, post-onset alterations in the 2f1-f2 distortion product otoacoustic emission (DPOAE). The present study investigates the frequency and level dependence of this ipsilateral OC effect in the anesthetized guinea pig, compares its magnitude and sign to OC effects elicited by contralateral sound ("contralateral" OC effect), and characterizes the influence of such activity on steady-state DPOAE amplitude. DPOAEs were measured with fine time resolution in response to primary stimuli varied systematically in frequency and level. DPOAEs showed rapid and remarkably stereotyped post-onset amplitude alterations. These ipsilateral OC effects were greater for high (8-12 kHz) than for low (2-4 kHz) f2 primary frequencies and for higher primary levels (70-80 dB SPL). For any f2/f1 pair, the sign as well as the magnitude of the ipsilateral effects varied with. primary level ratio. For example, with L1 fixed at 75 and L2 varied in 1-dB steps from 60 to 75 dB SPL, DPOAE amplitude underwent a stereotyped progression from post-onset increases at the lowest levels of the f2 primary to post-onset decreases at the highest levels. At intermediate levels, near the region of sign change (L2 = 5-10 dB below L1), post-onset effects were often particularly large (as great as 20 dB). These large ipsilateral OC effects were always associated with "dips" in the DPOAE amplitude vs. level functions, and both disappeared after OC section. Although smaller in magnitude, contralateral OC effects were identical to ipsilateral effects in frequency and level dependence and in form.

ATP antagonists cibacron blue, basilen blue and suramin alter sound-evoked responses of the cochlea and auditory nerve.

The P2-purinergic receptor antagonists suramin, cibacron blue and basilen blue, the latter two being isomers of reactive blue 2, were studied for their effects on sound-evoked responses from the cochlea (cochlear microphonic, CM; summating potential, SP; distortion product otoacoustic emissions, DPOAE) and auditory nerve (compound action potential, CAP). Local application of these compounds (10-1000 microM) into the cochlear perilymph was associated with concentration-dependent response alterations. Effects of suramin on cochlear responses were minimal: High-intensity SP was reduced slightly at concentrations > or = 330 microM without significant alterations in CM or DPOAEs. The amplitude of the auditory nerve CAP was suppressed and its latency increased at drug concentrations > or = 100 microM. Cibacron blue and basilen blue were of greater potency in their effects on cochlear and auditory nerve responses. DPOAEs were generally reduced, low-intensity SP was reduced and high-intensity SP was increased and CM was little affected at drug concentrations 100-1000 microM. The CAP was suppressed and its latency increased at concentrations > or = 33 microM. Effects of suramin were largely reversible; those associated with cibacron blue and basilen blue generally were not. To the extent that these drugs acted selectively as antagonists of ATP receptor-mediated activity, results support the hypothesis that endogenous ATP exerts profound actions at the level of the cochlea and the auditory nerve.

Magnitude of the negative summating potential varies with perilymph calcium levels.

Previous results demonstrated that nimodipine, an L-type of Ca2+ channel antagonist, abolished the negative summating potential (SP) recorded from anesthetized guinea pigs (Bobbin et al., 1990), suggesting that Ca2+ is involved in generation of the negative SP. Therefore we examined the effect of changing concentrations of perilymph Ca2+ on this cochlear potential. Perilymph spaces of guinea pig cochleae were perfused with artificial perilymph solutions containing zero mM Ca2+, zero mM Ca2+ with 2 mM EGTA, 30 mM Mg2+ and increasing levels of Ca2+ (2, 4, 8, 16 mM) at a rate of 2.5 microliters/min for 10 min. Immediately after each period of perfusion the compound action potential of the auditory nerve (CAP), cochlear microphonics (CM) and the negative SP evoked by 10 kHz tone bursts of varying intensities were recorded from a wire inserted in the basal turn scala vestibuli. Decreasing the level of Ca2+ decreased the magnitude of the negative SP, whereas increasing the level of Ca2+ progressively increased the magnitude of the negative SP. Mg2+ (30 mM) suppressed the CAP to the same extent as zero mM Ca2+ with 2 mM EGTA, but only slightly increased the magnitude of the negative SP. These results support the hypothesis that Ca2+ and L-type Ca2+ channels are involved in the function of the hair cells and the generation of the negative SP. Mg2+ appears to be a selective antagonist of the Ca2+ channel involved in transmitter release.

Time-varying alterations in the f2-f1 DPOAE response to continuous primary stimulation. I: Response characterization and contribution of the olivocochlear efferents.

The f2-f1 distortion product otoacoustic emission (DPOAE) can be observed to undergo gradual alterations in amplitude during continuous ipsilateral stimulation with primary tones. In the present experiments, we characterized the dependence of these amplitude alterations on several stimulus variables (intensity, duration, frequency) and on DPOAE type (quadratic vs cubic) and tested the hypothesis that such alterations are mediated by the olivocochlear (OC) efferents. Responses were recorded in urethane-anesthetized guinea pigs with sectioned middle ear muscles before and after intracochlear application of antagonists (curare, 1 microM; bicuculline, 10 microM; tetrodotoxin, 1 microM) or before and after OC efferent section at the midline of the floor of the IVth ventricle. We confirm previous reports of continuous stimulation-related alterations in the amplitude of the quadratic distortion product, f2-f1, and report a novel, suppressive 'off-effect' apparent in f2-f1 amplitude following a short rest from such stimulation. Response alterations were sensitive to primary intensity and to duration of rest from continuous stimulation, but were not clearly frequency-dependent over the ranges tested. Corresponding alterations in the amplitude of the cubic nonlinearity, 2f1-f2 were very small or absent. Amplitude alterations in f2-f1 were reduced but not blocked by OC efferent antagonists (curare, bicuculline) and were largely unaffected by TTX or by midline brainstem section. All of these manipulations, however prevented completely the known efferent-mediated contralateral sound suppression of both f2-f1 and 2f1-f2 DPOAEs. Taken together, these results do not provide support for efferent control of the f2-f1 amplitude alterations observed during continuous ipsilateral stimulation.

Intracochlear salicylate reduces low-intensity acoustic and cochlear microphonic distortion products.

Salicylate is well-known to produce reversible hearing loss and tinnitus. The site and mechanism of salicylate's ototoxic actions, however, remain unresolved. Recent experiments demonstrating primarily low-intensity effects on cochlear afferent outflow and effects on otoacoustic emissions (OAEs) suggest that salicylate acts to compromise active, energy-enhancing processes within the cochlea (i.e., the active process). We tested this hypothesis by examining the effect of salicylate on distortion product emissions. Distortion product responses to two-tone stimulation were monitored in the guinea pig before, during, and after intracochlear administration of increasing concentrations of salicylate (0.6-5 mM). These responses were recorded as acoustic signals in the ear canal spectrum (ADP), and as present in the cochlear microphonic (CM) recorded from a wire in basal turn scala vestibuli (CMDP). We also recorded the CM response to a single tone. Cochlear perfusion of salicylate resulted in a dose-responsive reduction in ADPs that was greater for low intensities of stimulation. CMDPs also demonstrated a concentration-dependent reduction at low intensities, but were increased slightly, though not significantly, by salicylate when elicited by high intensity primaries. CM was essentially unchanged by intracochlear salicylate. These results are consistent with an action of salicylate that involves the outer hair cells (OHCs) and are in harmony with the hypothesis that salicylate may selectively compromise the active process.

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.

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.

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.

Time-varying alterations in the f2-f1 DPOAE response to continuous primary stimulation. II. Influence of local calcium-dependent mechanisms.

The distortion product otoacoustic emission (DPOAE) corresponding to the frequency f2-f1 displays stereotyped, time-varying amplitude alterations during continuous primary tone stimulation. The origin of these alterations is unknown; however, evidence that efferent neurons contribute little to the changes has been presented (Kujawa et al., 1994a, 1995; Lowe and Robertson, 1995). The present investigation examines the hypothesis that these alterations in f2-f1 amplitude are a reflection of local, Ca(2+)-dependent mechanisms involving the outer hair cell (OHC) response to sustained stimulation. Experiments were performed using urethane-anesthetized guinea pigs with sectioned middle ear muscles. Intracochlear perfusion was employed to reversibly lower perilymph Ca2+ levels and to introduce antagonists and agonists of L-type Ca2+ channels. Manipulations that lowered available Ca2+ (zero Ca2+ artificial perilymph; zero Ca2+ with BAPTA) or that blocked its entry into the cell via L-type Ca2+ channels (nimodipine) reduced, prevented or reversed the perstimulatory changes in f2-f1 DPOAE amplitude. These perilymph manipulations also reduced the overall amplitude of this distortion component while perfusion of an L-type Ca2+ channel agonist (Bay K 8644) increased its amplitude. Mg2+ did not substitute for Ca2+, suggesting that these are not merely divalent cation effects. Results are consistent with the hypothesis that continuous stimulation-related changes in f2-f1 DPOAE amplitude are sensitive to perilymph Ca2+ levels and to the function of L-type Ca2+ channels. However, nimodipine also reduced the endocochlear potential (EP) and Bay K 8644 increased the EP. The sensitivity of both the perstimulatory changes in f2-f1 DPOAE amplitude and the EP to the latter drugs leaves their site(s) of action unresolved.

Effects of adenosine 5'-triphosphate and related agonists on cochlear function.

Several lines of evidence implicate a neurotransmitter/modulator role for ATP in the cochlea. Most of the work supporting such a notion has been accomplished using in vitro preparations of sensory hair cells or other cochlear tissues. Little is known regarding the functional consequences of ATP receptor activation in vivo. In the present experiments, we tested ATP and related agonist analogs for their effects on sound-evoked responses of the cochlea (cochlear microphonic, CM; summating potential, SP; distortion product otoacoustic emissions, DPOAE) and auditory nerve (compound action potential, CAP) in vivo and on outer hair cell (OHC) currents and cell length in vitro. In vivo, local application of these compounds was associated with concentration- and intensity-dependent response alterations. The slowly-hydrolyzable P2y agonist, ATP-gamma-S, was clearly of greatest in vivo potency: At low to moderate stimulus intensities, micromolar concentrations of this drug reduced all responses, in particular CAP and DPOAEs, which fell to the level of the noise floor. At high intensities, response suppression was smaller and SP was increased. In vivo effects of ATP, ATP-alpha-S and 2-Me-S-ATP were qualitatively similar to, but smaller in magnitude and requiring higher concentrations than those observed for ATP-gamma-S. Adenosine was without significant effect on responses of the cochlea and auditory nerve. In vitro, effects of ATP-gamma-S and ATP were similar: both induced inward currents in OHCs held at -60 mV without producing observable (> 0.3 micron) changes in OHC length. Results suggest that endogenous ATP influences cochlear function through receptors at several sites in the cochlea. Results suggest further that these response alterations are mediated, at least in part, by receptors of the P2y subtype.

In vivo release of neuroactive amino acids from the inferior colliculus of the guinea pig using brain microdialysis.

Microdialysis techniques were used to measure in vivo release of neuroactive amino acids from the central nucleus of the inferior colliculus (ICC) in anesthetized guinea pigs. Concentric dialysis probes were implanted in the ICC and perfused with Ringer solution of various compositions at a flow rate of 2.0 microliters/min. Consecutive 10-min fractions of the dialysate were collected for up to 3 h under different experimental conditions, frozen and assayed for amino acid content by high performance liquid chromatography (HPLC). There was an initial high outflow of amino acids which declined to stable baseline levels after 2 h. Following this stabilization period, perfusion with a medium containing 100 mM KCl produced an increase in the extracellular levels of aspartate (Asp), glutamate (Glu), gamma-aminobutyric acid (GABA) and glycine (Gly). Only the increases in GABA and Gly were statistically significant. None of the increases occurred in the presence of 2.0 mM cobalt suggesting the release of amino acids is calcium dependent. Histological examination revealed that tissue damage was minimal and largely confined to the immediate vicinity of the probes. We were also able to show that the blood brain barrier (BBB) appeared to heal 2 h after probe implantation. Thus, following intravenous injection of [3H]alpha-aminoisobutyric acid (AIB), which does not cross the intact BBB, no isotope was recovered in the dialysate. These results demonstrate that microdialysis is a unique and suitable method to monitor changes in the extracellular levels of amino acid neurotransmitters in a central auditory structure.(ABSTRACT TRUNCATED AT 250 WORDS)

Longitudinal threshold changes in older men with audiometric notches.

Age-related hearing loss (presbycusis) is a multifactorial process that results chiefly from the accumulating effects of noise damage and aging on the cochlea. Noise damage is typically evidenced clinically by a discrete elevation (notch) of the auditory thresholds in the 3-6 kHz region of the audiogram whereas aging affects the highest frequencies first. To determine whether the presence of such high-frequency notches influences auditory aging, we examined the 15 year change in audiometric thresholds in 203 men from the Framingham Heart Study cohort. The mean age at the first hearing test was 64 years (range 58-80). Occupational and recreational noise exposure over the 15 years was assumed to be minimal due to the age of the subjects. The presence or absence of a notch was determined using a piecewise linear/parabolic curve fitting strategy. A discrete elevation of the pure-tone thresholds of 15-34 dB in the 3-6 kHz region was deemed a small notch (N1), and elevations of 35 dB or greater were deemed large notches (N2). Absence of a notch (N0) was encoded those ears with <15 dB elevation in the 3-6 kHz region. The presence and absence of notches correlated with the subjects' history of noise exposure. The 15 year pattern of change in age-adjusted pure-tone thresholds varied significantly by notch category. There was less change over time in the notch frequencies (3-6 kHz) and significantly greater change in the adjacent frequency of 2 kHz in the N2 group as compared to the N0 and N1 groups. The adjacent frequency of 8 kHz showed a significant, but smaller, change in the N1 group as compared to the N0 and N2 groups. The change at 2 kHz was independent of the starting hearing level at E15, whereas the changes at 4-8 kHz were influenced by the hearing level at E15. These data suggest that the noise-damaged ear does not 'age' at the same rate as the non-noise damaged ear. The finding of increased loss at 2 kHz suggests that the effects of noise damage may continue long after the noise exposure has stopped. The mechanism for this finding is unknown but presumably results from prior noise-induced damage to the cochlea.

Predictors of hearing threshold levels and distortion product otoacoustic emissions among noise exposed young adults.

AIM: To examine the relations between noise exposure and other risk factors with hearing function as measured by audiometric thresholds and distortion product otoacoustic emissions. METHODS: A total of 456 subjects were studied (393 apprentices in construction trades and 63 graduate students). Hearing and peripheral auditory function were quantified using standard, automated threshold audiometry, tympanometry, and distortion product otoacoustic emissions (DPOAEs). The analysis addressed relations of noise exposure history and other risk factors with hearing threshold levels (HTLs) and DPOAEs at the baseline test for the cohort. RESULTS: The cohort had a mean age of 27 (7) years. The construction apprentices reported more noise exposure than students in both their occupational and non-occupational exposure histories. A strong effect of age and years of work in construction was observed at 4, 6, and 8 kHz for both HTLs and DPOAEs. Each year of construction work reported prior to baseline was associated with a 0.7 dB increase in HTL or 0.2 dB decrease DPOAE amplitude. Overall, there was a very similar pattern of effects between the HTLs and DPOAEs. CONCLUSIONS: This analysis shows a relatively good correspondence between the associations of noise exposures and other risk factors with DPOAEs and the associations observed with pure-tone audiometric thresholds in a young adult working population. The results provide further evidence that DPOAEs can be used to assess damage to hearing from a variety of exposures including noise. Clarifying advantages of DPOAEs or HTLs in terms of sensitivity to early manifestations of noise insults, or their utility in predicting future loss in hearing will require longitudinal follow up.

Otoacoustic Emissions.

Otoacoustic emissions are low-intensity sounds that are produced in the cochlea and transmitted through the middle ear apparatus to the ear canal. They can be detected and extracted from the background noise in the ear canal through the use of a sensitive microphone and selective filtering or averaging techniques. The technical aspects of emission recording are very similar to those associated with the detection and capture of auditory evoked potentials. Emissions provide an acoustic link to a physiological window through which we can view the auditory periphery using frequency-specific stimuli that are presented at low and moderate intensities. The window provides an opportunity to examine cochlear activity that occurs prior to stimulation of the nervous system.Tonal emissions occur spontaneously in approximately 40% of people who have normal thresholds for pure-tone stimuli. SOAE and other types of emissions may be influenced by both ipsilateral and contralateral stimuli. One form of interaction results in suppression of the emission, and the tuning patterns associated with suppression of emissions by ipsilateral stimuli have characteristics that are similar to tuning patterns associated with single cochlear hair cells and individual neurons of the auditory nerve. These findings and other lines of evidence support the conclusion that an emission having tonal characteristics is produced from a very restricted region of the cochlear partition.Emissions may be evoked by brief click or tonal stimuli, and by continuous tonal stimuli, in virtually all individuals who have normal pure-tone thresholds and uncompromised middle ear systems. The EOAE are compromised by conditions that compromise the function of the cochlea, and they hold promise as tools that might be employed in screening for hearing loss. Preliminary findings suggest that screening employing TEOAE produces a yield that is similar to that produced by screening programs based on auditory brainstem responses. Emissions may offer advantages over current screening methods because of the ease with which they can be recorded and their apparent independence from neurological influence.Many questions regarding the origin and nature of emissions remain unanswered, but they appear to offer great sensitivity to the status of the auditory periphery. DPOAE provide an opportunity to scan the cochlear partition from base to apex with frequency-specific stimuli, and give the examiner a detailed view of the status of the end organ. The study of DPOAE holds great promise in refinement of site of lesion identification. It is exciting to witness the development of a tool to help clinical examiners probe the function of the previously inaccessible cochlea.

Conditioning-related protection from acoustic injury: effects of chronic deefferentation and sham surgery.

The inner ear can be made less vulnerable to acoustic injury by a "conditioning" treatment involving exposure to a moderate-level acoustic stimulus before the acoustic overexposure. The present study was designed to explore the role of the olivocochlear (OC) system in this "protection." Guinea pigs were divided into a number of groups: some (trauma-only) were exposed to a traumatic noise for 4 h at 109 dB SPL; others (condition/trauma) were conditioned by daily exposure to the same noise at 85 dB SPL before the traumatic exposure. In OC-intact animals, the condition/trauma group showed significantly less permanent threshold shift (PTS) than the trauma-only group as measured via compound action potentials and distortion-product otoacoustic emissions (DPOAEs). Other animals with identical noise-exposure regimens underwent deefferentation surgery before the start of conditioning: the OC bundle (OCB) was cut in the brain stem, either at the midline (cutting the crossed OCB to both ears) or at the sulcus limitans (cutting all OC fibers to 1 side). Lesion success was quantified by measuring OC fascicles to the outer hair cell region in each ear. The results from the surgical groups showed that total loss of the OCB significantly increased the noise-induced PTS, whereas loss of the COCB only did not; that the conditioning exposure in deefferented animals increased, rather than decreased, the PTS from the traumatic exposure; and that animals undergoing sham surgery (brain stem cuts that failed to transect the OCB) appeared protected whether or not they received the conditioning noise exposure. The latter result suggests that conditioning-related protection may arise from a generalized stress response, which can be elicited by noise exposure, brain surgery, or a variety of other means. The former results make an OC role in the conditioning process, per se, difficult to assess, given the large effects of OC activity on general acoustic vulnerability.

Long-term sound conditioning enhances cochlear sensitivity.

Sound conditioning, by chronic exposure to moderate-level sound, can protect the inner ear (reduce threshold shifts and hair cell damage) from subsequent high-level sound exposure. To investigate the mechanisms underlying this protective effect, the present study focuses on the physiological changes brought on by the conditioning exposure itself. In our guinea-pig model, 6-h daily conditioning exposure to an octave-band noise at 85 dB SPL reduces the permanent threshold shifts (PTSs) from a subsequent 4-h traumatic exposure to the same noise band at 109 dB SPL, as assessed by both compound action potentials (CAPs) and distortion product otoacoustic emissions (DPOAEs). The frequency region of maximum threshold protection is approximately one-half octave above the upper frequency cutoff of the exposure band. Protection is also evident in the magnitude of suprathreshold CAPs and DPOAEs, where effects are more robust and extend to higher frequencies than those evident at or near threshold. The conditioning exposure also enhanced cochlear sensitivity, when evaluated at the same postconditioning time at which the traumatic exposure would be delivered in a protection study. Response enhancements were seen in both threshold and suprathreshold CAPs and DPOAEs. The frequency dependence of the enhancement effects differed, however, by these two metrics. For CAPs, effects were maximum in the same frequency region as those most protected by the conditioning. For DPOAEs, enhancements were shifted to lower frequencies. The conditioning exposure also enhanced both ipsilaterally and contralaterally evoked olivocochlear (OC) reflex strength, as assessed using DPOAEs. The frequency and level dependence of the reflex enhancements were consistent with changes seen in sound-evoked discharge rates in OC fibers after conditioning. However, comparison with the frequency range and magnitude of conditioning-related protection suggests that the protection cannot be completely explained by amplification of the OC reflex and the known protective effects of OC feedback. Rather, the present results suggest that sound conditioning leads to changes in the physiology of the outer hair cells themselves, the peripheral targets of the OC reflex.

Single olivocochlear neurons in the guinea pig. I. Binaural facilitation of responses to high-level noise.

Single medial olivocochlear (MOC) neurons were recorded from the cochlea of the anesthetized guinea pig. We used tones and noise presented monaurally and binaurally and measured responses for sounds up to 105 dB sound pressure level (SPL). For monaural sound, MOC neuron firing rates were usually higher for noise bursts than tone bursts, a situation not observed for afferent fibers of the auditory nerve that were sampled in the same preparations. MOC neurons also differed from afferent fibers in having less saturation of response. Some MOC neurons had responses that continued to increase even at high sound levels. Differences between MOC and afferent responses suggest that there is convergence in the pathway to olivocochlear neurons, possibly a combination of inputs that are at the characteristic frequency (CF) with others that are off the CF. Opposite-ear noise almost always facilitated the responses of MOC neurons to sounds in the main ear, the ear that best drives the unit. This binaural facilitation depends on several characteristics that pertain to the main ear: it is higher in neurons having a contralateral main ear (contra units), it is higher at main-ear sound levels that are moderate (approximately 65 dB SPL), and it is higher in neurons with low discharge rates to main-ear stimuli. Facilitation also depends on parameters of the opposite-ear sound: facilitation increases with noise level in the opposite ear until saturating, is greater for continuous noise than noise bursts, and is usually greater for noise than for tones. Using optimal opposite-ear facilitators and high-level stimuli, the firing rates of olivocochlear neurons range up to 140 spikes/s, whereas for moderate-level monaural stimuli the rates are <80 spikes/s. At high sound levels, firing rates of olivocochlear neurons increase with CF, an increase that may compensate for the known lower effectiveness of olivocochlear synapses on outer hair cells responding to high frequencies. Overall, our results demonstrate a high MOC response for binaural noise and suggest a prominent role for the MOC system in environments containing binaural noise of high level.