Olivocochlear Efferents Research Articles

Medial olivocochlear efferent activity in awake guinea pigs.

Cochlear outer hair cells receive numerous connections from the medial olivocochlear efferent neurons. Medial olivocochlear efferent activity is highly dependent on the level of anesthesia. The present study was thus designed to investigate the efficiency of contralateral white noise stimulation on the distortion product otoacoustic emissions (DPOAEs) in a large number of awake guinea pigs, and to compare in the same animals the effect of urethane- and pentobarbitone-anesthesia. The monitoring of DPOAEs during contralateral white noise stimulation in awake animals requires the development of a soft restraining box, together with a conditioning technique for the animals to accept the contralateral sound and DPOAEs monitoring device. This technique allows us to demonstrate that contralateral sound suppression is much stronger in awake than in anesthetized animals. In all the cases, the contralateral sound suppression was abolished 3 h after i.m. injection of gentamicin, an aminoglycoside antibiotic which blocks the medial olivocochlear efferents. These results suggest that future studies have to explore the function of medial olivocochlear efferents in awake animals.

Medial olivocochlear efferent reflex in humans: otoacoustic emission (OAE) measurement issues and the advantages of stimulus frequency OAEs.

Otoacoustic emissions (OAEs) are useful for studying medial olivocochlear (MOC) efferents, but several unresolved methodological issues cloud the interpretation of the data they produce. Most efferent assays use a "probe stimulus" to produce an OAE and an "elicitor stimulus" to evoke efferent activity and thereby change the OAE. However, little attention has been given to whether the probe stimulus itself elicits efferent activity. In addition, most studies use only contralateral ( re the probe) elicitors and do not include measurements to rule out middle-ear muscle (MEM) contractions. Here we describe methods to deal with these problems and present a new efferent assay based on stimulus frequency OAEs (SFOAEs) that incorporates these methods. By using a postelicitor window, we make measurements in individual subjects of efferent effects from contralateral, ipsilateral, and bilateral elicitors. Using our SFOAE assay, we demonstrate that commonly used probe sounds (clicks, tone pips, and tone pairs) elicit efferent activity, by themselves. Thus, results of efferent assays using these probe stimuli can be confounded by unwanted efferent activation. In contrast, the single 40 dB SPL tone used as the probe sound for SFOAE-based measurements evoked little or no efferent activity. Since they evoke efferent activation, clicks, tone pips, and tone pairs can be used in an adaptation efferent assay, but such paradigms are limited in measurement scope compared to paradigms that separate probe and elicitor stimuli. Finally, we describe tests to distinguish middle-ear muscle (MEM) effects from MOC effects for a number of OAE assays and show results from SFOAE-based tests. The SFOAE assay used in this study provides a sensitive, flexible, frequency-specific assay of medial efferent activation that uses a low-level probe sound that elicits little or no efferent activity, and thus provides results that can be interpreted without the confound of unintended efferent activation.

The effect of vestibular nerve section upon tinnitus.

This paper reviews the published evidence regarding the effect of vestibular nerve section upon tinnitus. This is of relevance not only for those performing and undergoing this procedure, but also for those considering the hypothesis that auditory efferent system dysfunction may be influential in tinnitus perception. The auditory medial efferent fibres within the internal auditory canal run within the inferior vestibular nerve, only joining the cochlear nerve at the anastomosis of Oort, a bundle of 1300 fibres running from the saccular branch of the inferior vestibular nerve to the cochlear nerve. Vestibular nerve section procedures therefore section this efferent olivocochlear pathway, and ablate efferent influence upon that cochlear. If auditory efferent dysfunction is involved in tinnitus perception, this ablation might influence the tinnitus status of that patient. A literature search identified 18 papers mentioning tinnitus status after vestibular nerve section, describing the experiences of a total of 1318 patients. The proportion of patients in whom tinnitus was said to be exacerbated postoperatively ranged from 0% to 60%, with a mean of 16.4% (standard deviation 14.0). The proportion of patients in whom tinnitus was unchanged was 17% to 72% (mean 38.5%, standard deviation 15.6), and in whom tinnitus was said to be improved was 6% to 61% (mean 37.2%, standard deviation 15.2). In the majority of patients undergoing this procedure, ablation of auditory efferent input (and thus total efferent dysfunction) to the cochlea was not associated with an exacerbation of tinnitus. The finding of this review is that efferent dysfunction after vestibular nerve section does not consistently worsen tinnitus.

The inner hair cell afferent/efferent synapses revisited: a basis for new therapeutic strategies.

Within the cochlea, the sensory inner hair cells, which transduce the mechanical displacement of the basilar membrane into neural activity, release glutamate that acts on postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor channels located on dendrites of primary auditory neurons. Up to now, it has been thought that the auditory nerve responses passively reflected the motion of the basilar membrane supporting the organ of Corti. Here, we show that dopaminergic lateral olivocochlear efferents drive a permanent gain control at the site of auditory action potential initialization. A dysfunction of this system leads to the development of early signs of excitotoxicity. With the knowledge of the molecular mechanisms involved at this first synaptic complex in the cochlea, it is now possible to envisage local treatments for spiral ganglion neurons, either to stop an excitotoxically induced hyperexcitability (probably the starting point of most posttraumatic tinnitus) or to prevent neuronal death (neural presbycusis).

A new aspect of aminoglycoside ototoxicity: impairment of cochlear dopamine release.

Aminoglycoside ototoxicity is a well-documented process via several pathophysiological pathways. The protective role of cochlear dopamine, released from the lateral olivocochlear efferents, was implicated previously in case of ischemia or acoustic trauma, as it postsynaptically inhibits the effect of excessively released glutamate from the hair cells. In our in vitro superfusion experiments we showed that neomycin dose- dependently inhibits the dopamine release from isolated guinea pig cochlea, while gentamicin and kanamycin was ineffective on it. After chronic application of neomycin the dopamine outflow did not change significantly, suggesting an adaptive process. In our experiments we have found a possibly new action site of one of the aminoglycoside antibiotics, neomycin.

Cholinergic Modulation of Stellate Cells in the Mammalian Ventral Cochlear Nucleus

The main source of excitation to the ventral cochlear nucleus (VCN) is from glutamatergic auditory nerve afferents, but the VCN is also innervated by two groups of cholinergic efferents from the ventral nucleus of the trapezoid body. One arises from collaterals of medial olivocochlear efferents, and the other arises from neurons that project solely to the VCN. This study examines the action of cholinergic inputs on stellate cells in the VCN. T stellate cells, which form one of the ascending auditory pathways to the inferior colliculus, and D stellate cells, which inhibit T stellate cells, are distinguished electrophysiologically. Whole-cell recordings from stellate cells in slices of the VCN of mice demonstrate that most T stellate cells are excited by cholinergic agonists through three types of receptors, whereas all D stellate cells tested were insensitive to cholinergic agonists. Nicotinic excitation in T stellate cells has two components. The faster component was blocked by alpha-bungarotoxin and methyllycaconitine, suggesting that receptors contained alpha7 subunits; the slower component was insensitive to both. Muscarinic receptors excite T stellate cells by blocking a voltage-insensitive, "leak" potassium conductance. Our results suggest that cholinergic efferent innervation enhances excitation by sounds of T stellate cells, opposing the inhibitory action of cholinergic innervation in the cochlea that is conveyed indirectly through the glutamatergic afferents. The inhibitory action of D stellate cells on their targets is probably not affected by cholinergic inputs. Excitation of T stellate cells by cholinergic efferents would be expected to enhance the encoding of spectral peaks in noise.

Dopamine inhibition of auditory nerve activity in the adult mammalian cochlea.

Efferent feedback systems provide a means for modulating the input to the central nervous system. The lateral olivocochlear efferents modulate auditory nerve activity via synapses with afferent dendrites below sensory inner hair cells. We examined the effects of dopamine, one of the lateral olivocochlear neurotransmitters, by recording compound and single unit activity from the auditory nerve in adult guinea pigs. Intracochlear application of dopamine reduced the compound action potential (CAP) of the auditory nerve, increased the thresholds and decreased the spontaneous and driven discharge rates of the single unit fibres without changing their frequency-tuning properties. Surprisingly, dopamine antagonists SCH-23390 and eticlopride decreased CAP amplitude as did dopamine. In some units, both SCH-23390 and eticlopride increased the basal activity of auditory nerve fibres leading to an improvement of threshold sensitivity and a decrease of the maximum driven discharge rates to sound. In other units, the increase in firing rate was immediately followed by a marked reduction to values below predrug rates. Because CAP reflects the summed activity of auditory nerve fibres discharging in synchrony, both the decrease in sound-driven discharge rate and the postexcitatory reduction account for the reduction in CAP. Ultrastructural examination of the cochleas perfused with eticlopride showed that some of the afferent dendrites were swollen, suggesting that the marked reduction in firing rate may reflect early signs of excitotoxicity. Results suggest that dopamine may exert a tonic inhibition of the auditory nerve activity. Removal of this tonic inhibition results in the development of early signs of excitotoxicity.

Role of Biophysical Specialization in Cholinergic Modulation in Neurons of the Ventral Cochlear Nuclei

In contacting arrays of different types of neurons whose axons have differing targets in the brain stem, the auditory pathway is subdivided into parallel ascending pathways, each of which carries a different type of information. Several distinct arrays of neurons in the ventral cochlear nuclei have anatomical and biophysical specializations which enable them to extract differing facets of acoustic information and to convey it up the auditory pathway. T stellate cells have higher input resistances and have lower firing thresholds than bushy or octopus cells, enabling their firing to be modulated by small currents. Cholinergic currents, driven by neurons in the ventral nucleus of the trapezoid body that are likely to include medial olivocochlear efferents, excite T stellate cells, but have subtle effects on the firing of bushy cells, and have no detectable influence on octopus cells and D stellate cells. We suggest that cholinergic excitation of T stellate cells contributes toward shifting their acoustic dynamic ranges and increasing the encoding of spectral peaks in noisy conditions and in awake animals.

Prevalence and ultrastructural morphology of axosomatic synapses on spiral ganglion cells in humans of different ages

Axosomatic synapses were found on human spiral ganglion cells (HSGCs). Ultrastructural characterization and calculation of the prevalence of these synapses were performed by electron microscopic semi-serial sections of both type I and type II HSGCs, in specimens from subjects of ages 1 day, 14 days, 21 years and 51 years. Synapses on type I HSGCs were extremely rare. In contrast, axosomatic synapses were present on approximately 50% of type II HSGCs of a young adult. This prevalence seemed to vary by age. Thus, no synapses were found in a 1-day old neonate, few in a 14-day old, and on approximately 15% of the type II SGCs from a 51-year old specimen. The origin of the nerve fibers synapsing on the type II HSGCs could not be determined. In view of the fact that some of the fibers projected from the intraganglionic spiral bundle, which is known to contain olivocochlear efferents, these fibers may represent an efferent pathway to the spiral ganglion. However, since there was morphological evidence of more than one type of nerve fiber synapsing on type II HSGCs, other neural origins must be considered. Although the physiological function of these synapses is unknown, they may mediate pre-synaptic neural modulation of the type II HSGCs at the level of the spiral ganglion.

Predicting Vulnerability to Acoustic Injury with a Noninvasive Assay of Olivocochlear Reflex Strength

Permanent noise-induced damage to the inner ear is a major cause of hearing impairment, arising from exposures occurring during both work- and pleasure-related activities. Vulnerability to noise-induced hearing loss is highly variable: some have tough, whereas others have tender ears. This report documents, in an animal model, the efficacy of a simple nontraumatic assay of normal ear function in predicting vulnerability to acoustic injury. The assay measures the strength of a sound-evoked neuronal feedback pathway to the inner ear, the olivocochlear efferents, by examining otoacoustic emissions created by the normal ear, which can be measured with a microphone in the external ear. Reflex strength was inversely correlated with the degree of hearing loss after subsequent noise exposure. These data suggest that one function of the olivocochlear efferent system is to protect the ear from acoustic injury. This assay, or a simple modification of it, could be applied to human populations to screen for individuals most at risk in noisy environments.

Olivocochlear efferent vs. middle-ear contributions to the alteration of otoacoustic emissions by contralateral noise

The medial olivocochlear efferent bundle is the key element of a bilateral efferent reflex activated by sound in either ear and acting directly on cochlear outer hair cells (OHC) via numerous cholinergic synapses. It probably contributes to regulating the mechanical activity of the cochlea. Otoacoustic emissions, being sounds emitted by the cochlea as a reflection of its activity and suppressed by efferent activation, are increasingly considered to be the privileged tool for a noninvasive assessment of the efferent reflex. However, confounding effects on otoacoustic emissions can occur. A primary influence is middle-ear muscle reflex activation, which shares common features with the effects of cochlear efferent activation. We report a systematic comparison of the responses of human otoacoustic emissions to efferent activation by low-level noise in the contralateral ear to various middle-ear manipulations (reflex contractions of the stapedius muscle induced by high-level contralateral noise; moderate middle-ear pressure changes). The profiles of level and phase changes of otoacoustic emissions as a function of frequency were highly specific to the origin of the effects. The changes induced by middle-ear manipulations matched the predictions computed from a standard lumped-element middle-ear model, with one or two peaks around the resonance frequency(ies) of the involved subsystem, stapes or tympanic membrane. In contrast, the efferent effect was completely different, exhibiting a broadband-level suppression associated with a small phase lead. We propose that a careful vector analysis of otoacoustic emission modifications enables the identification of the contribution of the efferent reflex without ambiguity even when it is mixed with middle-ear effects. Thereby, otoacoustic emissions can be used more reliably as noninvasive probes of efferent olivocochlear function.

Neurochemical evidence of dopamine release by lateral olivocochlear efferents and its presynaptic modulation in guinea-pig cochlea

In this study, using an in vitro superfusion technique for the first time, we provide direct neurochemical evidence of the transmitter role of dopamine at the level of lateral olivocochlear efferent fibres of the guinea-pig cochlea. Our results revealed that nerve terminals are able to take up and release dopamine upon axonal stimulation. Since dopamine is thought to protect the afferent nerve fibres from damage due to acoustic trauma or ischaemia, enhancement of the release of dopamine, a potential therapeutic site of these injuries, was investigated. Positive modulation of dopamine release has been shown by a D 1 dopamine receptor agonist, an antagonist and piribedil. Furthermore, negative feedback on the stimulation-evoked release of dopamine via D 2 dopamine receptors has been excluded. Electrical stimulation of the cochlear tissue produced a significant and reproducible release of [ 3H]dopamine, which could be blocked by tetrodotoxin (1 μM) and cadmium (100 μM), proving that axonal activity releases dopamine and its dependence on Ca 2+ influx verifies its neuronal origin. Nomifensine, a high-affinity dopamine uptake blocker, prevented the tissue from taking up [ 3H]dopamine from the bathing solution, also indicating the neural origin of dopamine released in response to stimulation. SKF-38393 (a selective D 1 agonist) increased both the resting and electrically evoked release of dopamine. Piribedil (a D 3/D 2/D 1 agonist), a drug under investigation, known to prevent acoustic trauma or ischaemia-induced hearing loss, had a similar and concentration-dependent increasing effect on both resting and evoked release of dopamine. The effect of both drugs on stimulation-evoked release could be prevented by SKF-83566 (a selective D 1 antagonist). However, SKF-83566 alone enhanced the resting and axonal conduction-associated release of dopamine. D 2 agonists and antagonists failed to modulate the release of dopamine, indicating the lack of negative feedback modulation of dopamine release. Our results suggest that the release of dopamine was subjected to modulation by a D 1 receptor agonist and an antagonist. In addition, it is concluded that D 2 receptors are not involved in the modulation of dopamine release. This observation may have clinical relevance in the prevention or therapy of particular types of hearing loss, because enhanced dopaminergic input into the primary auditory neuron may inhibit the (over)excitation of this neuron by glutamatergic input from inner hair cells.

Feedback control of the auditory periphery: Anti-masking effects of middle ear muscles vs. olivocochlear efferents

Both MEM and MOC systems are sound-evoked reflexes to the auditory periphery which can be elicited by sound in either ear. Both MEM and MOC systems can increase thresholds in the auditory periphery: the MEM system acts by stiffening the ossicular chain, the MOC system by decreasing outer hair cell amplification of sound-induced motion in the inner ear. MEM-induced attenuations are largest for low frequency stimuli, MOC-induced attenuations are largest for mid- to high-frequency sounds. Both MEM and MOC systems can have anti-masking effects. The MEM reflex can decrease the masking of high-frequency signals by low-frequency noise (i.e., the upward spread of masking). The MOC reflex is complementary in that it minimizes masking of high-frequency transient signals by high-frequency continuous noise. MEM anti-masking arises by reducing suppressive masking and can improve masked thresholds at high frequencies. MOC anti-masking arises by counteracting excitatory masking. It does not improve masked thresholds, but can improve the detectability of small suprathreshold intensity increments. Anti-masking effects of both MEM and MOC systems should be reduced in cases of sensorineural hearing loss.

Changes in cochlear mechanics during vocalization: evidence for a phasic medial efferent effect

The mustached bat, Pteronotus p. parnellii, has a finely tuned cochlea that rings at its resonant frequency in response to an acoustic tone pip. The decay time (DT) and frequency of these damped oscillations can be measured from the cochlear microphonic potential (CM) to study changes in cochlear mechanics. In this report, we describe phasic changes that occur in synchrony with communication sound vocalizations of the bat. Three animals with chronically implanted electrodes were studied. During the experiments, 1–2 ms tone pips were emitted from a speaker every 200 ms. This triggered a computer analysis of the resulting CM to determine the DT and cochlear resonance frequency (CRF) of the ringing. The time relative to vocalizations was determined by monitoring the output of a microphone placed near a bat's mouth. Similar results were obtained from all three bats tested. In a representative case, the average DT was 2.33±0.25 ms while the bat was quiet, but it decreased by 46% to 1.26±0.75 during vocalizations, which indicates a greater damping of the cochlear partition. Sometimes, DT started decreasing immediately before the bat vocalized. After the end of a vocalization, the return to baseline values varied from rapid (milliseconds) to gradual (1–2 seconds). The CRF also changed from baseline values during vocalization, although the amount and direction of change were not predictable. When gentamicin was administered to block the action of medial olivocochlear (MOC) efferents, DT reduction was still evident during vocalization but less pronounced. We conclude that phasic changes in damping occur in synchrony with vocalization, and that the MOC system plays a role in causing suppression. Since suppression can begin prior to vocalization, this may be a synkinetic effect, mediated by neural outflow to the ear in synchrony with neural outflow to the middle ear muscles and the muscles used for vocalization.

Efferent-mediated protection of the cochlear base from acoustic overexposure by low doses of lithium.

Many studies on anaesthetized animals and a few on awake animals have suggested that the cholinergic olivocochlear efferent feedback to outer hair cells can participate in the protection of the cochlea from acoustic overexposure. Lithium is known to stimulate acetylcholine synthesis and release in the brain and it is likely to act similarly at the level of the cochlear efferent synapses. We demonstrate here that, in the awake guinea-pig with a chronically implanted electrode on the round window of the cochlea, the temporary threshold shift induced by 1 minute exposure to different pure tones at around 90 dB sound pressure level (SPL) was reduced by as much as 40 dB, when exposure occurred after lithium treatment. The protection effect was not observed in anaesthetized animals. The effect was seen across the test frequency range of 6.4-12.5 kHz, suggesting that both 'fast' and 'slow' efferent effects are likely to be mediated by acetylcholine. Together our results provide new evidence that the olivocochlear efferents can provide a more efficient protection from acoustic overexposure when animals are awake.

Short-term Effectiveness of Medial Efferents does not Predict Susceptibility to Temporary Threshold Shift in the Guinea Pig

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Frequency spacing of multiple spontaneous otoacoustic emissions shows relation to critical bands: a large-scale cumulative study

Multiple spontaneous otoacoustic emissions (SOAEs), recorded in one ear, are not randomly spaced on the frequency scale. Extent and origin of spacing order, however, are not clear. Therefore, the raw data of all human SOAE surveys were pooled, and the intervals of all possible emission pairs in each ear were in total outlined according to size on a distribution diagram ( n = 5245, for intervals up to 2 3 octave). Prevalence was increased for intervals between the benchmarks of 1 and 2 critical bands (CB). This CB–2CB range was further characterized by preference of intervals with low-order frequency ratios like 5:4 or 6:5, whereas outside CB–2CB there were no such effects. The results are discussed in the context of current knowledge of the origin of critical bands. Experiments are proposed that test the hypothesis of an influence of the olivocochlear efferents on SOAE spacing.

Neuronal calcium sparks

Outer hair cells (OHCs) amplify the sound-evoked motion of the basilar membrane to enhance acoustic sensitivity and frequency selectivity. Medial olivocochlear (MOC) efferents inhibit OHCs to reduce the sound-evoked response of cochlear afferent neurons. OHC inhibition occurs through the activation of postsynaptic α9α10 nicotinic receptors tightly coupled to calcium-dependent SK2 channels that hyperpolarize the hair cell. MOC neurons are cholinergic but a number of other neurotransmitters and neuromodulators have been proposed to participate in efferent transmission, with emerging evidence for both pre- and postsynaptic effects. Cochlear inhibition in vivo is maximized by repetitive activation of the efferents, reflecting facilitation and summation of transmitter release onto outer hair cells. This review summarizes recent studies on cellular and molecular mechanisms of cholinergic inhibition and the regulation of those molecular components, in particular the involvement of intracellular calcium. Facilitation at the efferent synapse is compared in a variety of animals, as well as other possible mechanisms of modulation of ACh release. These results suggest that short-term plasticity contributes to effective cholinergic inhibition of hair cells.

Auditory efferents involved in speech-in-noise intelligibility.

Following studies proposing that medial olivocochlear efferents might be involved in the processing of complex signals in noise, we tested the involvement of efferent feedback in speech-in-noise intelligibility. Two approaches were used: measures of speech-in-noise intelligibility in vestibular neurotomized patients with cut efferents and comparison with normal hearing subjects; and correlations between effectiveness of olivocochlear feedback, assessed by contralateral suppression of otoacoustic emissions and speech-in-noise intelligibility in normal subjects. Contralateral noise improved speech-in-noise intelligibility in normal ears. This improvement, which was almost absent in de-efferented ears of vestibular neurotomized patients, was correlated with the strength of the olivocochlear feedback. Together, these results suggest that olivocochlear efferents play an antimasking role in speech perception in noisy environments.

Developmentally regulated expression of calcitonin gene-related peptide in the superior olive

During postnatal development, the expression of calcitonin gene-related peptide (CGRP) and its mRNA was investigated in the superior olivary complex of the hamster in order to better understand its role in the development of the efferent olivocochlear (OC) pathway. Although both the peptide and its mRNA were expressed at birth in a few periolivary cells, neither CGRP mRNA nor any immunoreactivity could be detected in the lateral superior olive until after postnatal day (P) 5. By P9, CGRP expression had significantly increased and was mostly contained within the lateral superior olive. Between P7 and P18, there appears to be a transient increase in the transcript expression both in periolivary regions and in the lateral superior olive. Notably, both peptide and mRNA expression decreased precipitously throughout the superior olive after P18. In comparison, although both the facial and trigeminal motor nuclei had significant CGRP expression at birth, the facial motor nucleus demonstrated a decrease in the level of CGRP expression between P1 and P6, while the trigeminal motor nucleus reached a maximal level of expression around P18. If CGRP expression is related to synaptogenesis in OC neurons, as has been suggested for certain motor neurons, then we predict that the ephemeral increases in transcript expression in OC neurons are related to synaptogenetic mechanisms in the cochlear periphery. Importantly, the time course for CGRP expression in lateral OC neurons indicates that their OC terminals in the cochlear periphery may not begin forming synapses until near the end of the 1st postnatal week.