Cochlea and auditory nerve

Handbook of Clinical Neurology, Vol. 160 (3rd series) Clinical Neurophysiology: Basis and Technical Aspects K.H. Levin and P. Chauvel, Editors https://doi.org/10.1016/B978-0-444-64032-1.00029-1 Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 29

Cochlea and auditory nerve JOS J. EGGERMONT* Department of Psychology, University of Calgary, Calgary, AB, Canada Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada

Abstract The transduction process in the cochlea requires patent hair cells. Population responses that reflect this patency are the cochlear microphonic (CM) and summating potential (SP). They can be measured using electrocochleography (ECochG). The CM reflects the sound waveform in the form of outer hair cell (OHC) depolarization and hyperpolarization, and the SP reflects the average voltage difference of the OHC membrane potential for depolarization and hyperpolarization. The CM can be measured using ECochG or via the so-called otoacoustic emissions, using a sensitive microphone in the ear canal. Neural population responses are called the compound action potentials (CAPs), which by frequency selective masking can be decomposed into narrow-band action potentials (NAPs) reflecting CAPs evoked by activity from small cochlear regions. Presence of CM and absence of CAPs are the diagnostic hallmarks of auditory neuropathy. Increased and prolonged SPs are often found in M
enière’s disease but are too often in the normal range to be diagnostic. When including NAP waveforms, M
enière’s disease can be differentiated from vestibular schwannomas, which often feature overlapping symptoms such as dizziness, hearing loss, and tinnitus. The patency of the efferent system, particularly the olivocochlear bundle, can be tested using the suppressive effect of contralateral stimulation on the otoacoustic emission amplitude.

The cochlea, or inner ear, is embedded in the petrous bone. It is innervated by the auditory nerve, which reaches the cochlea via the internal auditory canal and is flanked by the vestibular and facial nerves. There are two types of hair cells in the cochlea: inner hair cells (IHCs) and outer hair cells (OHCs). The IHCs receive up to 95% of the auditory nerve’s afferent innervation (Spoendlin and Schrott, 1988), but are fewer in number than the OHCs by a factor of three to four (He et al., 2006).

SOUND TRANSDUCTION IN THE COCHLEA The basilar membrane (BM) presents the first level of frequency analysis in the cochlea because of its changing stiffness and nearly constant unit mass from base to apex. This forms a frequency-tuned delay line. High-frequency sound produces maximal BM movement at the “base” of the cochlea (near the stapes) whereas low-frequency

sound also activates the apical parts of the BM. Thus each site on the BM has a characteristic frequency (CF), to which it responds maximally in a strict tonotopic order (Robles and Ruggero, 2001). BM movements produce motion of hair cell stereocilia, which open and close transduction channels therein (Michalski and Petit, 2015). This results in the generation of hair cell receptor potentials and the excitation of auditory nerve fibers (ANFs). In a normal ear the movement of the BM is nonlinear, i.e., the amplitude of its movement is not proportional to the sound pressure level (SPL) but increases proportionally less for increments in higher SPLs. In a deaf ear, the BM movement is called passive as it just reacts to the SPL. The passive BM movement only activates the IHCs at levels of
40 dB above normal hearing threshold (von B
ek
esy, 1960). In normal ears, for lower sound levels and up to about 60 dB above hearing

*Correspondence to: Jos J. Eggermont, Ph.D., Department of Psychology, Department of Physiology and Pharmacology, University of Calgary, 2500 University Drive N.W., Calgary, AB, Canada, T2N 1N4. Tel: 1-403-220-5214, E-mail: [email protected]

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J.J. EGGERMONT recruitment, reduced frequency selectivity, and changes in temporal processing. This manifests in hearingimpaired listeners as difficulties in speech understanding, especially in complex acoustic backgrounds (Oxenham and Bacon, 2003).

COCHLEAR MICROPHONICS AND SUMMATING POTENTIALS Fig. 29.1. Steps in the cochlear amplification of basilar membrane (BM) motion for BM movement toward scala vestibuli. This is the excitatory phase and causes depolarization. BM movement in the direction of the scala tympani produces hyperpolarization. IP, inner pillar; RL, reticular lamina; TM, tectorial membrane. From Guinan, J.J., Salt A, Cheatham, M.A., 2012. Progress in cochlear physiology after B
ek
esy. Hear Res 293, 12–20, with permission from Elsevier.

threshold, the so-called “cochlear amplifier” provides a mechanical amplification of BM movement in a narrow segment of the BM near the apical end of the passive traveling wave envelope. The OHC-motor action provides this amplification and provides a frequency-dependent boost to the BM motion, which enhances the mechanical input to the IHCs, thereby promoting enhanced frequency tuning and increased sensitivity. The nonlinear amplification comprises the following steps as labeled in Fig. 29.1.(1) A fluid-pressure difference across the BM, resulting from an inward stapes movement, causes it to move up (purple arrow). (2) The upward BM movement causes rotation of the organ of Corti toward the modiolus and shear of the reticular lamina relative to the tectorial membrane that deflects OHC stereocilia in the excitatory direction (green arrow). (3) This stereocilia deflection opens mechanoelectrical transduction channels, which increases the receptor current driven into the OHC (blue arrow) by the potential difference between the endocochlear potential (+100 mV) in the scale media and the OHC resting potential (40 mV). This depolarizes the OHC. (4) OHC depolarization causes conformational changes in prestin molecules that induce a reduction in OHC length (red arrows). The OHC contraction pulls the BM upward toward the reticular lamina, which amplifies BM motion when the pull on the BM is in the correct phase. Outward stapes movement causes downward BM movement and results in OHC hyperpolarization, expansion of the OHCs, and a further downward push on the BM. In contrast to OHCs, which are displacement detectors, IHCs are sensitive to velocity of the fluid surrounding the stereocilia caused by the contraction and expansion of the OHCs (Guinan et al., 2012). Functional consequences of loss of this nonlinear amplification process are hearing loss, loudness

Both inner and OHCs generate receptor potentials in response to sound (Russell and Sellick, 1978; Dallos et al., 1982). It has long been known that population responses from the cochlea can be recorded at remote sites such as the round window (RW), tympanic membrane, or even from the scalp, and can be used clinically (Eggermont et al., 1974; Fig. 29.2). These population responses are called the cochlear microphonic (CM) and the summating potential (SP). The CM is produced almost exclusively from OHC receptor currents and when recorded from the RW membrane is dominated by the responses of OHCs in the basal turn. The SP is a direct-current component resulting from the nonsymmetric depolarization–hyperpolarization response of the cochlea, which can be of positive or negative polarity, and is likely also generated dominantly by the OHCs (Russell, 2008). The compound action potential (CAP) of the ANFs is mixed in with the CM and SP, and is described in Section “Compound Action Potentials of the Auditory Nerve”.

OTOACOUSTIC EMISSIONS Kemp (1978) discovered that sound could evoke “echoes” from the ear. These echoes, now called otoacoustic emissions (OAEs), result from the action of the cochlear amplifier. Their generation is as follows: as a traveling wave moves apically along the BM it generates distortion due to nonlinearities in the OHC mechanoelectrical transduction channels, producing the nonlinear growth of BM motion. As a result of irregularities due to variations in cellular properties some of this energy travels backwards in the cochlea and the middle ear to produce OAEs (Guinan et al., 2012). Normal human ears generally exhibit spontaneous OAEs (SOAEs). SOAEs arise from multiple reflections of forward and backward traveling waves that are powered by cochlear amplification likely via OHC-stereocilia resonances (Shera, 2003). OAEs can be measured with a sensitive microphone in the ear canal and provide a noninvasive measure of cochlear amplification. SOAEs can have such high levels that the sound can be heard by another person without amplification and also by the patient as a form of objective tinnitus (Guinchard et al., 2016). There are two main types of OAEs in clinical use. Transient-evoked OAEs (TEOAEs) are evoked using a

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Fig. 29.2. Stimulus-evoked potentials in the cochlea. In response to short tone-bursts three stimulus-related potentials can be recorded from the cochlea. These potentials, i.e., CM, SP, and CAP, appear intermingled in the recorded response. By presenting the stimulus alternately in phase and counterphase and averaging of the recorded response, a separation can be obtained between CM on the one hand and CAP and SP on the other. High-pass filtering provides a separation between SP and CAP. This can also be obtained by increasing the repetition rate of the stimuli, which results in an adaptation of the CAP but leaves the SP unaltered. From Eggermont, J.J., 1974. Basic principles for electrocochleography. Acta Otolaryngol Suppl 316, 7–16, with permission from Taylor & Francis Ltd., www.tandfonline.com.

click stimulus. Distortion product OAEs (DPOAEs) are evoked using a pair of primary tones with frequencies f1 and f2 (f1 < f2) and with a frequency ratio f2/f1 <1.4. In addition to the stimulus tones, the spectrum of the sound in the ear canal contains harmonic and intermodulation distortion products—resulting from the nonlinearities in the OHC transduction process—at frequencies that are simple arithmetical combinations of the two tones. The most commonly measured DPOAE is at the frequency 2f1–f2 (Siegel, 2008). Recording of these OAEs has become the main method for newborn and infant hearing screening (Wolff et al., 2010).

AUDITORY NERVE FIBERS The cell bodies of ANFs in mammals form the spiral ganglion, which runs along the modiolar edge of the organ of Corti. The peripheral axons of type I afferents (also known as radial fibers) contact only a single IHC (Robertson, 1984). However, each mammalian IHC provides input to 5–30 type I afferents (depending on the species and location of the IHC), allowing parallel processing of sound-induced activity (Rutherford and Roberts, 2008). Type I neurons constitute 90%–95% of cochlear nerve afferents (Spoendlin, 1969; Liberman, 1982). Both

the peripheral axons (also called dendrites) and the central axons as well as the cell bodies of type I afferent neurons in mammals are myelinated. In humans, cell bodies as well as the pre- and postsomatic nerve fiber segments lack myelin (Ota and Kimura, 1980), which has consequences for stimulation with a cochlear implant (Rattay et al., 2013). The small population of afferent axons in the mammalian cochlea (type II) is unmyelinated (Liberman et al., 1990), and each type II axon synapses with many OHCs. They may be monitoring (like muscle spindles) the state of the motor aspects of the OHCs, but likely do not contribute to the perception of sound. Recently, Flores et al. (2015) suggested that type II cochlear afferents might be involved in the detection of noise-induced tissue damage. They implied that this represents a novel form of sensation, termed auditory nociception, potentially related to “pain hyperacusis” (Tyler et al., 2014). Nearly all recordings of action potentials in mammalian ANFs are from axons of type I neurons, and nearly all type I neurons fire action potentials spontaneously. The spontaneous firing rate (SFR) ranges from less than 5 spikes/s to
100 spikes/s, irrespective of the ANFs’ characteristic frequency (Kiang et al., 1965; Tsuji and Liberman, 1997). ANFs with high SFRs are found in

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spiral ganglion neurons (SGNs) with large diameter peripheral axons, also known as dendrites, and contact IHCs predominantly on the inner pillar face (cf. Fig. 29.1). Low- and intermediate-SFR fibers contact the modiolar face and have synapses with larger ribbons and more vesicles than synapses with high-SFR fibers. Because the up to 30 afferent synapses on each IHC display this range of characteristics, and because ANFs of the same CF show a range of SFRs, it is likely that each IHC synapses with high-SFR as well as medium- and low-SFR ANFs (Rutherford and Roberts, 2008). HighSFR neurons have low thresholds and their stimulusdriven firing rate saturates at low SPL. Medium and low SFR neurons have higher threshold and typically do not show saturating firing rates (Fig. 29.3), which facilitates detecting speech in background noise. Thus, reduced speech understanding in the presence of normal hearing sensitivity may result from selective loss of low-SFR neurons (Kujawa and Liberman, 2009).

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Fig. 29.3. Typical examples of firing rate–intensity (RI) functions of the three different fiber types, demonstrating the relationship between threshold, spontaneous firing rate, and Rl shape. CAP threshold in this frequency range was 25 dB SPL. ( ), fiber with threshold below CAP threshold, high spontaneous rate (84.4 spikes/s) and saturating Rl function; (●), fiber with threshold near CAP threshold, low spontaneous rate (0.2 spikes/s) and sloping-saturating RI function; (), fiber with threshold above CAP threshold, zero spontaneous rate and straight Rl function. Reprinted from M€uller, M., Robertson, D., Yates, G.K., 1991. Rate-versus-level functions of primary auditory nerve fibres: evidence for square law behaviour of all fibre categories in the guinea pig. Hear Res 55 (1), 50–55, with permission from Elsevier.

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COMPOUND ACTION POTENTIALS OF THE AUDITORY NERVE The compound action potential is a weighted average of single-nerve fiber action potential contributions across all activated fibers in the auditory nerve. However, because the single nerve fiber response is generally diphasic (unless there is a conduction block as, e.g., in vestibular schwannomas), the dominant contributions to the CAP are from the ANFs with the shortest latencies, i.e., the activated fibers with the highest characteristic frequencies.

NARROW-BAND COMPOUND ACTION POTENTIALS In order to investigate the responses from ANFs with longer latencies it is helpful to divide the cochlear partition into small regions about 3 mm long (corresponding to about ½ octave in frequency) and study the narrow-band CAPs (NAPs) evoked on these small segments. Since the human cochlea is innervated by about 25,000 afferent nerve fibers, such a 3-mm segment (
10% of the BM length) is assumed to comprise about 2500 individual nerve fibers, albeit there are location-specific differences (Spoendlin and Schrott, 1988, 1989). For this procedure, the level of a wide-band noise is set such that the CAP is completely masked. Then this noise is high-pass filtered with a number of discrete high-pass cut-off frequencies separated by ½ octave resulting in various high-pass noise maskers. Subtracting CAP responses obtained in the presence of these highpass noise maskers, with cut-off frequencies being ½ octave apart, results in NAPs, which can be assigned to particular narrow-band segments each characterized by a central frequency (CF). This method was introduced in animal research (Teas et al., 1962). Eggermont (1976c, 1979b) used this method for transtympanic electrocochleography (ECochG). An example of such a separation of the CAP into NAPs for the normal hearing human cochlea upon click stimulation is shown in Fig. 29.4. The click intensity is 90 dB p.e. SPL—about 60 dB above the normal hearing threshold—and the NAPs are essentially diphasic in shape with latencies ranging from 1.4 to 5.8 ms. In this example, the CAP latency is 1.4 ms and is therefore mainly dominated by the most basal contributions; due to the diphasic waveforms the contributions from segments with lower CFs tend to cancel each other and are therefore not seen in the CAP. Since in this basal part of the cochlea the traveling wave velocity is around 20 m/s (Eggermont, 1976c), these 3-mm wide narrow bands are traversed by the traveling wave in about 0.15 ms. One may say therefore that these single nerve fibers will fire in nearly perfect synchrony. This implies

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CLINICAL USE OF COCHLEAR AND AUDITORY NERVE POTENTIALS

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Fig. 29.4. High-pass noise masking and the derivation of narrow-band action potentials (NAPs) in humans. The upper two traces show the whole nerve CAP for a normal ear in response to a 90-dB p.e. SPL click and below it the situation where just complete masking by wide-band noise occurs. On the left-hand side the effect of high-passing the noise at successively higher cut-off frequencies can be seen. Subtraction of two subsequent CAPs results in the set of narrow-band CAPs in the right-hand side. Note, negative is down.

that for the most basal part of the cochlea the NAP reflects the unit-response—i.e., single fiber— waveform contribution to the CAP. A plot of the NAP amplitude (negative deflection only) as a function of the CF, which may be related to distance from the stapes (Greenwood, 1961; von B
ek
esy, 1963), shows for a click level of 90 dB p.e. SPL (Fig. 29.5) a gradual increase in amplitude for higher central frequencies. For lower click levels, the contributions from both the high- and the low-frequency side rapidly decrease, while the central region (about 3 kHz) still contributes the same NAP amplitude. For relatively low click intensities—70 dB SPL, which is
40 dB above threshold—the activation area is reduced to a more or less frequency-selective region. The click spectrum level was within 5 dB between 500 Hz and 8 kHz, but the external ear canal and middle ear resonances favor the parts in the spectrum around 2–3 kHz, where the human ear has its greatest sensitivity. In normal ears, and ears with high-frequency hearing loss, click-evoked CAP thresholds will reflect the patency of this 2–4 kHz region.

Cochlear microphonics, SPs, and CAPs can be recorded from the promontory of the human cochlea by inserting (under local anesthesia) an electrode through the eardrum (Portmann and Aran, 1971; Eggermont et al., 1974), from the eardrum itself (Salomon and Elberling, 1971), or from the external ear canal (Yoshie et al., 1967; Ferraro et al., 1985). The CAP is also represented by wave I of the auditory brainstem response (ABR) (see Chapter 33); however, the amplitude is larger if the recording electrode is put closer to the source, for instance in the ear canal or better even on the cochlea. Namely, at the cochlear wall (promontory) the CAP of an 80-dB HL tone pip is typically 10–30 mV, at the eardrum one records 1–3 mV, in the ear canal maximally 1 mV, and at the earlobe or mastoid (as in ABR recording) about 0.1–0.3 mV (Eggermont et al., 1974). A detailed description of the transtympanic ECochG method, with basic and clinical findings, can be found in Eggermont (1976b, 2017).

DIAGNOSIS BASED ON THE WAVEFORM OF THE COMPOUND ACTION POTENTIAL The thresholds of the CAP for tone pips, as measured by ECochG (Fig. 29.2), are reliable indicators of hearing sensitivity and can be used to construct detailed audiograms (Eggermont and Odenthal, 1974). These can be used, in combination with ABRs, to determine the cochlear or retrocochlear origin of sensorineural hearing loss (Eggermont et al., 1980; Santarelli et al., 2009). CAPs capture the synchronous activation of the ANFs. Low SPLs activate the low-threshold high-SFR fibers and increasing sound levels gradually activate medium- and then high-threshold low-SFR fibers (Fig. 29.3). Typical CAP waveforms and their presumed reflection of the underlying disturbances in the peripheral hearing organ can best be studied by using the NAP derivation. Fig. 29.6 shows such a (for just a few midfrequency CFs in these cases) NAP analysis for a normal ear, a M
enière ear, and for an ear affected by an acoustic neuroma (vestibular schwannoma). For the normal ear the NAPs at the three central frequencies show essential biphasic shapes (cf. Fig. 29.4). For the M
enière ear the recorded CAP is dominated to a large extent by the relatively large negative SP. The NAP analysis, however, shows that the unit contribution is composed of two biphasic waveforms with a delay of about 1 ms. This may point to repeated firing by the fibers in the indicated narrow-bands in response to the same

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Fig. 29.5. Narrow-band response parameters as a function of central frequency. For clicks of 70, 80, and 90 dB p.e. SPL, narrowband amplitudes are shown as a function of distance from the stapes; it is observed that for the highest intensity the amplitudes decrease by about 3 dB per octave toward the lower CFs. Lowering the click intensity results in a decrease for contributions from both the apical and basal part of the cochlea, while the central part still contributes the same. The latency data (right ordinate) show an exponential dependency on the distance (top abscissa) from the stapes, and a definite effect of stimulus intensity thereupon is noted. From Eggermont, J.J., 1976. Electrocochleography. In: Keidel, W.D., Neff, W.D. (Eds.), Handbook of sensory physiology, vol. 5 (Pt. 3), Springer-Verlag, New York, pp. 626–705, with permission of Springer Nature.

click. This fact may contribute to the overrecruitment often observed in M
enière ears but this will need a more detailed study. The narrow-band SP appears to be present only in the CF ¼ 3.5 kHz range. The acoustic neuroma ear shows essentially the same type of broad CAP waveform as found in the M
enière ear. However, the SP here is much smaller than the CAP and appears not to account for the broadening of the CAP in the same way as in the M
enière ear. High-pass masking shows that the NAPs are monophasic in this situation. Addition of the NAPs to form the CAP therefore does not produce cancellation of activity after the onset of the CAP, as found in normal and M
enière ears, but instead produces a broad CAP. In this situation the NAP waveform may reflect a change in the unit contribution from diphasic to monophasic as a result of nerve conduction block due to the presence of the tumor. Again, the narrow-band SP is largest in the CF ¼ 3.5 kHz range. The mechanisms that produce these striking differences in NAPs may be very useful in differential

diagnosis. Especially, the close similarity of the CAP waveforms for the M
enière ear and the neuroma ear is completely removed when looking at the narrow-band responses.


DIAGNOSING MENIÈRE’S DISEASE One of the most striking findings in electrocochleographic studies of M
enière’s disease is the broad CAPSP waveform that becomes more pronounced with the duration of the disease (Fig. 29.7). This is caused dominantly by a relatively large, compared to the superimposed CAP, SP. Although the SP amplitude is not that much different from normal ears, its duration is often increased (Gibson et al., 1977) and it is not affected by hearing loss in M
enière patients up to levels of 50 dB HL (Eggermont, 1979a). In contrast, the CAP amplitude decreases with hearing loss such that the SP/CAP amplitude ratio (Eggermont, 1976a), or the SP-area/ CAP-area ratio (Ferraro and Tibbils, 1999) alone or in

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enie`re’s ear, and a neuroma ear. As has been observed consistently in many cases, there is a typical M
enie`re’s and acoustic neuroma type of action potential waveform, which is very distinct from normal. The distinction between both pathologies on the basis of the CAP waveform in general presents difficulties. A narrow-band analysis shows that the individual NAP waveforms are different for all three hearing states, which may be of help in further diagnosis but also provides an insight in the location of the disturbance. Again, note that negative is down. SP, summating potential.

combination with the amplitude ratio, is used in diagnosis of M
enière’s disease. Currently, using these measurements resulted in some studies (Al-momani et al., 2009) in a diagnosis with a sensitivity of 92% and specificity of 84%, but distinctly lower values in others (Oh et al., 2014).

SCREENING FOR VESTIBULAR SCHWANNOMA In a large study Eggermont et al. (1980) compared the use of ECochG and ABR in the diagnosis of surgically confirmed vestibular schwannoma in 45 patients. ECochG results provide evidence that, for hearing losses up to at least 60 dB HL, the origin is cochlear. We concluded that ECochG as the sole test for detection of vestibular schwannoma was of limited diagnostic value. In combination with ABR, ECochG generally provides a clear N1 in cases where ABR wave I cannot be detected, and so raises its diagnostic value (see Chapter 33). Let’s start with the CAP phenomenology in these tumor ears (Fig. 29.8). First of all, the waveforms were

distinctly different from those in normal ears and often also from those in ears with cochlear hearing loss. However, they tended to be comparable to those in M
enière ears (see section “Diagnosing M
enière’s Disease”). In 30% of the studied vestibular schwannoma cases, Eggermont et al. (1980) found that the N1 latencies were longer than those of Menière’s disease. Whereas larger CAP duration is found with use of tone burst stimulation, especially for 2 kHz, it does not occur in the NAP derivation (Fig. 29.6). Most cases with abnormally long N1 latencies also had monophasic narrow-band contributions. In this situation, the usual canceling of positive and negative deflections leading to sharply peaked CAPs is lacking. The result is broad CAPs and abnormally long CAP latencies in the middle intensity range. Correspondingly, the width of the CAP, resulting from the monophasic NAP contributions, can be distinctly larger than in normal ears, whereas the amplitude of the SP is clearly lower than in M
enière’s disease. Thus the abnormally broad CAPs, especially those with short latencies, are due to this NAP effect and not to a pronounced SP, as in Menière’s disease.

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Fig. 29.7. Left: Human cochlear action potentials as recorded in response to 2-kHz tone bursts (envelope shown near abscissa) between 95 and 15 dB HL in a normal ear. Note the off response at nearly all levels of stimulation. The scaling changes with intensity as indicated. Right: CAPs to 2-kHz tone bursts in a M
enie`re ear. There was an interval of about a year between the recording times (dates top right). Quite dramatic changes are noted in the waveforms for the approximately 1-year time difference. From Eggermont, J.J., 1976. Electrocochleography. In: Keidel, W.D., Neff, W.D. (Eds.), Handbook of sensory physiology, vol. 5 (Pt. 3), Springer-Verlag, New York, pp. 626–705, with permission of Springer Nature.

AUDITORY NEUROPATHY From the very beginning there has been confusion about the meaning of the term “auditory neuropathy.” This was best expressed by Rapin and Gravel (2003): “The term ‘auditory neuropathy’ is being used in the audiology/ otolaryngology literature for a variety of individuals (mostly children) who fulfill the following criteria: (1) understanding of speech worse than predicted from the degree of hearing loss on their behavioral audiograms; (2) recordable otoacoustic emissions and/or CM; together with (3) absent or atypical auditory brain stem responses. To neurologists, the term neuropathy has a more precise connotation: it refers to pathology of peripheral nerve fibers rather than pathology in their neuronal cell bodies of origin.” The diagnosis of “auditory neuropathy” in audiology usually does not require more than the presence of a

superficial phenomenology consisting of recordable OAEs and absent or very poorly defined ABRs, together with mild to moderate audiometric hearing loss but severe problems with speech understanding. However, there is quite a bit more differentiation with respect to underlying genetic and peripheral hearing mechanisms. This has led (among others) to use of the new term “synaptopathy,” which puts one of the underlying mechanisms in the IHC ribbon synapses (Khimich et al., 2005; Kujawa and Liberman, 2009; Moser et al., 2013). Another umbrella term is “dys-synchrony,” which can describe anything from the nonsynchronous transmitter substance released from the ribbon synapses, resulting in onset desynchrony in the ANF firings, to changes in the peripheral dendrite of the spiral ganglion slowing down of action potentials along the ANFs (Rance and Starr, 2015a,b), which also results in a large spread of spike latencies and hence poorly shaped ABRs.

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Fig. 29.8. (A) CAP waveforms in response to 2-kHz tone burst stimulation in three ears with acoustic neurinoma. Depending on the individual case and on stimulus intensity, broad characteristic waveforms or nearly normal CAPs can be found. It appears that the CAP waveform is not consistently abnormal in acoustic neurinoma ears. (B) Narrow-band AP waveforms in acoustic neurinoma ears. From dominantly monophasic NAPs in the left series to strictly biphasic narrow-band responses in the right series, reminding us of a sensorineural hearing loss, the relationship to the CAP waveforrn is clear. From Eggermont, J.J., Don, M., Brackmann, D., 1980. Electrocochleography and auditory brainstem electric response in patients with pontine angle tumors. Ann Otol Rhinol Laryngol 89 (Suppl. 75), 1–19.

Gene mutations underlying two common forms of auditory neuropathy are in OTOF resulting in synaptopathy (Wichmann, 2015) and in OPA1 resulting in neuropathy of the spiral ganglion dendrites (Huang et al., 2009).

Santarelli et al. (2011, 2013) compared acoustically and electrically evoked potentials of the auditory nerve in patients with postsynaptic or presynaptic auditory neuropathy with underlying mutations in the OPA1 or OTOF

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B Fig. 29.9. Transient evoked otoacoustic emission (TEOAE) amplitude reduction under intracerebral electrical stimulation (ICES) of the auditory cortex. TEOAEs were recorded in the right ear of patient no. 2 (NS), without (A) and with ICES (B) of the auditory cortex. The temporal waveforms are shown in the left panel (amplitude in micropascals plotted against time in milliseconds), with an analysis time between 2.6 and 20 ms after the stimulus onset (stimulus artifact rejected). ‘I’ indicates the TEOAE amplitude in decibels SPL. The power frequency spectra are shown in the right panel (fast Fourier transform, between 0.25 and 6 kHz), with evoked response in outlined plots and random noise in solid plots. For the sake of graphic clarity, the amplitude scale of all the curves has been expanded by a factor of two. From Perrot, X., Ryvlin, P., Isnard, J., et al., 2006. Evidence for corticofugal modulation of peripheral auditory activity in humans. Cereb Cortex 16 (7), 941–948, by permission of Oxford University Press.

gene, respectively. Among nonisolated auditory neuropathy disorders, mutations in the OPA1 gene are believed to cause disruption of auditory nerve discharge by affecting the unmyelinated portions of human ANFs. Transtympanic ECochG was used to record click-evoked responses from two adult patients carrying the R445H OPA1 mutation, and from five children with mutations in the OTOF gene. The CM amplitude was normal in all subjects. Prolonged negative responses were recorded as low as 50–90 dB below behavioral threshold in subjects with OTOF mutations, whereas in the OPA1 disorder the prolonged potentials were correlated with hearing threshold. A CAP was superimposed on the prolonged activity at high stimulation intensity in two children with mutations in the OTOF gene while classical CAP waveforms were absent in the OPA1 disorder. Cochlear implantation where the activation of the auditory nerve bypasses the lesion resulted in much improved speech discrimination (Santarelli et al., 2015).

THE EFFERENT SYSTEM AND THE COCHLEA By recording of evoked otoacoustic emissions during presurgical functional brain mapping for refractory epilepsy, Perrot et al. (2006) showed that corticofugal modulation of peripheral auditory activity exists in humans. In 10 epileptic patients, electrical stimulation of the contralateral

auditory cortex led to a significant decrease in TEOAE amplitude (Fig. 29.9; Section “Otoacoustic Emissions”), whereas no change occurred under stimulation of nonauditory contralateral areas. These findings provide evidence of a cortico-olivocochlear pathway, originating in the auditory cortex and modulating contralateral active cochlear micromechanisms via the medial olivocochlear efferent system, in humans.

EFFECTS OF OLIVOCOCHLEAR BUNDLE ACTIVITY A group of nerve fibers, termed the crossed olivocochlear bundle (COCB), that project from the superior olive to the inner ear was first described by Rasmussen (1946). Subsequently, Fex (1962) and Wiederholt and Kiang (1970) showed that COCB stimulation in general reduced the spike-discharge rate for tones at the characteristic frequencies of the fibers. Realizing that the COCB could be activated by contralateral sound, Buño (1978) found that contralateral tonal stimulation at low sound intensities, but >20 dB above the nerve-fiber threshold for ipsilateral activation, decreased the ipsilateral sound-evoked activity of about 25% of the units studied. Two types of efferents innervate the cochlea: the efferents projecting underneath the IHCs and synapsing with the SGN dendrites, and those connecting directly to the OHCs (Fig. 29.10). These efferents originate from

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ACKNOWLEDGMENTS This research was supported by Alberta InnovatesHealth Solutions, the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Campbell McLaurin Chair for Hearing Deficiencies.

REFERENCES

Fig. 29.10. Origin and distribution of efferent fibers of the right and left OCB in the superior olivary complex, to the right cochlea. Line thickness (cat data) indicate the proportion of crossed and uncrossed fibers projecting from each medial OCB (MOCB) and lateral OCB (LOCB) to inner hair cells (IHCs) and outer hair cells (OHCs) of the right cochlea. Only the crossed fibers from the left OCB and uncrossed fibers from the right OCB are shown. Modified from Yasin, I., Drga, V., Plack, C.J., 2014. Effect of human auditory efferent feedback on cochlear gain and compression. J Neurosci 34 (46), 15319–15326.

different areas in the superior olivary complex in the brainstem and run through the vestibular nerve. Most authors use the terms lateral and medial efferent systems to designate the efferents below the IHC and those of the OHCs, respectively. The lateral efferents, which represent about 50% to 65% of the olivocochlear bundle fibers, are unmyelinated and project dominantly toward the ipsilateral cochlea. The medial efferents are myelinated and reach the OHCs via the crossed and uncrossed components of the olivocochlear bundle. The crossed component predominates the medial efferent innervation.

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