Trends In Amplification

Trends In Amplification

VOLUME 9, NUMBER 1, 2005

Auditory neuropathy/dys-synchrony is a form of hearing impairment in which cochlear outerhair cell function is spared but neural transmission in the auditory pathway is disordered.This condition, or group of conditions with a common physiologic profile, accounts for approx-imately 7% of permanent childhood hearing loss and a significant (but as yet undetermined)proportion of adult impairment. This paper presents an overview of the mechanisms under-lying auditory neuropathy/dys-synchrony-type hearing loss and the clinical profile for affectedpatients. In particular it examines the perceptual consequences of auditory neuropathy/dys-synchrony, which are quite different from those associated with sensorineural hearing loss, andconsiders currently available, and future management options.

Auditory Neuropathy/Dys-synchrony and Its Perceptual Consequences

Gary Rance, PhD, MSc, BEd, Dip Aud, MAudSA(CC)

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From the Department of Otolaryngology, The University of Melbourne, East Melbourne, Australia

Reprint requests: Gary Rance, The University of Melbourne, School of Audiology, 172 Victoria Parade,East Melbourne 3002, Australia; e-mail: [email protected]

©2005 Westminster Publications, Inc., 708 Glen Cove Avenue, Glen Head, NY 11545, U.S.A.

Introduction

The terms auditory neuropathy/dys-synchrony(AN) and auditory dys-synchrony (AD) have beenused to describe a form of hearing impairment inwhich cochlear amplification (outer hair cell)function is normal but afferent neural conductionin the auditory pathway is disordered (Starr et al.,1996; Berlin et al., 2001). This paper provides anoverview of the clinical features associated withthis condition, the various mechanisms that mayproduce the AN/AD result profile, the unique per-ceptual disruptions that arise as a result, and theconsequences for aural rehabilitation.

The Auditory Neuropathy/Dys-synchrony Result Pattern

The clinical findings that define auditory neu-ropathy/dys-synchrony are the demonstration ofouter hair cell integrity in evoked otoacousticemission and/or cochlear microphonic record-ings, in conjunction with the inability to recordevoked neural activity at the level of the VIIInerve (compound action potential) and brainstem(auditory brainstem response) (Figure 1). Assuch, the electrophysiologic result profile is clas-sically “retrocochlear,” but the exact sites of ori-gin and the pathologic mechanisms involved are

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Trends In Amplification Volume 9, Number 1, 2005

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Figure 1. ABR recordings for a 3-year-old child with AN/AD type hearing loss.The dotted line represents the point at which the stimulus reached the cochlea. Thetop tracings show no repeatable potentials to alternating clicks presented at 100dBnHL. The middle tracing pairs show repeatable cochlear microphonic responsesbut absent brain stem response waveforms to unipolar stimuli at 80 dBnHL. Theasterisks indicate the positive peaks in the cochlear microphonic waveform. Thefinal tracings, in which only the stimulus artefact is evident, were obtained torarefacting clicks presented with the tubephone clamped.

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yet to be determined. Other clinical features con-sistent with the AN/AD pattern include the pres-ence of permanent or fluctuating hearing loss ofvarying degrees, normal radiologic findings, ab-sence of middle-ear muscle reflexes, and speechperception deficits out of proportion with the be-havioral audiogram.

Decreased hearing sensitivity can result fromdysfunction occurring at various sites in the pe-ripheral and central auditory pathways. The mostcommon form of permanent hearing loss is theresult of an abnormality at the level of the cochleaand can be related to a loss or malfunction of theinner hair cells, loss or malfunction of thecochlear amplifier (which is thought to reside inthe outer hair cells and provide an increase inhearing sensitivity of up to 30–40 dB) or a dis-ruption of the driving force for the inner hair cell,known as the endocochlear potential (Ryan andDallos, 1975). Cochlear level hearing deficit isvariously referred to as sensory, inner ear, haircell, cochlear, and sensorineural hearing loss. Thelast term has been used in recognition that somecochlear losses may also involve damage to neur-al elements that occur, for example, as a resultsensory deprivation.

Hearing deficit can also be the result of ab-normal transmission of neural signals through theauditory pathway or disordered processing ofthose signals in the auditory brainstem. Suchlosses, which can produce the auditory neuropa-thy/dys-synchrony result profile, have (until theadvent of preneural assessment techniques) beenindistinguishable from those centered at thecochlea. In recent times, however, the combina-tion of preneural physiologic measures such asthe cochlear microphonic and the otoacousticemission, with neural responses such as the com-pound action potential and auditory brainstem re-sponse has made it possible to identify neuraltransmission disorders in subjects with cochlear(outer hair cell) function.

The Auditory Brainstem Response

The auditory brainstem response arises from ac-tivity occurring in the auditory pathway in the 10to 15 ms immediately following the presentationof an abrupt auditory stimulus. The waveformcomplex consists of seven major peaks that aretypically plotted with vertex positive waves point-ing upwards and are labelled by Roman numer-als. The neural generators responsible for the au-

ditory brainstem response are yet to be clearly de-fined. The data suggest that both wave I and waveII are compound action potentials, with the for-mer arising from the distal portion and the laterfrom the proximal (brainstem) portion of the au-ditory nerve (Hashimoto et al., 1981; Møller andJannetta 1981). The later waves are thought tohave multiple generators, and are thought to havecontributions from the superior olive and lemnis-cal pathways up to and including the inferior col-liculus (Melcher et al., 1996a, 1996b, 1996c).

Auditory Brainstem Responses in Ears withNormal Hearing and Sensorineural Hearing Loss

Auditory brainstem response testing has been inwidespread use as both a hearing screening anddiagnostic measure for over 25 years. In subjectswith normal hearing, repeatable auditory brain-stem response waveforms can be reliably obtainedto acoustic click and tone-burst stimuli presentedat levels around 10–20 dBnHL (Hyde et al., 1990;Durieux-Smith et al., 1991; Stapells et al., 1994).In ears with significant hearing impairment, a rea-sonably close relationship between hearing leveland auditory brainstem response threshold hasbeen demonstrated (Gorga et al., 1985; Hyde etal., 1990; Picton et al., 1994; Stapells et al., 1995;Stapells and Oates, 1997). Mean auditory brain-stem response/behavioral threshold difference lev-els of 10 dB or less have been obtained in thesestudies for both child and adult subjects.

This close correlation between auditory brain-stem response thresholds and the behavioral au-diogram in subjects with normal hearing or sen-sorineural loss allows a subject’s audiogram to bepredicted from evoked potential findings withreasonable confidence. Auditory brainstem re-sponse thresholds (when responses are obtained)typically overestimate the hearing levels slightly,and response absence at maximum presentationlevels (about 100 dBnHL for acoustic clicks andabout 100–110 dBnHL for tone bursts) is consis-tent with behavioral hearing levels in the severe-to-total hearing loss range (Brookhouser et al.,1990; Rance et al., 1998).

Auditory Brainstem Responses in Ears withAuditory Neuropathy/Dys-synchrony

In ears with auditory neuropathy/dys-synchrony,auditory brainstem responses are absent (orgrossly abnormal) at maximum stimulus presen-

Rance Auditory Neuropathy/Dys-synchrony and Its Perceptual Consequences

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tation levels regardless of behavioural hearinglevel (Starr et al., 1996; Rance et al., 1999;Sininger and Oba, 2001).1 In such cases, disrup-tion of the auditory brainstem response is thoughtbe the result of either a reduction in the numberof neural elements available to contribute to theresponse, or a disruption in the temporal integri-ty of the neural signal.

The main positive peaks in the auditory brain-stem response are separated by only about 1 ms.Thus, successful recording of the averaged re-sponse requires that the timing of discharges with-in the auditory brainstem be almost identical aftereach test stimulus. Various authors have suggest-ed that a dys-synchrony in the neural firing of theorder of fractions of a millisecond (Starr et al.,1991; Sininger et al., 1995; Kraus et al., 2000) issufficient to disrupt the response and render theaveraged potentials unrecognizable.

Cochlear Microphonics

The cochlear microphonic is a receptor potentialproduced by the polarization and depolarizationof the cochlear hair cells. As such, the response ispreneural and shows little or no latency delayfrom the onset of the stimulus. Starr et al.(2001a) for example, found that the initial peakin the cochlear microphonic waveform occurredin a group of normal subjects only 0.42 (0.2 msafter the stimulus reached the eardrum. Thecochlear microphonic is recorded and extractedfrom the electroencephalograph in the same wayas the auditory brainstem response, and appearsas an alternating current potential that provides abioelectric analog of the input (hence the termmicrophonic). As a result, this potential, unlikethose produced by neural activity, shows a directphase relationship with the stimulating waveform(Dallos and Cheatham, 1976).

In the past, cochlear microphonics have beendifficult to distinguish from the electrical artifactthat often accompanies the generation of a stim-

ulus at the transducer (Eggermont, 1976). Thisdifficulty occurs because of the temporal proximi-ty of the cochlear microphonic response to theonset of the stimulus and because the cochlear mi-crophonic response so closely resembles the stim-ulating waveform. The use of insert earphones inrecent times has overcome this problem by re-moving the transducer from the recording site(i.e., reducing stimulus artifact) and by introduc-ing a time delay as the stimulus passes down theearphone tube that separates the cochlear poten-tials from the artifact (Berlin et al., 1998).

The cochlear microphonic, when recordedfrom extra-tympanic sites such as the scalp or earcanal, is thought to be dominated by the activityof the outer hair cells (Dallos, 1973; Dallos andCheatham, 1976; Norton et al., 1989). In the past,it was confused with the early components of theauditory brainstem response and was originallybelieved to be generated by the auditory nerve.However, the response does differ from neuralpotentials in a number of clinically obvious ways.

Most important, the cochlear microphonic issensitive to the phase of the eliciting stimulus andcan be identified by the 180° phase shift in the re-sponse that occurs when the stimulus phasechanges (in the case of acoustic click stimuli)from rarefaction to condensation clicks (Sohmerand Pratt, 1976; Berlin et al., 1998) (see the mid-dle tracings of Figure 1). In contrast, the polarityof neural responses is unaffected by the phase ofthe stimulus waveform, although variations in thelatency of the compound action potential (Wave Iin the auditory brainstem response) with thestimulus phase can give the appearance of re-sponse phase changes (Stockard et al., 1979).

The cochlear microphonic through its abilityto reflect the integrity of cochlear hair cells canplay a significant role in the identification of earswith auditory neuropathy/dys-synchrony. As dis-cussed previously, an absence or severe abnor-mality of the auditory brainstem response at max-imum presentation levels in ears with sen-sorineural hearing loss is consistent with signifi-cant cochlear damage. In such cases, the cochlearmicrophonic would also be expected to be absent.The presence of this response is indicative of atleast some degree of outer hair cell function andis therefore suggestive of neural transmission ab-normality in ears with absent or disrupted brain-stem potentials (Chisin et al., 1979; Starr et al.,1991; Berlin et al., 1993; Starr et al., 1996; Berlinet al., 1998).


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1An operational definition for grossly abnormalresponses is yet to be determined but could includeresponses with latencies more than two standard devia-tions beyond the normal range, amplitudes significantlybelow normal and abnormal waveform morphology.Such definitions need to be applied with cautionhowever, as severe sensory hearing loss can result inauditory brainstem responses that show prolongedlatencies and poorly defined waveforms.

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Otoacoustic Emissions

An otoacoustic emission is a release of sound en-ergy in the cochlea that is recordable in the earcanal (Kemp, 1978). This sound appears to be aby-product of the active bioelectric process thatexists within the normal cochlea. This activeprocess, which is thought to enhance both thethreshold sensitivity and frequency tuning of theinner ear transduction system, is considered to re-side in the outer hair cells (Davis, 1983).

The relative ease with which otoacousticemission testing can be performed, and the factthat emissions can be obtained in subjects of allages, has led to the widespread investigation anduse of this response as a hearing-screening tool.Although the data has, on the whole, suggestedthat the ability of otoacoustic emission-based pro-cedures to predict audiometric threshold is limit-ed, emission testing has proven to be useful as ascreening measure capable of differentiating be-tween ears with normal cochlear (outer hair cell)function and those with sensorineural hearingloss (Harris and Probst, 2002).

Approximately 99% of ears with audiometricthresholds in the normal range (<20 dBHL) haverecordable emissions for both the transient(Kemp, 1978; Bonfils et al., 1988; Kapadia andLutman, 1997) and distortion product (Lonsbury-Martin et al., 1990; Bonfils and Avan, 1992) testparadigms. In ears with cochlear hearing deficithowever, the probability of eliciting an otoa-coustic emission decreases as the degree of hear-ing loss increases such that the transiently evokedotoacoustic emission is absent in all cases withaverage hearing losses above 35 dBHL (Kemp,1978; Collet et al., 1993), and the distortionproduct otoacoustic emission is absent for all earswith losses above 60 dBHL (Lonsbury-Martin etal., 1990; Bonfils and Avan, 1992; Gorga et al.,1997). As such, emission absence in an ear withnormal middle ear function is indicative of signif-icant cochlear hearing loss, whereas otoacousticemission presence is indicative of normal periph-eral (middle ear and cochlear outer hair cell)function.

The otoacoustic emission response, in provid-ing an indirect measure of the function of thecochlear amplifier and outer hair cells, offers ameans of differentiating between sensory and au-ditory neuropathy/dys-synchrony type hearingloss. Ears with absent auditory brainstem re-sponses because of sensorineural hearing loss typ-

ically show audiometric thresholds in the severeto profound hearing loss range. Cochlear damagesufficient to cause a hearing loss of this degreetypically disrupts the active cochlear mechanismsthat generate the otoacoustic emission, resultingin response absence. Otoacoustic emission pres-ence in ears with absent auditory brainstem re-sponses is therefore suggestive of AN/AD ratherthan sensory type hearing loss.

Possible Mechanisms Producing the Auditory Neuropathy/

Dys-synchrony Result Pattern

Patients with the physiologic characteristics thathave been broadly categorized as auditory neu-ropathy/dys-synchrony can present with a rangeof clinical symptoms. The variability in the clini-cal features seen in this group may represent dif-fering degrees of the same pathology or may bethe result of a range of distinct auditory pathwaydisorders. Some possible sites of lesion includethe cochlear inner hair cells, the synapse betweenthe inner hair cells and type 1 auditory nervefibers, and the auditory nerve itself (Starr et al.,1996; Rance et al., 1999; Amatuzzi et al., 2001).

Inner Hair Cell Loss

One mechanism that could produce the auditoryneuropathy/dys-synchrony result pattern ispathology restricted to the inner hair cells. A pe-ripheral site of a lesion such as this is consistentwith the observation in AN/AD patients that eventhe earliest auditory brainstem response wavesare absent, including wave I, which represents thefirst action potential in the auditory nerve. A spe-cific inner hair cell abnormality could result in thedecrement of the entire auditory brainstem re-sponse complex, with the preservation of outerhair cell responses.

At this stage, the integrity of inner hair cellfunction in living patients cannot be determinedbecause suitable diagnostic tests are not available.There are, however, biologic precedents for se-lective inner hair cell loss in both the BronxWaltzer mouse (Lenoir and Pujol, 1984; Schrottet al., 1989) and the Beethoven mouse models(Bussoli et al., 1997).

The auditory neuropathy/dys-synchronyphysiologic profile has been chemically induced


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in chinchillas treated with antineoplastic agents(carboplatin) that produce selective inner haircell lesion (Takeno et al., 1994, Wake et al., 1996;Liberman et al., 1997; Harrison, 1998; Salvi et al.,1999).2 Auditory brainstem response thresholddisruption in these animals was considered to bedue to a diminution in response amplitude thatresulted from a reduction in the number of ele-ments contributing to the volume conducted po-tential rather than from an increase in the firingthreshold for the surviving elements because sin-gle-unit responses from inferior colliculus neu-rons showed normal response thresholds. Assuch, these findings suggest a mechanism where-by patients with auditory neuropathy/dys-syn-chrony-type hearing loss could demonstrate nor-mal or near normal behavioral hearing thresholds(as has been reported in many human cases) inconjunction with severely disordered evoked po-tential findings. Behavioral hearing thresholdswere however, not determined in the Harrison,(1998) study or in any of the mentioned investi-gations with experimental animals. Yet to be de-termined is whether normal sensitivity in a limit-ed number of units in the central auditory systemis sufficient for behavioral detection of low-levelsounds.

Recent findings presented by Amatuzzi et al.(2001) have confirmed that selective inner haircell loss can occur in humans. These authors car-ried out a detailed histologic evaluation of 15nonsurvivors from a neonatal intensive care unitand identified 2 babies with loss of both innerand outer hair cells, 2 with loss of outer hair cellsalone, and 3 babies with selective inner hair cellloss. Each of the cases with specific inner hair cellloss had an auditory brainstem response assess-ment before they died that showed no response atscreening levels (40 dBnHL). None showed anyevidence of cochlear neuron damage, suggestingthat the mechanism for auditory brainstem re-sponse disruption was a paucity of contributingneural activity due to the reduced number ofinner hair cells rather than an insult to the neur-al elements themselves.

The results presented by Amatuzzi et al.(2001) are inconsistent with the findings from alarge body of adult human temporal bone work

that has failed to show patterns of specific innerhair cell loss. The results for these oxygen-de-prived youngsters do, however, fit with recent an-imal histologic evidence that suggests certaintypes of cochlear insult, notably those caused byto prolonged hypoxia, can have a greater effecton inner than outer hair cell survival (Bohne,1976; Shirane and Harrison 1987a; Billet et al.,1989).

The Synapse Between the Inner Hair Cells and Auditory Nerve Terminals

A disorder at the synapse between the cochlearinner hair cells and type 1 auditory nerve fibershas also been proposed as a mechanism thatcould produce the auditory neuropathy/dys-syn-chrony result pattern (Starr et al., 1991). At thebase of the inner hair cell are anatomic structuresinvolved in the storage and release of neuro-transmitters. Neurotransmitters act upon recep-tor sites in auditory nerve dendrites and initiatethe generation of action potentials. Disorders atthis site may be presynaptic (involving the releaseof transmitters) or postsynaptic (affecting theability of the receptor sites on the auditory nervedendrite to respond these substances) (Starr etal., 2000).

Mechanisms by which synaptic disruptionmight occur in the auditory pathway in humansubjects are yet to be determined. Genetic dys-function involving disruption of the otoferlin(OTOF) protein, which affects transmitter releaseand has been found in the inner hair cells has,however, been identified in subjects presentingwith the auditory neuropathy/dys-synchrony re-sult pattern (Varga et al., 2003).

Auditory Nerve Abnormality

As the term auditory neuropathy suggests, the af-fected site in many patients is thought to be theauditory nerve itself. Starr et al. (1996) coinedthe expression as 8 of the 10 subjects in their se-ries had evidence of other peripheral nerve ab-normality in addition to hearing loss.

The general (nonauditory) symptoms of pe-ripheral neuropathy include weakness and muscleatrophy (if the motor nerves are involved) senso-ry loss, paresthesia (unusual sensations), anddysesthesia (discomfort). The commonly used di-agnostic criteria include absent ankle jerks or re-duction of vibration sense in the feet, abnormal


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2It should be noted that there is no evidence that carbo-platin treatment results in specific inner hair cell loss inhuman subjects.

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results on nerve conduction studies, and abnor-mal sural nerve biopsy specimens.

Generalized neuropathic disorders have beenindicated in 30% to 40% of reported auditoryneuropathy/dys-synchrony cases overall andabout 80% of patients with symptom onset oc-curring after age 15. The site of the disorder af-fecting the auditory nerve and auditory brainstemin these cases may be the myelin sheath or theneuron itself.

Myelin Disorder

Myelin serves in the central nervous system as anelectrical insulator. It is manufactured and main-tained by specialized cells known as oligoden-droglia. The myelin sheath consists of a lamellarstructure of lipids and proteins that wrap concen-trically around the axon. Partial or complete lossof myelin can have profound effects on the gen-eration and propagation of action potentials with-in auditory nerve fibers. Demyelination results inan increase in membrane capacitance and a de-crease in membrane resistance, leading to a de-layed excitation, a reduction in the velocity of ac-tion potential propagation, and an increase inconduction vulnerability (McDonald and Sears,1970; Rasminsky and Sears, 1972; Pender andSears, 1984). Fibers that are demyelinated to dif-fering degrees conduct neural signals at differentspeeds, and the synchrony of discharges can beaffected.

Although neurons that are not entirely myeli-nated are capable of conducting action potentials,they do so with prolonged refractory periods andan impaired ability to transmit high-frequencypulse trains (McDonald and Sears, 1970;Rasminsky and Sears, 1972; Pender and Sears,1984). As a result, repetitive activation of de-myelinated fibers results in a progressive increasein the conduction time of the action potential andmay lead to an intermittent or total block in theirpropagation (conduction block) (Rasminsky andSears, 1972).

The pathophysiologic changes in neural con-duction properties associated with demyelinationare likely to have profound effects on the audito-ry brainstem response which is reliant on the rel-atively precise synchronous response of a popula-tion of auditory nerve fibers to a transientacoustic stimulus. Reductions in the temporalsynchrony of demyelinized VIII nerve fibers arelikely to lead to a significant reduction in the am-

plitude of the averaged evoked response. More-over, with more advanced lesions, the propaga-tion of the action potential is likely to become increasingly vulnerable, and the risk of depolar-ization block is increased—especially for the rel-atively repetitious stimuli used to generate theauditory brainstem response.

Axonal Neuropathy

Axonal damage can occur in isolation as a resultof specific disease processes or can occur in con-junction with or as a consequence of demyelinat-ing conditions. As such, the functional distinctionbetween myelin and axon related disorders canbe blurred in some cases (Rapin and Gravel,2003). Axonal neuropathies reduce the numberof neural elements but do not directly affect con-duction speed. The refractory periods of surviv-ing elements also tend to be normal, allowing areasonably unimpaired response to high-ratestimuli (Kuwabara et al., 1999). The classic signsof axonal neuropathy in the auditory pathway are,therefore, a reduction in the amplitude of thewhole nerve action potential and auditory brain-stem response rather than an increase in latencyor a broadening of these potentials (as is the casefor myelin related disorders). However, the ab-sence of any evoked brainstem responses in mostauditory neuropathy/dys-synchrony cases meansthat axonal and myelin related neuropathies areclinically indistinguishable.

Accurate differentiation between axonal anddemyelinating neuropathies can only really bemade from a histologic examination of the affect-ed nerves. In the case of the auditory nerve, thiscan only be achieved on postmortem examinationof the temporal bone or the brainstem at thepoint of entry of the auditory nerve.

Peripheral nerve studies can be done by tak-ing a biopsy specimen of a small portion of an-other more accessible sensory nerve, and the re-sults can be used to infer the function of the au-ditory nerve. Analyses of the sural nerve have, forexample, been used in auditory neuropathy/dys-synchrony patients in this way (Butinar et al.,1999; Starr et al., 2001b).

In summary, neuropathic disorders of the pe-ripheral nervous system, including the auditorynerve, can result in varying degrees of axon lossand myelin damage. Abnormal function in the au-ditory system resulting in the auditory neuropa-thy/dys-synchrony result pattern may therefore


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be related to disrupted neural synchrony resultingfrom myelin damage, a reduction in the numberof functioning fibers caused by axonal loss, or inmany cases, a combination of both.

Auditory Neuropathy or Auditory Dys-synchrony?

The previous sections have outlined a range ofdifferent pathologic mechanisms and sites of le-sion that could produce the physiologic profiletermed auditory neuropathy by Starr and col-leagues in 1996. Some of these mechanisms, suchas selective inner hair cell loss, may not directlyaffect the function of the auditory nerve, whichhas led some groups to suggest that the auditoryneuropathy label is inappropriate at best, and atworst, is clinically misleading. Berlin et al. (2002)for example has suggested that implying the pres-ence of an auditory nerve/brainstem abnormalitymay have serious clinical consequences, dissuad-ing for example, clinicians from consideringcochlear implantation in subjects who might be ex-pected to benefit significantly from this procedure.

The term auditory dys-synchrony has beenproposed as an alternative to auditory neuropathy(Berlin et al., 2001). As discussed previously, theabsence of an auditory brainstem response in earswith measurable hearing levels is thought, insome cases at least, to be caused by a lack of tem-poral consistency in auditory brainstem responseto series’ of audible stimuli. Myelin disorders cancertainly affect the synchrony of neural dis-charges. However, some of the other mechanismsconsidered to result in a lack of measurable brain-stem potentials may not involve dys-synchrony.Marsh (2002) for example argues that the tem-perature-dependant form of neuropathy is likelyto reflect a conduction block rather than a dis-ruption of the timing of neural signals. Auditorybrainstem response absence in cases of axon-re-lated neuropathies and inner hair cell lesions arealso thought not to be primarily related to syn-chrony disruptions but to reduced numbers ofneural elements contributing to the volume-con-ducted response.

Clearly, neither “auditory neuropathy” nor“auditory dys-synchrony” is adequate to describethe entire group of patients with absent auditorybrainstem responses but present cochlear hair cellresponses. The lack of an appropriate label is sim-

ply a reflection of our current inability to deter-mine specific mechanisms in specific cases. Forthe purposes of this paper the term auditory neu-ropathy/dys-synchrony will be used.

Clinical Profile

Etiology

In most cases, auditory neuropathy/dys-syn-chrony type hearing loss presents in conjunctionwith specific medical risk factors. AN/AD can,however, occur in the absence of obvious medicalproblems or established hearing-related risk cate-gories. For example, 3 of the 20 subjects present-ed in a survey of pediatric cases conducted in ourlaboratory (Rance et al., 1999) had no health con-cerns in their histories or evidence of permanenthearing loss of any kind in their immediate or ex-tended families. The Sininger and Oba (2001)survey of adult and pediatric cases found that au-ditory neuropathy/dys-synchrony occurred with-out associated risk factors in 27% of patients.

A number of different etiologies have been as-sociated with the auditory neuropathy/dys-syn-chrony result profile. These conditions can bebroadly categorized as transient neonatal insults,infectious processes, and genetic or syndromalconditions.

Neonatal InsultsThirteen of the 20 auditory neuropathy/dys-syn-chrony children described in the Rance et al.(1999) report presented with serious neonatalhealth concerns. This high proportion may havebeen associated with the manner in which thechildren were identified, with 12 of the subjectsdetected in an at-risk screening program. Sub-sequent findings presented by Sininger and Oba.(2001) have confirmed this result, however.Approximately 80% of the patients from their au-ditory neuropathy/dys-synchrony database withonset at less than 2 years of age (59 cases) pre-sented with neonatal and/or familial risk factors.In fact, they found that almost half of their infantcases had both genetic and neonatal health fac-tors and suggested that some children may bepredisposed towards developing auditory neu-ropathy/dys-synchrony if they suffer some formof neonatal insult.


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The most commonly reported neonatal con-ditions associated with auditory neuropathy/dys-synchrony are anoxia and hyperbilirubinemia(Stein et al., 1996; Berlin et al., 1997; Deltenre etal., 1999; Rance et al., 1999; Simmons andBeauchaine, 2000; Starr et al., 2000; Sininger andOba, 2001; Franck et al., 2002; Madden et al.,2002; Dunkley et al., 2003). More than 50% ofearly onset AN/AD cases presented thus far haveshown one or both of these conditions in theirneonatal histories.

Excessive amounts of bilirubin (a byproduct ofred-blood cell metabolism), which is often associ-ated with liver immaturity in the newborn, can betoxic to the central nervous system and can resultin significant neurologic insult known as ker-nicterus (Shapiro, 2003). Although many neo-nates (60%) experience some physiologic jaundicethat is not toxic, unconjugated bilirubin (notbound to the albumin protein) can cross theblood-brain barrier and cause icteric staining ofthe central nervous system. Even short-termepisodes of hyperbilirubinemia have been shownto result in both temporary and permanentevoked potential abnormalities, including elevat-ed auditory brainstem response thresholds(Hung, 1989) and prolonged auditory brainstemresponse wave (I-V) latencies (Nakamura et al.,1985; Tan et al., 1992), suggesting that both theperipheral and central auditory systems are vul-nerable to bilirubin insult.

Infectious ProcessesInfection-related causes of auditory neuropa-thy/dys-synchrony have been suggested in a smallbut significant number of the cases reported re-cently. Starr et al. (2000) estimated that postviralinfectious processes were involved in 10% of the67 patients from their AN/AD database. Specificetiologic details were not presented, but otherstudies have reported that mumps (Prieve et al.,1991) and meningitis (Sininger et al., 1995;Rance et al., 1999) can be associated with the au-ditory neuropathy/dys-synchrony.

Genetic and Syndromal FactorsThe auditory neuropathy/dys-synchrony resultprofile often occurs as a part of a generalizedneuropathic disorder. Hereditary motor and sen-sory neuropathies such as Charcot-Marie-ToothSyndrome (type I and II) make up a relativelyhigh proportion of the adult AN/AD cases report-ed to date. Sininger and Oba, (2001) for example,

report that 8 of their 13 patients with AN/ADsymptom onset at age 10 years or older were con-firmed hereditary motor and sensory neuropathysufferers. Charcot-Marie-Tooth syndrome is a ge-netic disorder which involves the degeneration ofthe myelin sheaths and is thought to be relatedto an abnormality in the peripheral myelin pro-tein 22 (PMP-22) on chromosome 17p 11.2(Kovach et al., 1999) or a mutation of MPZ gene(Starr et al., 2003). Loss of axons of the distalportions of the peripheral nerves has also beenreported with this condition (Chance andFishbeck, 1994; Ouvrier, 1996).

Auditory brainstem responses have been re-ported to be absent or grossly abnormal in pa-tients with Charcot-Marie-Tooth syndrome(Cassandro et al., 1986). Histopathologic resultshave shown evidence of cochlear hair cell survivalin conjunction with loss of cochlear spiral gan-glion cells and evidence of demyelinatingprocesses in the VIII nerve (Nadol, 2001).

Hereditary motor and sensory neuropathieshave also been linked to auditory neuro-pathy/dys-synchrony in recent studies involvingSlovene, Italian, and Bulgarian Gypsy families(Butinar et al., 1999; Leonardis et al., 2000). Theautosomal recessive condition, which in thesecases produced both myelin and axonal damage,was mapped to the long arm of chromosome 8(8q24). The disease process with this form ofneuropathy tends to produce severe, progressivemotor disabilities in early childhood and auditorypathway effects in adolescence.

Another inherited disease that is relativelycommonly associated with auditory neuropa-thy/dys-synchrony is Friedreich’s ataxia. Fourcases of this autosomal recessive condition weredescribed in the Sininger and Oba, (2001) series.Friedreich’s ataxia is a neurodegenerative condi-tion that is believed to be restricted to the brain-stem and cerebellar parenchyma. Auditory brain-stem response assessments in patients withFriedreich’s ataxia have typically shown eithercomplete response absence (Satya-Murti et al.,1980; Cassandro et al., 1986) or the presence ofwave I and absent later responses (Jabbari et al.,1983). Histopathology (Spoendlin, 1974) has in-dicated that cochlear neurons and spiral ganglioncells are affected in Friedreich’s ataxia, whereascochlear structures (organ of Corti and hair cells)are unimpaired.

Isolated cases of auditory neuropathy/dys-synchrony have been reported with other genetic


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disorders. Some of these include Ehlers-Danlossyndrome (Sininger and Oba, 2001), an autoso-mal-dominant connective tissue condition relat-ed to serious vascular abnormalities, and Stevens-Johnson syndrome, a rare cutaneous disease typ-ically triggered by drug therapy (Doyle et al.,1998). AN/AD has also been associated with syn-dromes affecting the immune system (Guillain-Barré syndrome) and mitochondrial enzymes(Deltenre et al., 1997; Corley and Crabbe, 1999).

Determination of genetic factors associatedwith AN/AD type hearing loss is currently an areaof vigorous investigation. Recent reviews of theliterature have been provided by Starr et al.(2003) and Rapin and Gravel (2003).

Age of Symptom Onset

The age of onset of auditory neuropathy/dys-syn-chrony type hearing loss has tended to fall intotwo distinct groups: those who present withsymptoms in infancy, and those in whom the con-dition develops in adolescence or early adult-hood. Only one in four auditory neuropathy/dys-synchrony cases are older than 10 years at symp-tom onset (Starr et al., 2000; Sininger and Oba,2001). Starr et al. (2000) suggest that this com-paratively low proportion may be because someaffected patients lose their emissions over time,and as such, may not be recognizable as auditoryneuropathy/dys-synchrony cases if otoacousticemission response and not cochlear microphon-ics are the diagnostic criterion.

Another reason for the higher proportion ofpediatric cases in the AN/AD spectrum could bebecause the physiologic test techniques requiredto identify the condition (auditory brainstem re-sponse/cochlear microphonics/otoacoustic emis-sion) are more frequently used in screening anddiagnostic programs in pediatric populations.Adult auditory neuropathy/dys-synchrony patientswith symmetrical hearing thresholds and reason-able speech perception, for example, are unlikelyto be considered for physiologic assessment.

The Prevalence of Auditory Neuropathy/Dys-synchrony

For the reasons outlined in the previous section,the prevalence of auditory neuropathy/dys-syn-chrony in adult populations is difficult to deter-mine. At this stage, data are also insufficient todetermine the condition’s prevalence in the well-

baby population, although the findings from uni-versal screening programs should soon providesome insights in this regard.

Limited data do exist describing the propor-tion of affected children in at-risk infant popula-tions (see Table 1 for details). Rance et al. (1999)presented results for 5,199 babies with specificrisk factors for hearing loss. Twelve of these chil-dren showed evidence of auditory neuropathy/dys-synchrony presenting with absent auditorybrainstem responses but present otoacousticemissions and/or cochlear microphonic respons-es. This represents a reasonably high prevalenceof 0.23% or 1 in every 433 of the subjects. Evenhigher AN/AD prevalence levels have been re-ported in other studies involving babies who havesuffered severe neonatal health problems:

• Stein et al. (1996) identified 4 babies with theauditory neuropathy/dys-synchrony result pat-tern in a consecutive series of 100 children un-dergoing auditory brainstem response assess-ment in a special care nursery.

• Psarommatis et al. (1997) found 2 cases in astudy involving 102 neonatal intensive care unitgraduates.

The higher incidences reported in these two stud-ies (2%–4%) might be anomalies resulting fromtheir small sample sizes. They do, however,demonstrate the significant risk of auditory path-way disorder that exists for children who havesuffered a rocky neonatal course.

The proportion of permanent hearing loss re-lated to auditory neuropathy/dys-synchrony inpediatric populations has been considered in anumber of recent investigations (Table 2).Methodologic differences between studies—some,for example, have used cochlear microphonictesting whereas others have used otoacousticemissions as their measures of preneural func-tion—make direct comparison difficult. Overallhowever, the results are reasonably consistentand suggest that auditory neuropathy/dys-syn-chrony accounts for approximately 7% of perma-nent hearing loss in children.

Measures of Outer Hair Cell Function

Cochlear microphonic and otoacoustic emissionstests have been used as indicators of cochlear(outer) hair cell function to aid in the identifica-tion of auditory neuropathy/dys-synchrony-type


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hearing loss. The results of these two techniquesare not always consistent in affected ears, how-ever. Such inconsistencies highlight the function-al differences between the two responses andraise questions as to the best way to measure pre-neural function in the clinic.

The presence of cochlear microphonic re-sponses was the primary identification methodused in the study by Rance et al. (1999). In addi-tion, transiently evoked otoacoustic emissions as-sessment was carried out in 33 of the affectedears. Robust otoacoustic emissions consistentwith the presence of the cochlear “active process”and at least some degree of outer hair cell func-tion were observed in 16 ears. However, 17 earsshowed no emission response despite the pres-ence of clear cochlear microphonic potentials.

Various explanations for this result mismatchwere considered, including subtle middle ear

pathology and the possibility that these ears hadsignificant outer hair cell loss and that thecochlear microphonic response was actually pro-duced by the inner hair cells. However, the mostlikely explanation seemed to be that the outerhair cells were present in these ears and wereable to polarize and depolarize (producing thecochlear microphonic response), but that theirfunction was impaired to the extent that theycould not generate the mechanical cochlearprocesses reflected by the otoacoustic emissions.

Subsequent studies have also presented audi-tory neuropathy/dys-synchrony cases with absentemissions and normal cochlear microphonics(Starr et al., 2000; Trautwein et al., 2000;Sininger and Oba, 2001). Starr et al. (2000), intheir survey of adults and children with auditoryneuropathy, found that in 19 of 63 ears (30%)TEOAEs could not be detected. Interestingly,


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Table 1. Prevalence of Auditory Neuropathy/Dys-synchrony in “At-Risk” Infant Populations

Study Population No. of Subjects No. of AN/AD Subjects % of Total

Stein et al. (1996) Special care nursery 100 4 4.00

Psarommatis et al. (1997) Intensive care unit 102 2 1.96

Rance et al. (1999) “At-risk” infants 5199 12 0.23

Table 2. Prevalence of Auditory Neuropathy/Dys-synchrony in Children with Permanent Hearing Loss

No. of Cases Permanent No. of AN/AD Study Population Hearing Loss Cases % of Total

Kraus et al. (1984) Hg. impaired children 48 7 14.58

Park Lee. (1998) Hg. impaired children 139 7 5.04

Vohr et al. (1998) Universal screening 111 2 1.80

Rance et al. (1999) “At-risk” infants 109 12 11.01

Berlin et al. (2000) Hg. impaired children 1000 87 8.70

Cone-Wesson et al. (2000) Universal screening 56 3 5.36

Lee et al. (2001) Hg. impaired children 67 2 2.98

Madden et al. (2002) Hg. impaired children 428 22 5.14

Tang et al. (2004) Hg. impaired children 56 1 1.78

Rance et al. (in press) “At-risk” infants 290 19 6.55

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these authors found no relation between behav-ioral hearing level and otoacoustic emissions re-sponse/absence in their subjects, a result consis-tent with the findings from Rance et al. (1999).

Another notable finding from the Starr et al.(2000) study was that otoacoustic emission re-sponses in some cases disappeared over time inthe absence of confounding factors such as mid-dle ear disease or the provision of amplification.In fact, 9 subjects in their sample who had origi-nally shown clear responses later lost their tran-sient evoked otoacoustic emissions. Deltenre et al.(1999) previously reported a similar result whenthey described the findings for 2 children whowere identified with auditory neuropathy in in-fancy (showing present otoacoustic emissions/cochlear microphonic responses and absent audi-tory brainstem responses) but who subsequentlylost their emissions. Cochlear microphonic re-sponses in these children were relatively un-changed, with similar amplitudes obtained beforeand after emission loss and only a slight morpho-logic change reported in one case. Consistentwith the findings of Rance et al. (1999) and Starret al. (2000), behavioral hearing levels in theDeltenre et al. (1999) cases did not seem to berelated to otoacoustic emission result. Behavioralaudiograms obtained before and after the emis-sion loss were unchanged in these children.

The mechanisms underlying the deteriora-tion of otoacoustic emissions in subjects withauditory neuropathy are unclear at this stage.These processes may become more obvious asmore cases are revealed and studied, but todate, no statistical relationship between otoa-coustic emission loss and any particular pathol-ogy or disease process has been identified(Sininger and Oba, 2001). The time-course overwhich otoacoustic emission deterioration occursis also uncertain and is clearly an issue thatwarrants further investigation. What is clear isthat using otoacoustic emission testing as thesole diagnostic indicator of auditory neuropa-thy/dys-synchrony in subjects with absent orabnormal auditory brainstem response resultswill fail to identify a significant number ofcases. A change in the operating definition ofauditory neuropathy may therefore be warrant-ed, making the presence of cochlear micro-phonic responses, which appear to be relativelyunchanged in patients with deteriorating otoa-coustic emissions, the primary measure of outerhair cell survival.

Behavioral Audiogram

Most reports on auditory neuropathy/dys-syn-chrony published before the mid-1990s de-scribed subjects with audiograms in the mild-to-moderate hearing loss range (Davis andHirsh, 1979; Worthington and Peters, 1980;Lenhardt, 1981; Kraus et al., 1984). This biastowards losses of lesser degree may reflect thatmany of these early patients were only identi-fied as a result of the inconsistency between be-havioral and electrophysiologic findings. In clin-ics where tests of preneural function were notavailable, ears with absent auditory brainstemresponses and hearing thresholds in the severe-to-profound range because of AN/AD wouldhave been indistinguishable from their sen-sorineural counterparts.

Subsequent findings have shown behavioralthresholds that range from normal levels to totalhearing loss. Rance et al. (1999), for example,found a reasonably even distribution of pure-toneaverage hearing levels across the audiometricrange (Figure 2). Starr et al. (2000) and Siningerand Oba (2001) have subsequently reported asimilar degree of audiometric variability in theirsurveys of clinical findings for affected childrenand adults. Starr et al. (2000) found averagehearing levels in 31% of ears at less than 35dBHL, 39% of ears between 35 and 70 dBHL, and30% of ears at more than 70dBHL. Madden et al.(2002) also found an even spread of behavioralaudiograms, with 6 (33%) in their group of 18 af-fected children presenting with audiograms in thenormal-to-mild range, 6 in the moderate-to-se-vere range, and 6 in the profound hearing lossrange.

Threshold Stability

Fluctuation in both hearing level and perceptualability is a reasonably common occurrence in pa-tients with auditory neuropathy/dys-synchrony.Five of the 14 children presented by Rance et al.(1999), for whom repeated measures were avail-able, showed significant hearing level fluctuationswith threshold variances of approximately 20 dB.An example of the findings for one such child canbe seen in Figure 3. These fluctuations, althoughnot as dramatic as those reported by Gorga et al.(1995) and Starr et al. (1998) for their patients


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Figure 2. The distribution of behavioral hearing thresholds (3-frequency average) for 38ears with auditory neuropathy (Rance et al., 1999).

Figure 3. Audiometric results for a 5-year-old child with auditory neuropathy/dys-synchronytype hearing loss. The five assessments were carried out over a 6-month period. Resultsobtained were considered to be an accurate reflection of the child’s acuity for that day (Ranceet al., 1999). Reproduced with permission of Lippincott, Williams Wilkins Publishing Group.

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with temperature-sensitive neuropathy, were re-ported by parents and teachers to produce cleardifferences in functional hearing generally andspeech understanding in particular. The Siningerand Oba (2001) and Starr et al. (2000) databasefindings have subsequently shown a similar pro-portion (29%) of ears with significant hearinglevel fluctuations.

In addition to these ears with level fluctua-tion that show no overall directional trend, caseshave been reported of long-term hearing deterio-ration and of long-term recovery with auditoryneuropathy/dys-synchrony. Starr et al. (2000)and Sininger and Oba (2001) found that approx-imately 15% of the subjects in their database(s)showed deterioration of greater than 10 dB atthree or more test frequencies over a series ofhearing evaluations. In contrast, these authorsfound 1 patient who showed a 15 to 20 dBthreshold improvement over time.

Other studies have reported dramatic hearinglevel improvements in affected children. Maddenet al. (2002) presented evidence of spontaneoushearing recovery in 9 of the 22 auditory neu-ropathy/dys-synchrony children in their sample.In most, the behavioral audiogram improved fromthe profound to the moderate-to-severe range,but in 4 subjects, hearing thresholds reportedlyimproved to normal or near-normal levels.Hearing recovery was more likely in this groupamongst the subjects who had suffered neonatalhyperbilirubinemia, and in all cases, had occurredbefore the age of 25 months.3 Other studies re-porting improvements in hearing includeStockard et al. (1983), Kileny and Robertson(1985), Stein et al. (1996), and Berlin et al.(1997).

Hearing Loss Configuration

Audiograms with a low-frequency emphasis (re-verse slope) are a reasonably common finding inboth adults and children with auditory neuropa-thy/dys-synchrony. Eleven (28.9%) of the 38 earspresented in Rance et al. (1999) showed this con-

figuration. The survey results presented bySininger and Oba (2001) and Starr et al. (2000)showed similar findings, with rising audiogramsreported in about 30% of ears in both studies.The high-frequency hearing loss configurationmost commonly seen with sensorineural typehearing loss was only observed in approximately10% of cases in these reports.

Acoustic Reflexes

Abnormal middle-ear muscle reflexes are a con-sistently reported finding for both adults and chil-dren with auditory neuropathy/dys-synchronytype hearing loss. Apart from isolated instances(3 of 44 subjects in Sininger and Oba, 2001; 1child in Deltenre et al., 1997) acoustic reflexeshave been absent to both ipsilateral and con-tralateral stimulation in almost all publishedcases, including those with normal or near-nor-mal audiometric thresholds. The mechanismunderlying this phenomenon has been a matterof some conjecture, but recent reports haveshown that nonacoustic middle-ear muscle re-flexes can be elicited in auditory neuropathypatients by tactile stimulation to the face, sug-gesting that the efferent components of the re-flex arc (facial nerve and stapedius muscle) areintact (Gorga et al., 1995; Starr et al., 1998).Furthermore, Konradsson (1996), in a study in-volving 4 children with unilateral auditory neu-ropathy/dys-synchrony, found that an acoustic re-flex in the AN/AD ear could be elicited by con-tralateral stimulation but that neither ipsilateralnor contralateral responses could be seen whenthe stimulus was directed to the affected side. Assuch, it is most likely that in patients with audi-tory neuropathy/dys-synchrony, the afferentpathway (auditory nerve) is not able to providesufficiently high or sufficiently synchronized ratesof discharge to activate the motor neurons of thestapedius muscle (Starr et al., 1998).

Evoked Potentials from the Central Auditory Pathways

As one of the signature features of the auditoryneuropathy/dys-synchrony result profile is theabsence or severe disruption of the auditorybrainstem response, it might be expected thatmore central evoked responses such as the middlelatency and cortical auditory evoked potential(CAEP) would be similarly affected. And yet,


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3Madden et al. (2002) did note that maturationalfactors could have contributed to the thresholdsimprovements in their subjects (test age range, 6–25months) but concluded that the observed changes were greater than would be predicted on the basis of development.

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many of the reported cases have shown clearlyidentifiable responses with reasonably normalmorphology and response latency (Gorga et al.,1995; Hood, 1999; Kraus et al., 2000; Rance etal., 2002; Zeng and Liu, in press). Figure 4 (fromRance et al., 2002) shows the similarity betweenaveraged CAEP waveforms obtained for a groupof AN/AD children with those from cohorts ofage-matched children with normal hearing andsensorineural hearing loss.

CAEPs may be recordable in some cases of au-ditory neuropathy/dys-synchrony because theyare less dependent on synchronous neural firingthan auditory brainstem responses. The peaks inthe normal auditory brainstem response wave-form are biphasic and are usually only separated

by approximately 1 ms. Small variations in thetiming of responses to individual stimuli can thuslead to cancellation in the averaged signal. Incontrast, the component peaks in the CAEP wave-form, which are much broader and are separatedby 50 to 100 ms in adult subjects (and longer inchildren), are more resistant to subtle fluctuationsin the timing of individual responses.

Evidence of the different tolerance of the au-ditory brainstem response and CAEPs to syn-chrony disruption has come from studies examin-ing the timing of component responses. Starr etal. (1991) manipulated the synchrony of auditorybrainstem responses by systematically varying thetiming of each stimulus relative to the start of theaveraging window. This study demonstrated that


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Figure 4. Grand mean cortical event-related potential waveforms in response to tones(left panel) and to speech (right panel) for children with normal hearing (top traces),sensorineural (SN) hearing loss (440 Hz: N = 17; /dæd/: N = 15, middle traces), andauditory neuropathy (AN) (N = 11, bottom traces). Reproduced with permission ofLippincott, Williams Wilkins Publishing Group.

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(for the cat auditory brainstem response at least),timing fluctuations of the order of tenths of a mil-lisecond are sufficient to disrupt the averaged re-sponse. In contrast, studies considering the timingof responses from the auditory cortex have showna much greater tolerance to temporal fluctuation.Michalewski et al. (1986), for example, deter-mined the latency of various cortical event relat-ed potentials, including N1 and P2, in normal adultsubjects for individual stimulus trials and showedpeak latency standard deviations of about 17 msfor the N1 potential and 22 ms for the P2 potential.These individual trials, when subjected to con-ventional signal averaging procedures, producedrobust waveforms.

The point at which synchrony disruptions as-sociated with auditory neuropathy/dys-synchronytype loss might begin to affect averaged poten-tials from the auditory cortex is unclear at thisstage. However, if the standard deviation of nor-mal temporal fluctuation in these potentials isaround 20 ms., then the level of dys-synchronyrequired to affect the CAEP waveform is likely tobe of the order of tens of milliseconds. This levelis significantly higher than that required to dis-rupt the auditory brainstem response and as such,the cortical event-related potentials can offer agross measure of the effect of peripheral neuraldisruption on the signal reaching the auditorycortex. Furthermore, these responses may offerinsights into the neural representation of speechin affected subjects (Rance et al., 2002).

Speech Perception in Adults withAuditory Neuropathy/Dys-synchrony

Speech perception difficulties are a consistently re-ported consequence of hearing impairment. Inpostlinguistically deafened adults with sen-sorineural loss, a reasonably strong relationship ex-ists between the behavioral audiogram and open-set speech understanding. Not surprisingly, sub-jects with greater degrees of loss typically showpoorer perception (Walden, 1984; Yellin et al.,1989). The exact cause(s) of the perceptual prob-lems in these cases is still a matter of debate, butthe general consensus is that speech understandingis limited by signal audibility for losses up to about60 dBHL and by a combination of audibility andcochlear distortion effects for losses of greater de-gree (Glasberg and Moore, 1989; Moore, 1995).

In contrast, speech perception ability in adultsdiagnosed with auditory neuropathy/dys-syn-chrony-type hearing loss has shown no correla-tion with the pure-tone audiogram (Starr et al.,2000; Zeng et al., 2001b), and in most cases,has been significantly poorer than would havebeen expected for sensorineural losses of equiv-alent degree. Starr et al. (1996) presentedopen-set speech perception findings for 8 of the10 subjects in their sample. Word recognitionscores ranged from 0% to 92% and were signif-icantly lower in 12 of the 16 ears than predict-ed from the norms generated by Yellin et al.(1989) for ears with sensorineural hearing loss.Similarly, Sininger and Oba (2001) reportedspeech discrimination scores (CID W-22 lists)for 36 of their (mostly adult) auditory neuropa-thy/dys-synchrony patients that showed 25(69%) fell below the Yellin et al. (1989) nor-mative range. Other examples of auditory neu-ropathy adults with extreme speech perceptiondifficulties have been presented by Jerger et al.,1992; Berlin et al., 1993; Sininger et al., 1995;Widen et al., 1995; Berlin et al., 1996; Kaga etal., 1996; Starr et al., 2000; Zeng et al., 2001a;Mason et al., 2003; Starr et al., 2003; and Zengand Liu, in press.

The data presented in these studies demon-strate that in many cases of adult auditory neu-ropathy/dys-synchrony, speech signal disruptioncan occur that is more extreme than that ob-served in sensorineural hearing loss. However,not all of the reported adult AN/AD cases haveshown unusually poor speech understanding (atleast in quiet listening conditions). For example,25% of the ears presented by Starr et al. (1996)and 30% of the Sininger and Oba (2001) sub-jects showed speech perception scores within thenormal range for sensorineural losses of equiva-lent degree. Most of the reported adult auditoryneuropathy/dys-synchrony cases have sufferedfrom progressive, generalized neuropathic con-ditions. It is therefore possible that in some ofthese patients with sensorineural-like speech per-ception ability, the disease process was less ad-vanced than in their more affected peers, andhence their perception at the time of the assess-ments was less disrupted. Longitudinal monitor-ing of these cases will in time make this situationclearer. What the current results do show, how-ever, is that good speech understanding is possi-ble in ears with absent or grossly abnormal audi-tory brainstem responses.


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In addition to the auditory neuropathy/dys-synchrony patients with “sensorineural-like”speech understanding, there have been cases of“normal” perception with AN/AD. Kraus et al.(2000) presented findings for a 24-year-oldwoman with an unremarkable medical historyand normal hearing thresholds who had experi-enced difficulties in background noise through-out childhood. She obtained a perfect wordrecognition score on a CUNY-Sentence assess-ment for stimuli presented in quiet, demonstrat-ing that open-set speech perception can beachieved despite measurable neural disruption inthe auditory brainstem. Assessment in noise (inthis case multi-talker babble) did show abnor-mally depressed results, however. On open-setword testing at a +3 dB signal-to-noise ratio forexample, this subject scored only 10% correctwhere the mean score for a control group of nor-mal subjects was 50%.

Shallop (2002) has also presented a case of awoman diagnosed with hearing thresholds in themild-to-moderate range when in her late 20s, butwho had reported difficulties in noise throughoutchildhood. Hearing in Noise Test (HINT) sentencetesting in this case also showed 100% perceptionin quiet listening conditions but extreme difficul-ty in noise. Word identification for this subject fellto 25% at a +15 dB signal-to-noise ratio and to0% at +12 dB. These cases illustrate the often-reported observation that adult auditory neu-ropathy/dys-synchrony sufferers have particularproblems in background noise and suggest thatalthough good speech understanding may be pos-sible in ideal listening circumstances, even theleast-impaired adult AN/AD subjects may strug-gle when redundancies in the speech signal arecompromised.

Speech perception difficulties in backgroundnoise are not unique to auditory neuropathy/dys-synchrony-type hearing loss. Patients with sen-sorineural loss are also known to struggle withcompeting signals (Bilger et al., 1984). The ef-fects of noise in AN/AD cases do, however, tendto be extreme. Zeng and Liu (in press), for exam-ple, recently studied in detail the perception of14 (mostly adult) subjects and found consistentreductions in speech recognition ability, even atsignal-to-noise ratios that show little or no effecton subjects with normal hearing (10 to 15 dB).

The mechanisms underlying these perceptu-al difficulties in noise are unclear. They are how-ever consistent with the findings of recent psy-

chophysical studies that have shown excessivemasking of pure tones in auditory neuropathy/dys-synchrony subjects by simultaneous noise, aswell as noise bursts presented before and afterthe test signal (Kraus et al., 2000; Zeng et al.,2001b; Zeng et al., in press).

In summary, most reported adult auditoryneuropathy/dys-synchrony patients have shownseverely disrupted speech perception. However,the proportion of AN/AD cases with particularspeech perception problems has yet to be deter-mined. Speech perception scores in 75% of theears in the Starr et al. (1996) sample were poor-er than expected from their behavioral audio-gram, but in most instances, speech perceptiondifficulty was the identifying characteristic inthese patients. As mentioned, there are docu-mented cases with perceptual abilities that fallwithin the expected performance range for sen-sorineural hearing loss, and there may be a pop-ulation of adults who would fit the AN/AD phys-iologic profile but who are yet to be identified.

Speech Perception in Children withAuditory Neuropathy/Dys-synchrony

As with adult patients, disproportionate speechperception difficulties have been a consistently re-ported symptom in children with auditory neu-ropathy/dys-synchrony. Anecdotal evidence, be-ginning with the first auditory brainstem responsepapers to identify the condition in children (Davisand Hirsch, 1979; Worthington and Peters,1980), has consistently suggested that young sub-jects with prelingual onset of AN/AD are at risk ofsignificant perceptual problems and delays inspeech and language development.

Despite the widely held concern regarding theintegrity of the speech signal in pediatric auditoryneuropathy/dys-synchrony cases, there has been apaucity of formal speech perception data presentedin the literature. Amongst the papers that have pre-sented formal data, it has been the opinion of the au-thors in almost all instances (Kraus et al., 1984; Starret al., 1991; Gravel and Stapells, 1993; Gorga et al.,1995; Berlin et al., 1996; Konradsson, 1996; Doyle etal., 1998; Starr et al., 1998; Miyamoto et al., 1999;Rance et al., 1999; Simmons and Beauchaine, 2000;Lee et al., 2001) that perceptual abilities poorer thanpredicted by the behavioral audiogram were appar-ent in some or all of their patients.


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Comparisons between open-set word scoresfrom subjects for whom 3-frequency average (1kHz /2kHz /4 kHz) hearing levels were available,and the norms provided by Yellin et al. (1989)are shown in Figure 5. Overall, excluding the earswith pure-tone averages of 80 dBHL or more, forwhom the minimum normal score in ears withsensorineural loss is zero, there are results for 41individual ears showing the auditory neuropathy/dys-synchrony result pattern. Open-set wordscores in 18 (44%) of these were within the ex-pected range, and 23 (56%) of 41 ears were ei-ther borderline abnormal or significantly poorerthan would have been expected for adults withequivalent degrees of sensorineural hearing loss.

As with adult auditory neuropathy/dys-syn-chrony subjects, affected children are often re-ported to have extreme difficulty in backgroundnoise even if their speech perception is good inquiet listening conditions. For example, in their

study involving 3 subjects with temperature-re-lated AN/AD, Starr et al. (1998) found that 2 chil-dren who had 100% open set discrimination inquiet (when well), scored below the 10th per-centile for age in background noise. Similarly,Gravel and Stapells (1993) found markedly ab-normal results on the Pediatric Speech Intel-ligibility Test for a child when assessed in thepresence of a competing signal. The use of per-sonal frequency modulated (FM) systems to im-prove signal-to-noise ratios has thus been recom-mended by a number of authors (Berlin, 1999;Kraus et al., 2000).

While the poor speech perception ability re-ported for many children with auditory neuropa-thy/dys-synchrony-type hearing loss is likely tobe the result of signal degradation in the audito-ry pathway, the test scores may in some instanceshave been influenced by nonauditory factors.Among adult subjects with late (postlinguistic)


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Figure 5. Open-set word/average hearing level comparisons for 46 children with auditoryneuropathy/dys-synchrony type hearing loss. The dashed line represents the minimumexpected score for ears with sensorineural hearing loss (Yellin et al., 1989). Contributingstudies are listed with the number of ears for each.Starr et al. (1991): 4 Starr et al. (1998): 2Sininger et al. (1995): 2 Miyamoto et al. (1999): 4Berlin et al. (1996): 2 Lee et al. (2001): 4Konradsson. (1996): 3 Rance et al. (2004): 14Picton et al. (1998): 2 Zeng et al. (in press): 9

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onset hearing loss, it is usual to assume that theknowledge of language structures and speechproduction abilities are uniform and are not like-ly to exert an influence over the speech percep-tion test results. Performance variations are there-fore considered to reflect differences in access tothe sensory input. In young children, generally,and children with prelingual onset hearing loss,in particular, the assumption of uniformity can-not be made (Boothroyd, 1995). As such, speechperception findings in youngsters with early-onsetauditory neuropathy/dys-synchrony may be lim-ited by factors unrelated to the quality of theneural signal provided to the brain by the audi-tory pathway.

Some nonauditory factors that could influ-ence speech perception test performance relate tothe child’s age and developmental level and in-clude speech production skills, concentrationspan, and cognitive abilities (Tyler, 1993;Boothroyd, 1995). Consideration of these fac-tors is particularly relevant to children with au-ditory neuropathy/dys-synchrony, as many af-fected subjects have had rocky neonatal periodsand are at high risk of neurodevelopmentaldelay (Franck et al., 2002). Such delays couldimpact their ability to perform in the test ses-sion and their overall progress in areas such asspeech and language development. Much of theliterature regarding children with auditory neu-ropathy/dys-synchrony has been anecdotal,with presented cases offering at best patchy de-tails about the general developmental progressof the subjects. One study involving subjectswith early-onset AN/AD that did look in depthat general developmental level was reported byFranck et al. (2002). This study examined long-term outcomes in 9 AN/AD children (8 of whomhad high-risk histories) and included neurolog-ic and psychological evaluation of various as-pects of development, including motor, cogni-tive, speech and language, and social and be-havioral skills. The pattern of developmentaldeficits varied, but all 9 children showed somedegree of global delay or neurologic abnormal-ity. Other studies to report general develop-mental delays in children with auditory neu-ropathy/dys-synchrony include Worthingtonand Peters (1980), Gravel and Stapells (1993),Deltenre et al. (1997), and Corley and Crabbe(1999).

One set of results in which the effect of gen-eral developmental factors on speech perception

testing can be excluded is that presented byKonradsson (1996). This study involved 3 chil-dren with unilateral auditory neuropathy/dys-synchrony who each showed perfect word dis-crimination scores for the better ear and dispro-portionately poor speech perception in theAN/AD affected ear. The poor speech perceptionresult in these cases was likely to be caused bywhatever mechanism disrupted the auditorybrainstem response. However, sensory depriva-tion might also have played a role in the dimin-ished auditory capacity of these subjects. Thehearing losses in the 3 children were all of mod-erate or severe degree. If the losses were presentfrom infancy at the levels obtained at the time oftheir speech assessments (6–11 years), then theseears are unlikely to have received any consistentauditory stimulation over an extended time peri-od. This sensory deprivation could, in itself, causealterations in the development and subsequentfunction of the auditory pathway, affecting thechild’s ability to make full use of their audition(Clopton and Silverman, 1978; Kitzes andSemple, 1985).

Long-term auditory deprivation may alsohave affected the speech perception abilities ofother auditory neuropathy/dys-synchrony chil-dren reported in the literature. Most of them hadnot been provided with consistent amplificationdespite significantly elevated hearing levels.

The level of a child’s speech and language de-velopment is another factor that can affect speechperception test performance (Boothroyd, 1995).Clearly this was not an issue in the unilateralcases presented by Konradsson (1996), but it mayhave affected the findings of some of the otherstudies involving children with significant bilat-eral hearing loses. The development of expressivespeech and language skills in children with audi-tory neuropathy/dys-synchrony has not yet beenaddressed in detail, but it is clear from anecdotalreports that children with AN/AD often have sig-nificant speech production and language devel-opment problems (Davis and Hirsh, 1979;Worthington and Peters, 1980; Gravel andStapells, 1993; Doyle et al., 1998). In some cases,these deficits may have affected the child’s abilityto score highly on both open- and closed-setspeech perception assessments.

In summary, the speech perception findingsfor children with early-onset auditory neuropa-thy/dys-synchrony have resembled their adultcounterparts, with many performing on formal


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assessments at levels poorer than would be ex-pected for ears with sensorineural hearing lossesof equivalent degree. However, it is unclear atthis stage if the perceptual difficulties facing thesechildren are qualitatively similar to those affect-ing adults with progressive neuropathic condi-tions. Furthermore, the effects of developmentalfactors associated with generalized neurologic ab-normality and the lack of auditory stimulationduring critical development periods (Deltenre etal., 1999) on speech perception test results havenot yet been fully considered in these children.

Management of AuditoryNeuropathy/Dys-synchrony

Amplification

The provision of hearing aids to patients (partic-ularly children) with auditory neuropathy/dys-synchrony is currently a controversial issue. Thereare two main arguments against amplification forthis population. The first relates to the issue ofsafety and the potential for damage to cochleaewith outer hair cell function. The second concernsthe inherent auditory pathway limitations inAN/AD subjects and the likelihood that conven-tional amplification will simply produce a louderbut equally distorted signal.

Hearing aids can cause significant noise ex-posure that results in both temporary and perma-nent shifts in hearing threshold (Macrae, 1991,1995). However, in children with sensorineuralhearing loss in the mild-to-severe range, long-term amplification (5–9 years in the childrenstudied by Macrae, 1995) at the real-ear insertionlevels prescribed by the National AcousticsLaboratories (NAL) model appears to pose littleor no risk of acoustic trauma, even with linearamplification techniques. High-gain amplificationstrategies necessary for adequate sound provisionfor children with profound loss (pure-tone aver-age ≥ 100 dBHL) have, however, produced sig-nificant threshold deterioration (up to 20 dB) insome cases (Macrae, 1995).

The potential for acoustic trauma throughover-amplification is theoretically greater in earswith normal micromechanical cochlear processes(Starr et al., 1991). Permanent outer hair celldamage is a particular concern in ears with audi-

tory neuropathy/dys-synchrony, as the efferentsuppression and acoustic reflex mechanisms thatare thought (amongst other things) to protect thecochlea from excessively loud sounds (Simmons,1964; Borg et al., 1984) may be inactive (Berlin etal., 1993; Sininger et al., 1995; Hood et al., 1996;Starr et al., 1996).

Thus, it has been recommended that otoa-coustic emissions be carefully monitored as ameasure of outer hair cell health in auditory neu-ropathy/dys-synchrony ears that are being ampli-fied (Hood, 1998) or that hearing aids not be con-sidered unless emissions have already disap-peared (Berlin, 1999). However, although otoa-coustic emission amplitude reduction has beendocumented in children with high-powered am-plification (Sininger and Oba, 2001; Trautwein etal., 2001), there have also been a number of re-ports of emission presence at normal amplitudesafter long-term aid use (Katona et al., 1993;Doyle et al., 1998; Rance et al., 1999; Berlin etal., 2000; Starr et al., 2000; Lee et al., 2001;Sininger and Oba, 2001). Overall, no correlationhas been established between hearing aid use andloss of otoacoustic emissions. Furthermore, a rea-sonably high proportion of subjects with AN/ADshow otoacoustic emission amplitude reductionand subsequent loss in ears that have not beensubjected to amplified sound at all (Deltenre etal., 1999; Starr et al., 2000).

The argument present by Hood (1998) andBerlin (1999) appears to be that hearing aid useshould be limited to minimize damage to theouter hair cells and preserve the active cochlearmechanisms reflected by the otoacoustic emis-sion. This contention is theoretically sound, butat this stage, there is no evidence that theprocesses generating the otoacoustic emissionhave any functional benefit in patients with au-ditory neuropathy/dys-synchrony. In fact, a num-ber of authors (Deltenre et al., 1999; Rance et al.,1999; Starr et al., 2000) have presented resultssuggesting that the presence or absence of evokedotoacoustic emissions is unrelated to either hear-ing threshold sensitivity or speech perceptionability in affected patients.

The second main argument against providinghearing aids to children and adults with auditoryneuropathy/dys-synchrony rests on the assump-tion that increasing the amplitude of auditory sig-nals will not overcome the pathologic mecha-nisms that have disrupted the auditory brainstemresponse and, in many cases, the unamplified


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speech signal. Berlin (1999), for example, advis-es against hearing aid fittings “not in an attemptto preserve (otoacoustic) emissions but simply be-cause hearing aids are designed to compensatefor missing outer hair cells.” The perceptual con-sequences of presenting high-level stimuli in earswith auditory neuropathy/dys-synchrony are yetto be fully investigated. As such, Cone-Wesson etal. (2001) have thus recommended that investi-gation of unaided speech perception perfor-mance-intensity functions be undertaken. Suchinvestigations may be useful in improving ourgeneral understanding of perceptual deficits inAN/AD and may also provide helpful clinical in-sights when considering management options forindividual subjects. A flat function, for example,may suggest that hearing aids will not substan-tially improve a particular subject’s speech per-ception ability. Furthermore, speech performancerollover, such as seen with various types of retro-cochlear abnormalities, may also argue againstthe usefulness of amplification (Cone-Wesson etal., 2001).

The potential for improvement in signal clar-ity with conventional amplification in ears withauditory neuropathy/dys-synchrony is unknownbut is likely to be limited. While there is some ev-idence that the firing properties of afferent fibersin the auditory pathway of normally hearing sub-jects show increased phase locking and synchro-nous discharge as sensation levels increase (Javel,1986; Phillips and Hall, 1990), similar improve-ments are yet to be demonstrated in subjects withauditory pathway abnormalities. What is clear inmost patients with auditory neuropathy/dys-synchrony is that stimulus level increases fail toproduce recordable auditory brainstem respons-es, even at levels well in excess of hearingthreshold. This suggests no significant increasein either the amount (conduction block) or thesynchrony of neural activity in the auditorybrainstem.

One way in which amplification can improvespeech perception ability in auditory neuropa-thy/dys-synchrony subjects with elevated hearingthresholds is by improving their access to speechsounds. A number of studies have now reportedaided/unaided threshold improvements consis-tent with the level of gain provided by their hear-ing devices (Berlin et al., 1996; Deltenre et al.,1999; Trautwein et al., 2000; Cone-Wesson et al.,2001). Similar results were obtained for most ofthe children reported in Rance et al. (1999). Most

of the subjects in this investigation showed aidedthresholds that improved in accordance with NALprescription targets to levels that afforded themcomplete access to the long-term 70-dBSPLspeech spectrum.

Approaches to Fitting Hearing Aids in Subjectswith Auditory Neuropathy/Dys-synchrony

The provision of hearing aids to subjects with au-ditory neuropathy/dys-synchrony has not beenapproached systematically. Many early-identifiedsubjects, such as the adult presented by Prieve etal. (1991) who had been a consistent aid user for28 years at the time of publication, were ampli-fied as if they had sensorineural hearing lossesbecause there was no evidence to suggest thatthey did not have a cochlear site of lesion.Management approaches for more recently iden-tified cases of AN/AD have tended to be morevaried, making interpretation of published resultsdifficult.

Some authors have considered that amplifi-cation should not be used at all for children withauditory neuropathy/dys-synchrony (Berlin,1999; Berlin et al., 2002), or that if hearing aidsare trialed, they should only be fit monaurallyand should be low-gain, wide-dynamic-rangecompression devices, even in subjects with se-vere-to-profound hearing loss (Hood, 1998). As aresult, many clinics around the world have pro-ceeded cautiously with aid fittings in newly diag-nosed children, often under-amplifying them andpotentially providing only limited access to thenormal speech spectrum.

Hearing-Aid Performance in Subjects withAuditory Neuropathy/Dys-synchrony

Despite the considerable debate that currently ex-ists about the potential risks and benefits of am-plification in auditory neuropathy/dys-synchronysubjects, relatively few studies have presented ev-idence of aided function (speech perception re-sults). Anecdotal reports of (on the whole) un-successful hearing aid fittings began to emergeabout the time that the condition was first identi-fied (Squires and Hecox, 1983; Kraus et al.,1984). Amongst adults with the late-onset formof AN/AD, acceptance of amplification has beenalmost universally poor, with reports rangingfrom little or no benefit (Berlin et al., 1993;Sininger et al., 1995; Widen et al., 1995; Berlin et


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al., 1996; Starr et al., 1996) to “detrimental ef-fects” (Starr et al., 1996). Starr et al. (1996) didnot elaborate on what these effects might be, butSininger et al. (1995) reported that amplificationin their 44-year-old subject with a moderate, pre-dominantly low-frequency loss “interfered ratherthan helped with communication”.

Anecdotal reports of hearing aid outcome inchildren with auditory neuropathy/dys-synchronyhave been more varied but in most cases havebeen poorer than would have been expected forears with equivalent degrees of sensorineuralhearing loss. Berlin and colleagues have suggest-ed in a series of articles (Berlin et al., 1996;Berlin, 1999, Berlin et al., 2002; Berlin et al.,2003) that hearing aids produce no obvious ben-efits, although these papers have generally failedto cite specific examples or provide even basic sta-tistics regarding the results obtained in their sam-ple. In summarizing their findings for 193 audi-tory neuropathy/dys-synchrony patients seenover a 20-year period, these authors have con-cluded that “while hearing aids improved detec-tion thresholds, the long-term value of hearingaids in understanding speech is far poorer thanpredicted based on the audiogram and/or articu-lation index alone” (Berlin et al., 2003). Berlin etal. (1998) did describe two pediatric cases forwhom they concluded that there was “no com-pelling evidence” that amplification had helped.Both of these subjects had, however, only recent-ly been fitted with low-gain hearing aids at thetime of writing. Furthermore, audiometric detailswere not provided, making it difficult to interpretthe outcome of these hearing aid trials.

Other authors have used conventional aidingstrategies in fitting hearing devices to young chil-dren with auditory neuropathy/dys-synchronyand still found that amplification was of little ben-efit. Trautwein et al. (2000), for example, usedthe standard desired sensation level (DSL) ampli-fication paradigm (Seewald et al., 1997) to fit an18-month-old AN/AD child who later received acochlear implant. Despite showing behavioralhearing levels in the profound range bilaterally,aided threshold testing in this child revealed goodaccess to the normal 70-dBSPL speech spectrum,particularly in the low-to-mid frequencies, wheredetection thresholds of about 40 to 55 dBHL wereobtained in both ears. Aided phoneme detectiontesting also revealed good speech sound aware-ness, with the child scoring 27/30 on the Ling SixSounds Test. However, despite the good sound ac-

cess provided by the amplification, speech dis-crimination was poor. Aided assessments at 3years of age revealed “no closed- or open-set dis-crimination”.

A number of authors have described preoper-ative findings for young cochlear implant candi-dates with auditory neuropathy/dys-synchronyand severe-to-profound hearing loss. Miyamoto etal. (1999) presented a child with Friedreich’sataxia who had shown progressive hearing dete-rioration and assorted balance and neurologicproblems. No formal results were presented inthis study, but it was the opinion of the authors(after only 1 month of aid use), that the speechperception benefits were minimal. Similarly,Shallop et al. (2001) presented 5 children withauditory neuropathy/dys-synchrony and conclud-ed that 4 “were indifferent to amplification”. Thefifth child also showed no benefit from amplifica-tion but had limited experience because discom-fort issues restricted device use to the assessmentsessions.

The presence of profound hearing loss in theMiyamoto et al. (1999) and Shallop et al. (2001)cases may have affected speech perception perfor-mance by limiting access to the amplified speechspectrum. No such problems were encounteredwith the child reported by Simmons andBeauchaine (2000), who presented with hearingthresholds that were primarily in the mild-to-moderate hearing loss range. Aided benefit, as inthe previously mentioned studies was, however,reported to be minimal, and amplification was re-moved after a “relatively short” time following a“lack of improvement in auditory behaviors”.

In contrast to the consistently poor findingswith amplification in adult subjects with auditoryneuropathy/dys-synchrony, a number of studieshave provided anecdotal reports of positive out-comes in at least some children with AN/AD.Katona et al. (1993) presented preliminary find-ings for a profoundly deaf AN/AD child fittedwith high-powered hearing aids (Phonak PP-C-LA) in infancy. These authors found no toleranceproblems and reported good sound awarenessand subjective performance at 8 months of age.Similarly, Franck et al. (2002) reported that ayoung child (2 years 10 months at publication)with severe-to-profound hearing loss was “show-ing some auditory benefit” with hearing aids thatwere initially set conservatively but were laterconfigured in accordance with the DSL targetsbased on the behavioral audiogram. Madden et


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al. (2002), in a larger scale investigation involv-ing 16 children with auditory neuropathy/dys-synchrony type hearing loss, also found evidenceof benefit with standard amplification and con-cluded that “patients in our study . . . have re-sponded well to conventional rehabilitation andamplification.”

A survey of amplification outcomes in 29 au-ditory neuropathy/dys-synchrony children fol-lowed by the House Ear Institute was presentedby Cone-Wesson et al. (2001). Fourteen (48%)had ceased to be consistent hearing aid-users,suggesting that they had received little or no ben-efit. Three children (10%), on the other hand,were considered to have shown “fair-to-good ben-efit,” as evidenced by improvement in aidedthresholds and speech perception, and 5 children(17%) showed threshold improvements but nomeasurable perceptual benefits. Among the othercases, who were too young or too difficult to as-sess, or both, reports from parents and teachersindicated that “some” children had shown benefitfrom amplification.

Aided Open-Set Speech Perception Results in Children with Auditory

Neuropathy/Dys-synchrony

To date only four publications have formally ad-dressed the issue of amplification benefit usingcomparisons of open-set aided and unaidedspeech perception findings. The results of thesestudies are summarized in Figure 6.

Deltenre et al. (1999) presented results for ayoung child who had suffered serious neonatalcomplications, including hyperbilirubinemia andrespiratory distress syndrome, after a prematurebirth at 28 weeks. The auditory neuropathy/dys-synchrony result pattern was identified in infan-cy, and hearing thresholds in the moderate hear-ing loss range were subsequently established.Amplification was withheld until this child’s otoa-coustic emissions spontaneously disappeared at 4years of age. The specifics of the aiding strategywere not defined, but the gain and maximumpower output values were broadly consistent withthe NAL/DSL prescriptions for sensorineural hear-


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Figure 6. Open-set speech perception results (aided/unaided) for children with auditoryneuropathy/dys-synchrony. Study A: Deltenre et al. (1999); Study B: Rance et al. (1999);Study C: Lee et al. (2001); Study D: Rance et al. (2002).

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ing loss of moderate degree. Improvements in thischild’s language skills were noted soon after fit-ting, and significant aided speech perception ben-efits were demonstrated on word identificationscore measurements at 6 and 7 years of age.Open-set word scores improved from 0% in thebinaural unaided condition to 80% in the binaur-al aided condition at the first of these assessmentsand from 28% (binaural unaided condition) to95% (binaural aided condition) at the second ofthese assessments.

In contrast, Lee et al. (2001) have presentedspeech perception data indicating no speech per-ception improvement with amplification in twoauditory neuropathy/dys-synchrony children withbilateral moderate-to-severe hearing loss. Neitherchild presented with any risk factors when theywere diagnosed and aided in infancy. No amplifi-cation details were provided, but the AN/AD di-agnosis was not made until the children were as-sessed as part of a school-based otoacoustic emis-sion survey program at 11 and 12 years of age,respectively. As such, it is reasonable to assumethat they were aided according to the prescrip-tions for sensorineural hearing loss. In both chil-dren, similar (poor) open-set speech perceptionscores on the Cantonese Speech DiscriminationTest were obtained in both the unaided and aidedconditions. That these children were unable to ef-fectively use their hearing for speech perceptiondespite early diagnosis and fitting and approxi-mately 10 years of listening experience suggeststhat the neural disruption, implied by the audito-ry neuropathy/dys-synchrony result pattern, wassignificantly affecting the integrity of the speechsignal in these subjects.

Variable aided open-set speech perception re-sults were obtained by Rance et al. (2002) in astudy involving 15 children with the auditoryneuropathy/dys-synchrony type hearing loss. Thechildren had typically been diagnosed in infancy,and had all been fit with conventional amplifica-tion to the level of their hearing loss at least 12months before speech perception was assessed.Each child scored at close to chance levels whenevaluated in the unaided condition using the PBKWords Test presented live voice at conversationallevels of about 70 dBSPL. In the aided condition,7 subjects showed no significant improvement de-spite being afforded complete access to the aidedspeech spectrum by their hearing devices.However, the other 8 children did show a signifi-cant aided benefit, with a mean PBK-phoneme

score of 67.2% and a mean difference score(aided–unaided) of 56.8%.

Amplification Outcomes and Degree of Hearing Loss

The relationship between sensorineural hearingloss and speech perception ability in postlinguis-tically deafened adults has been well documented(for reviews, see Walden, 1984 and Yellin et al.,1989). Not surprisingly, individuals with greaterdegrees of loss have consistently shown poorerdiscrimination ability. Similar results have beenobtained in studies involving children with sen-sorineural hearing loss (Bamford et al., 1981;Boothroyd, 1997; MacArdle et al., 1999). Ranceet al. (2002) sought to investigate the effect ofdegree of hearing loss on aided speech perceptionin children with auditory neuropathy/dys-syn-chrony type loss. This study compared the per-ceptual ability in a group of affected subjects witha cohort of age- and audiogram-matched childrenwith sensorineural hearing loss.

Aided open-set speech perception ability inthe children with sensorineural loss assessed inRance et al. (2002) was correlated with the au-diogram. Subjects with greater degrees of hear-ing loss tended to show poorer PBK scores thantheir counterparts with better audiometric thresh-olds. This was particularly the case for childrenwith average hearing levels in excess of 60 dBHL.Interestingly, this result was not influenced by theaudibility of the speech signal, as aided thresh-olds and articulation index scores were similaracross children. These findings are consistentwith the results of psychophysical studies in hear-ing impaired adults that suggest the limiting fac-tors in speech understanding are cochlear distor-tion effects, which increase with greater degreesof sensorineural hearing loss and are perhaps re-lated to the loss of the cochlear amplifier, ratherthan reduced audibility (Glasberg and Moore,1989; Moore, 1995).

Overall, aided speech perception ability in thegroup of children with auditory neuropathy/dys-synchrony was not correlated with pure tone sen-sitivity. Some children with hearing levels in thesevere-to-profound range showed reasonablespeech perception, and yet others with only mild-to-moderate hearing loss had negligible percep-tual ability (Figure 7). Aided PBK test perfor-mance among children with auditory neuropa-thy/dys-synchrony appeared to fall into two dis-


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tinct categories. A child either scored at chancelevels (<10%), suggesting no ability to make useof speech information, or performed at signifi-cant levels (>35%). Clearly, the subjects in theformer group, all but one of whom had nearcomplete access to the amplified speech spec-trum with aided articulation index values of 0.75or more, were suffering from significant distor-tion in the neural code.

In contrast, the other 8 auditory neuropa-thy/dys-synchrony subjects were able to make useof the access to the speech spectrum afforded bytheir hearing aids. In fact, the aided PBK scoresobtained for this subset of the AN/AD group wereindistinguishable from their sensorineural coun-terparts. That is, their speech perception scoreswere equivalent to the children with sensorineur-al hearing loss and were similarly correlated tothe degree of hearing loss. Once again, it is un-clear if these AN/AD children benefited from im-provements in the clarity of the neural represen-tation of speech or simply from being better ableto hear speech with amplification. What is clear isthat on speech perception testing (and anecdotalreports from teachers of the deaf and parents),the hearing aids afforded these children at leastsome degree of functional hearing.

Age at Intervention

Recent reports (Deltenre et al., 1999; Madden etal., 2002; Rance et al., 2002) describing amplifi-cation benefits in auditory neuropathy/dys-syn-chrony children do appear to be out of step withthe weight of anecdotal evidence presented thusfar. One possible explanation for the unusuallypositive findings in these papers may be relatedto the age at which the children received theirhearing devices. The children in each of thesestudies were identified and amplified in infan-cy. The link between speech and languagedeficits in children with prelingual sensorineur-al hearing loss is well established. So too are theameliorating effects of early diagnosis and in-tervention (Markides, 1986; Levitt and McGarr,1988; Ramkalawan and Davis, 1992). Recentstudies by Yoshinaga-Itano et al. (1998) andMøeller (2000) have shown that hearing-im-paired children who are amplified and receiveeducational support in the first 6 months of lifehave significantly greater potential for speechand language development than do childrenwho receive intervention at a later age. It thusseems logical that children with auditory neu-ropathy/dys-synchrony should show similar


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Figure 7. PBK phoneme scores in the aided test condition are shown as a function of 3-frequency average hearing level for children with sensorineural (open circles) andauditory neuropathy/dys-synchrony type hearing loss (filled circles).

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early intervention benefits (Deltenre et al.,1999). Concerns about the potential for benefitand for acoustic trauma have led to amplificationdelays of a number of years in many of the re-ported pediatric AN/AD cases. This sensory de-privation during critical developmental periodsmay in itself, have limited amplification outcomesin some cases.

Possible Differences Between Early- and Later-Onset Forms of Auditory

Neuropathy/Dys-synchrony

The positive amplification results reported forsome children with the auditory neuropathy/dys-synchrony result profile are inconsistent withthe findings for affected adults. It is unclear atthis stage whether the early-onset form ofAN/AD (which is typically related to neonatal in-sult) results in perceptual disruptions that arequalitatively different from those observed insubjects with the late-onset form of the condition(typically associated with generalized neuropa-thy abnormality). However, if they do representa similar level of neural disruption, one mightexpect the early-onset patients to cope betterbecause they grow up with an impaired but rea-sonably consistent neural signal. The late-onsetneuropathy cases, on the other hand, are facedwith a different and deteriorating neural signalat a time (usually adolescence or adulthood)when their ability to cope with these changesmay be reduced.

In summary, while amplification has shownlittle or no perceptual advantage in adult sub-jects with auditory neuropathy/dys-synchronytype hearing loss, some evidence suggests thata significant proportion of affected children canbenefit from conventional hearing aids. Thatbenefit has been documented with both anecdo-tal reports and speech perception tests. Pro-longed exposure to high levels of sound cancause cochlear insult, but there is no compellingevidence at this stage that amplification has re-sulted in a permanent threshold shift or evenpermanent changes to outer hair cell function inAN/AD children. Since the loss of otoacousticemissions can occur without amplification anddoes not appear to affect pure tone sensitivity orspeech perception, monitoring the effects ofnoise exposure with otoacoustic emissions maybe misleading.

Cochlear Implants

The first set of results for a confirmed auditoryneuropathy/dys-synchrony subject who had un-dergone cochlear implantation were presented inRance et al., 1999. Since then, the identificationof greater numbers of AN/AD cases with severe-to-profound hearing loss, the often poor speech-perception performance of affected subjects, andlimited success with conventional amplificationhas led many clinicians and patients to considerthe cochlear implant management option. Despitethe specific risks to cochlear structures during theprocedure (O’Leary et al., 1991; Gstoettner et al.,1997) and outcome uncertainties related to citeof lesion variability, hundreds of children andadults around the world with AN/AD-type hear-ing loss have undergone the procedure.

Most implanted auditory neuropathy/dys-synchrony subjects have shown no particular de-vice programming abnormalities and have re-ceived auditory sensations to electrical current atnormal presentation levels. Furthermore, thesepatients, who typically presented with no little orno preoperative speech discrimination ability,have generally shown significant perceptual ben-efits and have performed on a range of speechdiscrimination tasks at levels consistent with theirimplanted sensorineural peers (Trautwein et al.,2000; Shallop et al., 2001; Trautwein et al., 2001;Madden et al., 2002; Shallop, 2002; Mason et al.,2003; Peterson et al., 2003; Zeng and Liu, inpress). Postoperative speech production develop-ment has also been found to be equivalent inAN/AD cases to matched groups of sensorineuralchildren (Buss et al., 2002).

The dramatic improvements afforded by thecochlear implant device raise questions about theparticular advantages electrical stimulationstrategies provide in these cases. One obviousbenefit is that the implant device provides broadaccess to the speech spectrum. Preoperative hear-ing aid details have typically not been presentedin the recent case reports, but as most implantedindividuals have had profound hearing loss, it islikely that even with high-powered hearing aidsthey could not hear the entire range of speechsounds. Aided-audiograms obtained with thecochlear implant in auditory neuropathy/dys-syn-chrony cases have, in contrast, shown completeaccess to the normal speech spectrum (Trautweinet al., 2000; 2001; Shallop et al., 2001; Buss etal., 2002). Thus, the likely improved detection of


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speech sounds provided by a cochlear implant of-fers at least an opportunity for speech under-standing in these cases.

In addition to improved sound detection,there is also some evidence that electrical signalsproduced by cochlear implants may stimulate theauditory pathway more efficiently in some audi-tory neuropathy/dys-synchrony subjects than ispossible with acoustic stimulation. In most im-planted AN/AD cases, electrically evoked physio-logic responses such as the compound action po-tential (Trautwein et al., 2000; Shallop et al.,2001; Trautwein et al., 2001; Shallop, 2002) andauditory brainstem response (Shallop et al., 2001;Trautwein et al., 2001; Buss et al., 2002) havebeen recordable. In these subjects, for whom norepeatable brainstem responses could be observedto acoustic stimuli, this change represents eitheran improvement in the synchrony of neural firingor an increase in the number of contributingneural elements.

Considerable evidence from single unitrecordings in animal models also indicates thatelectrical stimulation provides a higher degree ofneural synchrony in the auditory pathway thanacoustic stimuli (Weiss and Rose, 1988; Parkins,1989; Dynes and Delgutte, 1992). Dynes andDelgutte (1992), for example, made dischargepattern recordings from auditory nerve fibers inanesthetized cats to bursts of sinusoidal current ata range of stimulus frequencies. These authorsfound that auditory nerve firing to electrical sig-nals, particularly at high stimulus frequencies,showed a greater degree of neural synchronythan had been observed in equivalent studiesusing acoustic signals.

In addition to the general synchrony advan-tage that appears to exist for electrical stimula-tion, the manner in which modern cochlear im-plant systems present their stimuli may also beconducive to generating synchronised neural ac-tivity. Stimulation of the spiral ganglion isachieved not via the presentation of a continuouselectrical analog of the acoustic waveform but bya series of biphasic current pulses. The discrete,pulsatile nature of these signals may in itself pro-duce more synchronized patterns of neural activ-ity (Berlin, 1999).

The presence of recordable electricallyevoked potentials and improved speech percep-tion observed in auditory neuropathy/dys-syn-chrony patients with cochlear implants may alsobe a reflection of the amount of neural activity

elicited rather than a synchrony improvement. Asdiscussed previously, scalp recorded brainstem re-sponses may be unrecordable in some AN/ADcases as a result of depletion in the number ofneural elements available to contribute to the vol-ume-conducted evoked potential. This situationis thought to occur in cases of selective inner haircell loss. Cochlear implants bypass this step in theauditory pathway, stimulating the neural ele-ments directly (Javel and Shepherd, 2000).

The positive cochlear implant results and theoften poor amplification outcomes reported forauditory neuropathy/dys-synchrony patients haverecently led to a great deal of enthusiasm for theprocedure as a management option. Some authors(Berlin et al., 2003) have even suggested that clin-icians should “bypass the hearing aid trial beforeimplantation.” Isolated cases of poor cochlear im-plant outcome in AN/AD patients have been re-ported in the literature, however. The case studypresented in Rance et al. (1999) is a clear exampleof a child with no obvious impediments to per-ceptual performance (apart from the postopera-tively diagnosed AN/AD) whose speech discrimi-nation and even sound detection with the cochlearimplant have been severely compromised. Resultsfor this subject showed no open or even closed-setspeech perception ability at 1year after implantand later findings (reported in Rance et al., 2002)after 3 years of consistent device use also showedno perceptual improvement.

Unlike most of his implanted auditory neu-ropathy/dys-synchrony counterparts, this subjectshowed no repeatable brainstem potentials toelectrical stimulation. Current evidence is insuffi-cient to draw firm conclusions, but it would ap-pear that an auditory pathway that can producerecordable evoked potentials to electrical stimu-lation is more likely to be able to support usefullevels of speech perception. Preoperative tech-niques that can test this ability, such as those thatuse a needle electrode placed on the cochlearround window to present an electrical stimulus,may have a significant role in the implant candi-dature process (WP Gibson, personal communi-cation, 1999).

Miyamoto et al. (1999) have also presented acase in which presumed neuronal loss in the VIIInerve and spiral ganglion may have produced apoor implant result in a child with Friedreich’sataxia. This child, who initially presented at 4years of age with only mild hearing loss and goodspeech perception (PBK phoneme score was 92%


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in the better ear), showed steady deterioration inhis hearing, physical status, and vision.

When implanted at age 10.9 years, he hadprofound hearing loss bilaterally and was scoringat near chance levels on open-set word testing.This child had no reported cochlear implant pro-gramming problems, and free-field testingshowed normal detection thresholds. However,despite being afforded good access to the speechspectrum, his speech perception ability was limit-ed, perhaps affected by his generalized neurolog-ic difficulties. His PBK phoneme score of 20%after 12 months of device use was similar to hislast preoperative result and was significantlypoorer than those of a control group of 7 childrenimplanted after progressive sensorineural loss.

Cochlear Implant Candidature

Specific criteria for cochlear implant candidaturevary from clinic to clinic, but in older childrenand adults, selection is typically based upon thepure-tone audiogram and a comparison of thecandidate’s aided speech perception ability withperformance norms for cochlear implantees.While results presented to date in most implantedauditory neuropathy/dys-synchrony patients havebeen promising, there is no evidence that theirspeech perception performance is significantlybetter than that of their sensorineural peers. Assuch, it would seem reasonable at this stage touse the standard preoperative selection criteriawhen considering candidates with AN/AD.

Most of the auditory neuropathy/dys-syn-chrony cases implanted thus far have presentedwith audiograms in the severe-to-profound hear-ing loss range. As discussed previously, however,a significant number of cases have lesser degreesof hearing loss but little or no ability to use thathearing. This group of patients is now being alsobeing considered for the procedure. Shallop(2002) has presented cochlear implant results fortwo auditory neuropathy/dys-synchrony patientswho were within the mild-to-moderate hearingloss range and who showed severe speech per-ception deficits and little or no benefit from con-ventional amplification. One is an adult diag-nosed with AN/AD in her late 20s but thought tohave had a fluctuating mild-to-moderate hear-ing loss throughout her childhood. Open-set pre-operative speech perception in quiet was 100%on HINT sentences, but she experienced extremedifficulty in speech discrimination tests involv-

ing background noise (0% discrimination score ata +12 dB signal-to-noise ratio) and consideredher hearing loss to be a significant disability. Atthe time of writing, her postoperative perceptualability had not yet been fully evaluated, but shehad shown improved word recognition in noiseand reported that her general ability to cope inchallenging auditory environments had improved.Shallop (2002) also mentions (but provides noresults) for a young auditory neuropathy/dys-syn-chrony child implanted despite the presence ofhearing thresholds in the moderate (45–70 dBHL)range.

Cochlear implant candidacy in young (<3years) children with sensorineural hearing loss istypically determined from audiometric findings. Inparticular, a child’s access to the amplified speechspectrum is considered. The correlation that existsbetween hearing levels and speech perception inears with this form of hearing loss allows percep-tual ability to be predicted and compared with ex-pected cochlear implant performance. Results ob-tained for auditory neuropathy/dys-synchronysubjects have, however, shown that for childrenwith AN/AD-type hearing loss, such predictionscannot be made. As such, a conservative selectionapproach requires that AN/AD candidates not beconsidered until their aided speech perceptionability can be accurately established. Unfor-tunately, such determinations are usually not pos-sible until the child is at least 2 or 3 years old,and it is now well established that implantationbefore that age range is highly desirable in hear-ing impaired children (Dowell et al., 2002).4

It may however be reasonable to consideryoung auditory neuropathy/dys-synchrony candi-dates based on their audiometric results if theypresent with hearing thresholds in the severe-to-profound range, as “no” instances have been re-ported of AN/AD children showing speech per-ception abilities superior to those expected forsensorineural losses of equivalent degree. SomeAN/AD subjects with lesser degrees of hearingloss do, however, show better aided speech per-


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4New techniques for the assessment of speech percep-tion ability that are based upon visual reinforcementmethods (such as the VRISD or habituation paradigms)are under development and may find clinical applica-tion in the near future (Houston et al., 2004).

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ception than that of an average implanted child(Deltenre et al., 1999; Rance et al., 2002), indi-cating that cochlear implantation should not, assuggested by some authors, be considered the pri-mary management option for all AN/AD cases.

In summary, cochlear implantation is cur-rently the most successful remediation strategyfor patients with poor sensitivity and speech un-derstanding caused by auditory neuropathy/dys-synchrony. Most implantees with this form ofhearing loss show good access to the normalspeech spectrum and speech perception abilitiescomparable with their sensorineural counter-parts. However, because isolated cases with poorresults have been reported, preneural assess-ment techniques need to be incorporated intothe preoperative test battery, and candidatesidentified with AN/AD condition need to becounseled accordingly.

Perceptual Disruption in Subjects withAuditory Neuropathy/Dys-synchrony

The fact that speech understanding is severely dis-rupted in many patients with AN/AD type hearingloss despite adequate sound detection suggeststhat distortion of suprathreshold cues is the limit-ing factor in perceptual performance. Under-standing the ways in which basic perceptual fea-tures are affected by auditory neuropathy/dys-synchrony, and how this impacts upon speech dis-crimination has been the aim of a number of re-cent psychophysics-based investigations.

Speech Perception and Psychophysics

The essential features of complex sounds, includ-ing speech, are the relative intensity of differentfrequencies (the spectrum and its shape) and howthese vary over time. A listener’s ability to under-stand speech depends on how well they can per-ceive these features. Various perceptual abilitiesthat underpin speech perception have been iden-tified and investigated in subjects with normalhearing and hearing impairment. Some of theseinclude frequency resolution, temporal resolution,and frequency discrimination.

Frequency Resolution

Frequency resolution, also referred to as frequencyselectivity, is the ability of the auditory system to

separate or resolve the components in a complexsound. Discrimination of vowel sounds in speech,for example, can only be achieved if the formantpeaks can be spectrally separated (resolved) andcoded independently in the auditory pathway(Moore, 1995). This spectral processing isthought to be achieved in the normal cochlea bymeans of basilar membrane mechanics and isaided by the active process that is mediated bythe outer hair cells, which leads to amplificationand sharpening of the peaks in basilar membranemovement (Yates et al., 1992).

Evidence for this outer hair cell contributionto resolution ability has been provided by lesionstudies in various animal models that have selec-tively destroyed one type of hair cells (inner orouter) while keeping the other intact. When outerhair cells are damaged by aminoglycosides oracoustic over-stimulation, for example, the resultis a significant broadening of both psychophysi-cal and neural tuning curves (i.e., reduced fre-quency resolution ability) (Ryan and Dallos,1975; Evans and Harrison, 1976; Liberman et al.,1986). In contrast, damage to the inner hair cellsthrough carboplatin treatment results in signifi-cant loss of sensitivity but normal frequency res-olution ability provided there is full outer hair cellretention and provided the active process mecha-nisms—typically inferred in animal studies fromthe presence of otoacoustic emissions—are func-tional (Wang et al., 1997; Salvi et al., 1999).

Sensorineural hearing loss has been shown innumerous studies to adversely affect frequency res-olution ability (for a review see Moore, 1995).There appear to be two mechanisms by which thisoccurs. First, the need for higher signal levels inpeople with hearing loss leads, in itself, to a re-duction in resolution because the basilar mem-brane travelling wave envelope is broader for high-level inputs (Moore and Glasberg, 1987; Glasbergand Moore, 1990). Second, in addition to this nor-mal effect of level, subjects with cochlear hearingloss often show a further reduction in resolutionability that is thought to be the result of a loss ofouter hair cell function, and hence, a disruptionof the active process (Sellick et al., 1982).

The speech perception ability of adult listen-ers with sensorineural hearing loss has been pos-itively correlated with frequency resolution abili-ty in a number of studies (Dreschler and Plomp,1980; Stelmachowitz et al., 1985; Moore, 1996).Furthermore, frequency resolution in cochlear im-plant patients (in this case the ability to distin-


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guish different electrode positions) has also beenrelated to speech perception (Henry et al., 2000).

If, in fact, frequency resolution is entirely de-termined by the active cochlear mechanisms, au-ditory neuropathy/dys-synchrony subjects withnormal otoacoustic emissions would be expectedto have normal resolution, at least at the basilarmembrane level. This was the finding of Abdala etal. (2000) who, in a distortion product otoacousticemission (DPOAE) suppression study, found evi-dence of normal cochlear tuning in both adult andpediatric subjects with AN/AD. These authors gen-erated DPOAE suppression tuning curves by sys-tematically varying the level and frequency of anipsilaterally presented masking tone in 4 AN/ADsubjects. The resulting suppression tuning curvesin these cases were indistinguishable from thoseof 15 normal control subjects, suggesting normalcochlear level frequency selectivity.

Psychophysical investigation of frequency res-olution in subjects with auditory neuropathy/dys-synchrony-type hearing loss has also, on thewhole, shown normal results. Cacace et al. (1983)presented findings for 2 adult subjects withFriedreich’s ataxia. Psychophysical tuning curveswere plotted for stimulus frequencies of 500 Hz, 1kHz, and 2 kHz in these subjects by using a si-multaneous masking paradigm. Thresholds wereobtained for tones at each of the test frequenciesin the presence of masking tones of varying fre-quency. The resulting tuning curves were foundto be sharply tuned and of normal morphology.Cacace et al. (1983) thus concluded that thestructure and function of the outer hair cells intheir patients was unaffected by the neural ab-normality and that their frequency selectivity wasnormal.

Evidence of normal frequency resolution insubjects with auditory neuropathy/dys-synchronytype hearing loss was also obtained in a recentstudy in our laboratory (Rance et al., 2004). Thisstudy sought to characterize the perceptual abili-ties of 14 affected children, correlating their re-sults on a range of psychophysical discriminationtasks with open-set speech perception perfor-mance. Data were also obtained from a cohort ofsubjects with sensorineural hearing loss matchedfor age and hearing level and from a group ofchildren with normal hearing.

An estimate of auditory filter width was ob-tained in each case using a notched noise mask-ing technique. In this procedure, a detectionthreshold for a 1-kHz tone was established in the

presence of white noise and again in the presenceof white noise with a 500-Hz notch centred at thestimulus frequency. The difference betweenthresholds obtained in the two conditions pro-vides an estimate of the subject’s ability to resolvethe signal from the noise (a greater release frommasking in the notched condition indicating bet-ter frequency resolution). Results obtained for thegroup of auditory neuropathy/dys-synchrony sub-jects in this study were similar to those of the nor-mally hearing children and in fact, suggested au-ditory filters that were significantly narrower thanthose of their peers with sensorineural hearingloss (Figure 8).

In contrast, Kraus et al. (2000) have present-ed results suggesting abnormal frequency resolu-tion in an adult AN/AD patient. This 24-year-oldsubject was assessed using a range of maskingparadigms, including a simultaneous maskingtask that broadly resembled the test procedureused in Rance et al., 2004. A masking differenceof only 3.5 dB was seen for this auditory neu-ropathy/dys-synchrony patient compared to amean difference of 18 dB obtained from a cohortof normally hearing subjects, suggesting severelyimpaired frequency selectivity. Kraus et al. (2000)interpreted this finding as indicating a centralcoding deficit (assuming normal cochlear func-tion from the presence of recordable otoacousticemissions).

In summary, frequency resolution ability,which is thought to be primarily related tocochlear-level processing, appears to be normalin most auditory neuropathy/dys-synchrony pa-tients reported thus far. This finding is consistentwith the presence of otoacoustic emission re-sponses in ears with AN/AD. These preneural re-sponses are suggestive of normal cochlear outerhair cell function and “active process” mecha-nisms, and it is well established that the sharp fre-quency tuning of the basilar membrane is contin-gent upon outer hair cell integrity (Evans andHarrison, 1976; Yates et al., 1992; Moore, 1997).

Temporal Resolution

Temporal resolution is the ability to perceivechanges in stimuli over time, for example, to de-tect a brief gap between two sounds or amplitudefluctuations in a continuous sound. The termrefers to the detection of variations in the overallamplitude (the envelope) of the signal ratherthan rapid pressure changes associated with the


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fine structure of the sound (Viemeister and Plack,1993). Results of studies examining the effects ofsensorineural hearing loss on temporal resolutionhave suggested that once the effects of reduced sen-sation level or reduced audible bandwidth are ac-counted for, most subjects perform as well as nor-mally hearing listeners (Moore, 1995; 1996).

In contrast, significant temporal resolutiondeficits have been demonstrated in auditory neu-ropathy/dys-synchrony subjects. Zeng et al.(1999) and Zeng et al. (in press), in related stud-ies involving 21 adults and children with AN/AD-type hearing loss, have shown abnormal resultson a range of temporal resolution measures, in-cluding gap detection (the identification of asilent period embedded within a burst of noise)and the temporal modulation transfer function(detection of sinusoidal amplitude fluctuations inthe level of steady-state noise). Starr et al. (1991)have also presented findings showing profoundlyimpaired use of temporal cues (gap detection,monaural stimulus separation) in an 11-year-oldsubject with progressive AN/AD.

Furthermore, Zeng et al. (2001b), Zeng et al.(in press), and Kraus et al. (2000) have presentedforward and backward masking data suggesting

wider than normal temporal windows in adult au-ditory neuropathy/dys-synchrony subjects. Thesestudies established detection thresholds for brieftonal stimuli presented at various timing intervalsrelative to the start and end of a longer durationmasker. Performance on this task is thought to pro-vide an estimate of how well a listener can sepa-rate sounds in time. Each of the subjects presentedin these investigations showed abnormal backwardand/or forward masking patterns, suggesting im-paired temporal resolution ability.

In addition to the inability of auditory neu-ropathy/dys-synchrony subjects to perceivemonaurally presented temporal cues (as in thepreviously mentioned studies), there is also evi-dence that affected subjects are impaired in theirability to integrate and make use of binaural tem-poral information. Abnormal masking level dif-ference results, for example, have been a consis-tently reported finding in the AN/AD literatureduring the last decade (Starr et al., 1991; Berlin etal., 1993; Starr et al., 1996; Hood, 1999). Thisassessment rests on the principle that a signal em-bedded in noise is more easily detected if eitherthe signal or the noise is out of phase relative to acompeting signal in the contralateral ear. The


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Figure 8. White/notched noise masker level differences for each subject. SN, sensorineural;AN/AD, auditory neuropathy/dys-synchrony (Rance et al., 2004).

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ability to make use of these interaural phase dif-ferences is thought to be contingent upon an ac-curate neural representation at the level of thelower brainstem. Subjects with auditory neu-ropathy/dys-synchrony typically show no mask-ing release with dichotic phase inversion, consis-tent with a degree of temporal disruption of theneural signal, whereas subjects with normal hear-ing usually show a masking level difference of ap-proximately 10 dB (Licklider, 1948).

Localization ability based on interaural tim-ing differences is another aspect of binaural au-ditory processing affected by auditory neuropa-thy/dys-synchrony-type hearing loss (Starr et al.,1991; Kaga et al., 1996; Zeng et al., in press).Subjects in the Zeng et al., study, for examplewere significantly impaired in their ability tomake lateralization judgements from temporalcues. Interestingly, these listeners showed normalsound localization for discriminations based uponinteraural intensity differences.

Severe speech perception difficulties havebeen consistently reported in AN/AD adult sub-jects with abnormal temporal resolution (Starr etal., 1991; Zeng et al., 1999; Zeng et al., 2001a;Zeng et al., in press). As such, these patients re-semble other subject groups in whom temporalprocessing disorders have been correlated withspeech perception deficits. Some of these includeelderly listeners (Gordon-Salant and Fitzgibbons,1993), patients with multiple sclerosis (Levine etal., 1993), and children with learning disabilities(Tallal, 1981; Kraus et al., 1996; Wright et al.,1997).

A correlation between temporal processingability and speech perception has also beendemonstrated for children with early-onset audi-tory neuropathy/dys-synchrony (Figure 9) (Ranceet al., 2004). Amplitude modulation detectionwas abnormal in many of the subjects in thisstudy, and the degree of the abnormality wasstrongly correlated with speech perception ability.


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Figure 9. Amplitude modulation detection thresholds in auditory neuropathy/dys-synchrony(AN/AD) subjects. Closed circles represent the findings for children in the AN/AD group withspeech perception scores > 60%. Open circles represent the children in the AN/AD group with speech scores <30%. Open triangles show the findings for children in the AN/AD <30% group unable to detect a modulation depth of 0 dB (100%). The enclosed area shows the mean ±2 SD range for the normal group (Rance et al., 2004).

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(See Figure 10 for details). Seven of the 14AN/AD children showed normal or only mildlyimpaired modulation detection ability, and all ofthese subjects demonstrated significant open-setspeech discrimination (≥ 60%). In the other 7subjects, however, the ability to perceive ampli-tude fluctuations even at relatively slow modula-tion rates was significantly depressed. C.N.C.phoneme scores in these cases indicated little orno open-set speech perception ability.

Because the auditory pathway abnormalitiesthat produce the auditory neuropathy/dys-syn-chrony result profile are unclear, it is difficult todetermine the exact mechanisms by which tem-poral cues are disrupted in affected subjects.Electrophysiologic results—in particular, the ab-sence or distortion of averaged potentials in theauditory brainstem—do, however, point to dis-ruptions in the synchrony of neural firing orsome form of conduction block in the peripheralauditory system. Such disruptions could resultin a time-smeared neural representation ofacoustic stimuli with the degree of temporal dis-tortion determined by the severity of the disrup-

tion (Starr et al., 1996; Zeng et al., 1999; Krauset al., 2000).

The absence of auditory brainstem responsein AN/AD subjects suggests a temporal disruptionof at least 0.5 ms (Sininger et al., 1995; Kraus etal., 2000), and it may have been that the audito-ry neuropathy/dys-synchrony children describedin Rance et al. (2004) with good speech percep-tion and reasonably normal temporal modulationtransfer function results had levels of brainstemasynchrony close to this limit. The impaired abil-ity to accurately encode even low-rate (10 Hz)amplitude changes seen in some cases does, how-ever, point to neural disruption of the order oftens of milliseconds and may suggest a differentpathologic mechanism.

Frequency Discrimination

Frequency discrimination is the ability to perceivechanges in frequency (or pitch) over time. Forsteady-state (pure tone) stimuli of 4 kHz andhigher, frequency discrimination is thought to de-pend primarily on place mechanisms based on


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Figure 10. Amplitude modulation detection threshold (10 Hz MF) plotted as a function ofconsonant-nucleus-consonant (CNC) phoneme score for auditory neuropathy/dys-synchronysubjects (Rance et al., 2004).

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spatial changes in the basilar membrane excita-tion pattern (Moore, 1973b; Sek and Moore,1995). In contrast, discrimination of stimuli oflower than 4 kHz is thought to be enhanced bythe use of temporal information (Moore, 1973a;1973b; Sek and Moore, 1995; Micheyl et al.,1998). It has been hypothesized that neural phaselocking is important in the fine-tuning of dis-crimination abilities in this range (whereas forhigher frequencies, limitations in neural refrac-tory period prevent phase-related responses).Sek and Moore (1995), for example, showedthat models of frequency discrimination basedsolely on excitation pattern information (andnot taking into account phase locking) could notexplain the variation of difference limens (DLF)across frequency. Specifically, these authorsfound that low-frequency DLFs are significantlysmaller than predicted by place of excitationmodels.

Several studies have measured DLFs to fixedtonal stimuli in adults with cochlear hearing loss(Tyler et al., 1983; Freyman and Nelson, 1986;1991; Moore and Peters, 1992). A high degree ofintersubject variability has been reported, butoverall, the findings indicate that discriminationability is degraded by cochlear damage.Interestingly, DLFs are not strongly correlatedwith either the subjects’ hearing levels or fre-quency resolution ability (Tyler et al., 1983;Moore and Peters, 1992), suggesting that as withnormally hearing subjects, temporal cues play animportant role in the discrimination process.

Frequency discrimination abilities in subjectswith auditory neuropathy/dys-synchrony are yetto be thoroughly investigated, but the data thathas been presented thus far suggests extremeperceptual deficits in this regard. Starr et al.(1991) measured “just noticeable differences”for pairs of 500-ms tone-burst stimuli at octavefrequencies from 250 Hz to 8 kHz in their 11-year-old AN/AD subject. Frequency discrimina-tion results in this case were consistently de-pressed, showing just noticeable differences ap-proximately 4.5 times higher than those ob-tained from 5 age-matched children across thetest frequency range.

Zeng et al. (2001a; 2001b; in press) alsofound impaired frequency discrimination abilityin 12 subjects with auditory neuropathy/dys-syn-chrony type hearing loss. In these studies, DLFswere obtained at octave frequencies (250 Hz-8kHz) using a three alternative forced-choice adap-

tive procedure. Results for the AN/AD cases wereconsiderably poorer than those obtained for acontrol group of normally hearing subjects. Thiswas particularly the case in the low-to-mid fre-quency range (≤ 2 kHz), where DLFs were aboutone order of magnitude worse than those of thecontrol group. A notable finding in the Zeng et al.subjects was that discrimination in the high-fre-quency range appeared to be less impaired, ap-proaching the normal range at the 8-kHz test fre-quency. This result pattern may reflect a disrup-tion of the low-frequency temporal discriminationprocesses in these AN/AD subjects, all of whomhad shown abnormal results on a range of tem-poral discrimination tasks (Zeng et al., 2001a:2001b; in press).

Frequency discrimination ability was similar-ly impaired in the auditory neuropathy/dys-syn-chrony children presented in Rance et al., 2004.In this study, the mean difference limen for 4-kHzpure tones was 4.5 times the normal value,whereas discrimination at 500 Hz averaged 11times poorer than that of the normally hearingcohort. Furthermore, a comparison of DLF ob-tained to FM tones (which do not offer phaselocking cues) and pure tones (which do) suggest-ed that AN/AD children are less able to usephase-locking cues than subjects with normalhearing, or their counterparts with sensorineuralhearing loss (Rance et al., 2004).

Frequency discrimination ability has alsobeen correlated with speech understanding insubjects with auditory neuropathy/dys-syn-chrony. For example, in the children assessed byRance et al. (2004), a strong relationship betweenopen set-word score and DLF was obtained for alltest conditions. As can be seen in Figure 11, thechildren the poorest frequency discriminationability typically presented with the most impairedspeech perception.

Disruption of Speech Perception in Auditory Neuropathy/Dys-synchrony Subjects

Strong correlations between fundamental pro-cessing deficits and speech perception difficul-ties have been found in many of the studies in-volving subjects with AN/AD type hearing loss.But what is it about specific temporal process-ing problems that can result in such extreme dif-ficulties with speech understanding? One possi-


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bility is that the disorder affects an individual’sability to cope with the dynamic nature ofspeech signals. To accurately discriminatephonemes in running speech, or even in individ-ual words, a listener must be able to perceivethe characteristic spectral shapes of phonemesand, in addition, be able to rapidly update thisperception to follow the flow of speech sounds.A listener must also be able to follow within-phoneme changes in spectral pattern that givecues to co-articulation. Auditory neuropathy/dys-synchrony subjects typically show normalspectral (frequency) resolution, and as such,there is reason to suppose that given a steadystimulus, they may be able to perceive the spec-tral shape adequately. However, their inabilityin many cases to perceive frequency and ampli-tude changes over time must lead to both asmearing of their spectral shape perception anda reduced ability to use amplitude envelope cuesin speech.

Summary and Future Developments

Research in the field of auditory neuropathy/dys-synchrony type hearing loss has been dominatedby discussion of the physiology underlying thecondition. Questions such as: What are the mech-anisms involved? Where is the site of lesion? andWhat should we call the disorder? have been ad-dressed in detail. Defining the functional effectsof this form of hearing loss and determining whatcan be done about them has received far less at-tention. Recent studies have, however, attempt-ed to address this situation, providing insightsinto the particular ways in which perception isdisrupted in affected patients and offering a basefor the development of AN/AD-specific manage-ment strategies.

The perceptual profiles of subjects with audi-tory neuropathy/dys-synchrony are quite differ-ent from those with sensorineural hearing loss.Where subjects in the latter group typically pre-


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Figure 11. Graph shows 500-Hz frequency discrimination limens for each subject plotted as a function of consonant-nucleus-consonant (CNC) phoneme score. SN, sensorineural; AN/AD, auditory neuropathy/dys-synchrony (Rance et al., 2004).

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sent with impaired frequency resolution and nor-mal temporal resolution, AN/AD patients usuallyshow normal frequency resolution and varyingdegrees of temporal disruption. The severity ofthis timing abnormality, which affects bothmonaural and binaural temporal processing aswell as the temporal aspects of frequency dis-crimination, appears to be strongly related tospeech perception performance.

The particular perceptual deficits caused byauditory neuropathy/dys-synchrony require dif-ferent management approaches. Cochlear im-plantation is currently the strategy of choice,with a high proportion of reported cases show-ing performance levels similar to their sen-sorineural peers. However, further research iswarranted to determine optimal signal process-ing strategies for AN/AD subjects. For example,consideration of stimulus pulse rates may be im-portant in some cases. The recent trend incochlear implant signal processing has been to-wards providing higher rates of stimulation to im-prove perception generally and specifically to aidin the encoding of temporal cues (Zeng et al., inpress). In some cases of auditory neuropathy/dys-synchrony, particularly those associated with ax-onal loss or demyelination, high presentationrates are more likely to produce adverse effectssuch as neural fatigue or conduction block(Stephanova and Daskalova, 2004). Such effectshave been suggested for two cases reported in theliterature thus far. The first was the case studypresented in Rance et al. (1999). The second wasa child described by Peterson et al. (2003) whoinitially performed poorly when programmedusing the ACE strategy (at a rate of 900 Hz perchannel) and subsequently improved when thepresentation rate was reduced to 720 Hz perchannel.

Despite concerns about the provision of hear-ing aids to patients with AN/AD-type hearingloss, there are a number of documented cases ofsignificant benefit with conventional amplifica-tion strategies. Consideration of the basic percep-tual problems associated with the condition maylead to refinements in aiding strategies and out-come improvements. For example, the psy-chophysical data indicates that detection of ampli-tude modulation is severely impaired in mostcases. Conventional hearing aids that use linearamplification do not enhance the acoustic differ-ences between sounds, and non-linear amplitude-compression circuits even reduce amplitude enve-

lope fluctuations in most circumstances (VanTasell, 1992). This has the overall effect of reduc-ing the level difference between low-level andhigh-level speech inputs and is obviously not de-sirable for listeners who already have difficulty per-ceiving amplitude fluctuations.

For subjects who do not derive benefit fromconventional hearing aids, the insights gainedfrom psychophysical investigations into AN/ADtype hearing loss may also provide a basis for thedevelopment of amplification devices that can betailored to emphasise the perceptual cues mostdisrupted by the neural transmission disorder.Further research using digital speech processingsystems for subjects with auditory neuropathy/dys-synchrony is required to determine howspeech perception might be optimized.

The use of frequency-transposition amplifica-tion strategies is one option that has been pro-posed to minimize the frequency discriminationdifficulties that affect many AN/AD subjects(Zeng et al., 2002; Zeng et al., in press). As dis-cussed previously, various studies have shownthat the discrimination of low-frequency signalsin affected subjects is disrupted to a greater de-gree than was observed for high-frequency stim-uli. These authors have suggested that either fil-tering out low-frequency sounds or transposingthe acoustic speech signal into the high-frequen-cy region may be beneficial in some cases. No for-mal results for this strategy have yet been pub-lished, but Zeng et al. (in press) indicate that theyhave successfully trialed a prototype device in “asmall number of AN subjects”.

Zeng et al. (2001b) and Zeng et al. (in press)have also suggested that temporal processingdifficulties in subjects with auditory neuro-pathy/dys-synchrony may be ameliorated by theuse of “envelope expansion algorithms”. The aimof such speech processing strategies would be toimprove speech perception in subjects with pooramplitude modulation detection ability by ex-panding the amplitude differences while main-taining the overall envelope shape and overalllevel in the speech signal, thereby making tem-poral envelope cues more salient. How success-ful such a strategy might be in an AN/AD subjectwith extreme amplitude modulation detectiondisruption is yet to be determined. As demon-strated in the Rance et al. (2004) and Zeng etal. (1999) findings, some affected individualsstruggle to perceive even 100% amplitude fluc-tuations. In such cases, gating-type strategies that


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preserve the peaks in the speech amplitude enve-lope while removing all other components in thesignal to produce amplitude fluctuations of effec-tively 100% could be useful. Such a processingstrategy could also conceivably enhance the sig-nal peaks by sharpening the transition from signalto no-signal periods.

Processing strategies that manipulate timingdifferences in the speech signal may also aid inthe perception of temporal cues in some subjectswith auditory neuropathy/dys-synchrony. Tallalet al. (1996) produced a processing algorithmthat combined a peak enhancement strategy sim-ilar to that described in the previous paragraphswith a temporal expansion algorithm that pro-longed the duration of the speech signal by 50%.The resulting fluent speech signal was consideredto have maintained its spectral integrity and nat-ural quality and when presented to a group ofchildren with temporal-processing-related lan-guage learning disorders, was easier to under-stand than unprocessed speech. Interestingly,Tallal et al. (1996) found that intensive trainingwith the acoustically modified signal subsequent-ly improved the ability of their subjects to processnatural speech, suggesting that habilitative pro-grams with specialized materials can improve per-ceptual abilities in some subjects with temporalprocessing deficits. The applicability of such pro-grams to subjects with auditory neuropathy/dys-synchrony type hearing loss is an area that needsto be investigated. To date no published studiesdescribe the use of modified training materialswith AN/AD subjects, although Zeng and Lui (inpress) have used modified stimuli to test speechperception. In this case, they used clear speechsentence materials that use slower presentationrates and enhanced phonemic differences andwere able to show a significant perceptual ad-vantage over nonmodified sentence materials.Hopefully further refinement of the perceptualprofiles for AN/AD patients will provide a frame-work for the development of individualized train-ing programs.

In summary, the findings for patients with au-ditory neuropathy/dys-synchrony published dur-ing the last 20 years provide a useful reminderthat whilst electroacoustic and evoked potentialresponses from the auditory pathways can offerpowerful diagnostic insights, these responses aresimply byproducts of complex physiologicprocesses and are not necessarily true indicatorsof perception. Attempts to characterize various

aspects of the AN/AD perceptual profile haveshown that results can be idiosyncratic despite acommon pattern of physiologic results. Whetherthe perceptual variability seen in this populationis due to different pathologic processes or differ-ent degrees of the same process is unclear. Whatis clear is that the management of affected pa-tients and their families needs to be flexible andtake into account individual differences.

References

Abdala C, Sininger YS, Starr A. (2000). Distortion prod-uct otoacoustic emission suppression in subjects withauditory neuropathy. Ear Hear 21:542-553.

Amatuzzi MG, Northrop C, Liberman C, et al. (2001).Selective inner hair cell loss in premature infants andcochlear pathological patterns from neonatal inten-sive care unit autopsies. Arch Otolaryngol Head NeckSurg 127:629-636.

Bamford JM, Wilson IM, Atkinson D, Bench J. (1981).Pure tone audiograms from hearing-impaired chil-dren. Predicting speech-hearing from the audiogram.Brit J Audiol 15(1):3-10.

Berli CI. (1999). Auditory neuropathy: Using OAEs andABRs from screening to management. Sem Hear21:307-315.

Berlin CI, Bordelon J, Hurley A, et al. (1997). Auto-immune inner ear disease: Basic science and audio-logical issues. In Berlin CI (ed): Neurotransmissionand Hearing Loss: Basic Science, Diagnosis andManagement. San Diego: Singular Publishing Group,137-146.

Berlin CI, Bordelon J, St. John P, et al. (1998). Reversingclick polarity may uncover auditory neuropathy in in-fants. Ear Hear 19:37-47.

Berlin CI, Hood LJ, Cecola RP, et al. (1993). Does Type Iafferent neuron dysfunction reveal itself through lackof efferent suppression? Hear Res 65:40-50.

Berlin CI, Hood LJ, Hurley MS, Wen H. (1996). Hearingaids: Only for hearing impaired patients with abnor-mal otoacoustic emissions. In Berlin CI (ed): HairCells and Hearing Aids. San Diego: SingularPublishing Group, 99-111.

Berlin CI, Hood LJ, Morlet T. (2000). The search for au-ditory neuropathy patients and connexin 26 patientsin schools for the deaf. ARO Abstract 2000 23:23-24.

Berlin CI, Hood LJ, Morlet T, et al. (2002). Auditory neu-ropathy/dys-synchrony: After diagnosis, then what?Sem Hear 23 (3):209-214.

Berlin CI, Hood LJ, Rose K. (2001). On renaming audi-tory neuropathy as auditory dys-synchrony. AudiolToday 13:15-17.


37

(11390)Rance 2/28/06 9:23 AM Page 37

Berlin CI, Hood LJ, Rose K, et al. (2003). Auditory neu-ropathy/dys-synchrony (AN/AD): Management andresults in 193 patients. Assoc Res Otol, Abstract#883.

Bilger RC, Nuetzel JM, Raninowitz WM, et al. (1984).Standardization of a test of speech perception innoise. J Sp Hear Res 21:32-48.

Billet TE, Thorne PR, Gavin JB. (1989). The nature andprogression of injury in the organ of Corti during is-chemia. Hear Res 41:189-198.

Bohne BA. (1976). Mechanisms of noise damage in theinner ear. In Henderson D, Hamernick RP, DosanjhDS, Mills JH (eds): Effects of Noise on Hearing. NewYork: Raven, 41-68.

Bonfils P, Avan P. (1992). Distortion-product otoacousticemissions: Values for clinical use. Arch OtolaryngolHead Neck Surg 111:1069-1076.

Bonfils P, Bertrand Y, Uziel A. (1988). Evoked otoa-coustic emissions: Normative data and presbyacusis.Audiol 21:27-35.

Boothroyd A. (1995). Speech perception tests and hear-ing impaired children. In Plant G, Spens KE (eds):Profound deafness and speech communication.London: Tyne Wear, 345-371.

Boothroyd A. (1997). Auditory capacity of hearing-im-paired children using hearing aids and cochlear im-plants: Issues of efficacy and assessment. ScandAudiol Suppl 41:17-25.

Borg E, Counter SA, Rosler G. (1984). Theories of mid-dle-ear muscle function. In Silman S (ed.): TheAcoustic Reflex: Basic Principles and ClinicalApplications. Orlando: Academic Press, 63-99.

Brookhouser PE, Gorga MP, Kelly WJ. (1990). Auditorybrainstem response results as predictors of behavioralauditory thresholds in severe and profound hearingimpairment. Laryngoscope 101:803-810.

Buss E, Labadie RF, Brown CJ, et al. (2002). Outcome ofcochlear implantation in pediatric auditory neuropa-thy. Otology Neurotol 21:328-332.

Bussoli TJ, Kelly A, Steel P. (1997). Localization of theBronx waltzer (bv) deafness gene to mouse chromo-some 5. Mamm Genome 11:714-717.

Butinar D, Zidar J, Leonardis L, et al. (1999). Hereditaryauditory, vestibular and motor neuropathy in aSlovenian Roma (Gypsy) kindred. Ann Neurol 41:36-44.

Cacace AT, Satya-Murti S, Gimes CT. (1983). Frequencyselectivity and temporal processing in Friedreich’sataxia. Ann Otol Rhinol Laryngol 91:276-280.

Cassandro E, Mosca F, Sequino L, et al. (1986).Otoneurological findings in Friedreich’s ataxia andother inherited neuropathies. Audiol 21:84-91.

Chance PF, Fischbeck KH. (1994). Molecular genetics ofCharcot-Marie-Tooth disease and related neu-ropathies. Hum Mol Genet 1:1503-1507.

Chisin R, Pearman M, Sohmer H. (1979). Cochlear andbrain stem responses in hearing loss following neona-tal hyperbilirubinemia. Ann Otol Rhinol Laryngol81:352-357.

Clopton BM, Silverman MS. (1978). Changes in latencyand duration of neural responding following devel-opmental auditory deprivation. Exp Brain Res 31:39-47.

Collet L, Levy V, Veuillet E. (1993). Click-evoked otoa-coustic emissions and hearing threshold in sen-sorineural hearing loss. Ear Hear 14(2):141-143.

Cone-Wesson B, Rance G, Sininger YS. (2001). Amplif-ication and rehabilitation strategies for patients withauditory neuropathy. In Sininger YA, Starr A, (eds),Auditory Neuropathy. San Diego: Singular Publish-ing, 233-250.

Cone-Wessonn B, Vohr BR, Sininger YS, et al. (2000).Identification of neonatal hearing impairment:Infants with hearing loss. Ear Hear 21:488-507.

Corley VM, Crabbe LS. (1999). Auditory neuropathy anda mitochondrial disorder in a child: Case study. J AmAcad Audiol 11:484-488.

Dallos P. (1973). The Auditory Periphery: Biophysics andPhysiology. New York: Academic Press.

Dallos P, Cheatham MA. (1976). Production of cochlearpotentials by inner and outer hair cells. J Acoust SocAm 61:510-512.

Davis H. (1983). An active process in cochlear mechan-ics. Hear Res 1:79-90.

Davis H, Hirsh SK. (1979). The audiometric utility of thebrain stem response to low frequency sounds. Audiol11:181-195.

Deltenre P, Mansbach AL, Bozet C, et al. (1999).Auditory neuropathy with preserved cochlear micro-phonics and secondary loss of otoacoustic emissions.Audiol 38(4):187-195.

Deltenre P, Mansbach AL, Bozet C, et al. (1997).Auditory neuropathy: A report on three cases withearly onsets and major neonatal illnesses. Electro-enceph Clin Neurophys 101:17-22.

Dowell RC, Dettman SJ, Blamey PJ, et al. (2002). Speechperception in children using cochlear implants:Prediction of long-term outcomes. Cochlear ImplantInt 3(1):1-18.

Doyle KJ, Sininger YS, Starr A. (1998). Auditory neu-ropathy in childhood. Laryngoscope 101:1374-1377.

Dreschler WA, Plomp R. (1980). Relations between psy-chophysical data and speech perception for hearing-impaired subjects. I. J Acoust Soc Am 61:1608-1615.

Dunkley C, Farnsworth A, Mason S, et al. (2003).Screening and follow up assessment in three cases ofauditory neuropathy. Arch Dis Child 81:25-26.

Durieux-Smith A, Picton TW, Bernard P, et al. (1991).Prognostic validity of brainstem electric response au-diometry in infants of a neonatal intensive care unit.Audiol 31:249-265.


38

(11390)Rance 2/28/06 9:23 AM Page 38

Dynes SBC, Delgutte B. (1992). Phase-locking of audito-ry-nerve discharges to sinusoidal electric stimulationof the cochlea. Hear Res 51:79-90.

Eggermont JJ. (1976). Electrocochleography. In KeidelWD, Neff WD (eds): Handbook of Sensory PhysiologyVol. V/3 Auditory System. Berlin: Springer Verlag,625-705.

Evans E, Harrison R. (1976). Correlation between outerhair cell damage and deterioration of cochlear nervetuning properties in the guinea pig. J Physiol 251:43-44.

Franck KH, Rainey DM, Montoya LA et al. (2002).Developing a multidisciplinary clinical protocol tomanage pediatric patients with auditory neuropathy.Sem Hear 23(3):225-237.

Freyman RL, Nelson DA. (1986). Frequency discrimina-tion as a function of tonal duration and excitation-pattern slopes in normal and hearing-impaired lis-teners. J Acoust Soc Am 71:1034-1044.

Freyman RL, Nelson DA. (1991). Frequency discrimina-tion as a function of signal frequency and level innormal-hearing and hearing-impaired listeners. J Speech Hear Res 31:1371-1386.

Glasberg BR, Moore BCJ. (1989). Psychoacoustic abili-ties of subjects with unilateral and bilateral cochlearimpairments and their relationship to the ability toperceive speech. Scand Audiol Suppl 31:1-25.

Glasberg BR, Moore BCJ. (1990). Derivation of auditoryfilter shapes from notched-noise data. Hear Res41:103-138.

Gordon-Salant S, Fitzgibbons PJ. (1993). Temporal fac-tors and speech recognition performance in youngand elderly listeners. J Speech Hear Res 31:1276-1285.

Gorga MP, Neely ST, Ohlrich B. (1997). From laboratoryto clinic: A large scale study of distortion productotoacoustic emissions in ears with normal hearingand ears with hearing loss. Ear Hear 11:440-455.

Gorga MP, Stelmachowicz PG, Barlow SM, et al. (1995).Case of recurrent, sudden sensorineural hearing lossin a child. J Am Acad Audiol 1:163-172.

Gorga MP, Worthington DW, Reiland JK, et al. (1985).Some comparisons between auditory brainstem re-sponse threshold, latencies, and the pure-tone au-diogram. Ear Hear 1:105-112.

Gravel JS, Stapells DR. (1993). Behavioral, electrophys-iologic, and otoacoustic measures from a child withauditory processing dysfunction: Case report. J AmAcad Audiol 1:412-419.

Gstoettner W, Plenk H Jr, Franz P, et al. (1997).Cochlear implant deep insertion: Extent of insertiontrauma. Acta Otolaryngol (Stockh) 111:274-277.

Harris FP, Probst R. (2002). Exploring cochlear statuswith otoacoustic emissions. The potential for newclinical applications. In MS Robinette TJ Glattke(eds.): Otoacoustic Emissions: Clinical Applications.New York: Thieme, 213-242.

Harrison RV. (1998). An animal model of auditory neu-ropathy. Ear Hear 11:355-361.

Hashimoto I, Ishiyama Y, Yoshimoto T, et al. (1981).Brainstem auditory evoked potentials recorded di-rectly from the human brainstem and thalamus.Brain 101:841-859.

Henry BA, McKay CM, McDermott HJ, et al. (2000). Therelationship between speech perception and elec-trode discrimination in cochlear implantees. J AcoustSoc Am 101:1269-1280.

Hood LJ. (1998). Auditory neuropathy: What is it andwhat can we do about it? Hear Journal 51(8):10-18.

Hood LJ. (1999). A review of objective methods of eval-uating neural pathways. Laryngoscope 101:1745-1748.

Hood LJ, Berlin C, Hurley A. Wen H. (1996). Suppressionof otoacoustic emissions in normal hearing individu-als. In Berlin C (ed): Hair Cells and Hearing Aids.San Diego, Singular Publishing Group, 57-72.

Houston DM, Ying EA, Pisoni DB, et al. (2004).Development of pre-word-learning skills in infantswith cochlear implants. Volta Rev 103(4):303-326.

Hung KL. (1989). Auditory brainstem responses in pa-tients with neonatal hyperbilirubinemia and biliru-bin encephalopathy. Brain Dev 11:297-301.

Hyde ML, Riko K, Malizia K. (1990). Audiometric accu-racy of the click ABR in infants at risk for hearingloss. J Am Acad Audiol 1:59-74.

Jabbari B, Schwartz DM, MacNeil DM, et al. (1983).Early abnormalities of brainstem auditory evoked po-tentials in Friedreich’s ataxia: Evidence of primarybrainstem dysfunction. Neurology 31:1071-1074.

Javel E. (1986). Basic response properties of auditorynerve fibers. In RA Altschuler, RP Hoffman. (eds.).Neurobiology of Hearing: The Cochlea. New York:Raven Press, 213-245.

Javel E, Shepherd RK. (2000). Electrical stimulation ofthe auditory nerve. III. Response initiation sites andtemporal fine structure. Hear Res 140:45-76.

Jerger JF, Ali A, Fong K, et al. (1992). Otoacoustic emis-sions, audiometric sensitivity loss, and speech un-derstanding: A case study. J Am Acad Audiol 1:283-286.

Kaga K, Nakamura M, Shinogami M, et al. (1996).Auditory nerve disease of both ears revealed by au-ditory brainstem responses, electrocochleographyand otoacoustic emissions. Scand Audiol 21:233-238.

Kapadia S, Lutman M. (1997). Are normal hearingthresholds a sufficient condition for click-evokedotoacoustic emissions? J Acoust Soc Am 101:3566-3576.

Katona G, Buki B, Farkas Z, et al. (1993). Transitoryevoked otoacoustic emission. (TEOAE) in a child withprofound hearing loss. Int J Ped Otorhinolaryngol21:263-267.


39

(11390)Rance 2/28/06 9:23 AM Page 39

Kemp DT. (1978). Stimulated acoustic emission from thehuman auditory system. J Acoust Soc Am 61:1386-1391.

Kileny PR, Robertson CMT. (1985). Neurological aspectsof infant hearing assessment. J Otolaryngol 11:34-39.

Kitzes LM, Semple MN. (1985). Effects of neonatal uni-lateral ablation: Single unit responses in the inferiorcolliculus. J Neurophysiol 51:1483-1500.

Konradsson KS. (1996). Bilaterally presented otoacousticemissions in four children with profound idiopathicunilateral hearing loss. Audiol 31:217-227.

Kovach MJ, Lin JP, Boyajiev S. (1999). A unique pointmutation in the PMP22 gene is associated withCharcot-Marie-Tooth disease and deafness. Am JHum Genet 61:1580-1593.

Kraus N, Bradlow AR, Cheatham J, et al. (2000).Consequences of neural asynchrony: A case of audi-tory neuropathy. J Assoc Res in Otolaryngol 1(1):33-45.

Kraus N, McGee TJ, Carrell TD, et al. (1996). Auditoryneurophysiologic responses and discriminationdeficits in children with learning problems. Science271:971-973.

Kraus NA, Ozdamar O, Stein L, et al. (1984). Absent au-ditory brainstem response: Peripheral hearing loss orbrainstem dysfunction? Laryngoscope 91:400-406.

Kuwabara S, Nakajima Y, Hattori T, et al. (1999).Activity-dependent excitability changes in chronic in-flammatory demyelinating polyneuropathy: A mi-croneurographic study. Muscle Nerve 21:899-904.

Lee JSM, McPherson B, Yuen KCP, et al. (2001).Screening for auditory neuropathy in a school forhearing impaired children. Int J PaedOtorhinolaryngol 61:39-46.

Lenhardt ML. (1981). Childhood auditory processing dis-order with brainstem evoked response verification.Arch Otolaryngol 101:623-625.

Lenoir M, Pujol R. (1984). Age-related structural inves-tigation of the Bronx Waltzer mutant mouse cochlea:Scanning and transmission electron microscopy. HearRes 11:1123-1134.

Leonardis L, Popovic M, Timmerman V, et al. (2000).Hereditary motor and sensory neuropathy associat-ed with auditory neuropathy in a Gypsy family. Eur JPhysiol 431:208-210.

Levine RA, Gardner JC, Fullerton BC, et al. (1993).Effects of multiple sclerosis brainstem lesions onsound lateralization and brainstem auditory evokedpotentials. Hear Res 61:73-88.

Levitt H, McGarr N. (1988). Speech and language devel-opment in hearing impaired children. In FH Bess(ed): Hearing Impairment in Children. Parkton, MD:York Press, 375-388.

Liberman MC, Chesney CP Kujawa SG. (1997). Effects ofselective inner hair cell loss on DPOAE and CAP in

carboplatin-treated chinchillas. Aud Neuro 1:255-268.

Liberman MC, Dodds LW, Learson DA. (1986). Structure-function correlation in noise damaged ears: A lightand electron-microscopic study. In Salvi RJ,Henderson D, Hamernik RP, et al (eds): Basic andApplied Aspects of Noise-Induced Hearing Loss. NewYork: Plenum, 163-176.

Licklider JCR. (1948). The influence of interaural phaserelation upon the masking of speech by white noise.J Acoust Soc Am 21:150-159.

Lonsbury-Martin BL, Harris FP, Stagner BB, et al. (1990).Distortion product emissions in humans: I. Basicproperties in normally hearing subjects. Ann OtolRhino Laryngol 141:3-14.

MacArdle B, Hazan V, Prasher D. (1999). Speech patternaudiometry in hearing impaired children. Brit JAudiol 33(6):383-393.

Macrae JH. (1991). Permanent threshold shift associatedwith overamplification by hearing aids. J Sp Hear Res31:403-414.

Macrae JH. (1995). Temporary and permanent thresh-old shift caused by hearing aid use. J Sp Hear Res31:949-959.

Madden C, Rutter M, Hilbert L, et al. (2002). Clinicaland audiological features in auditory neuropathy.Arch Otolaryngol Head Neck Surg 121:1026-1030.

Markides A. (1986). Age at fitting of hearing aids andspeech intelligibility. Brit J Audiol 21:165-167.

Marsh RR. (2002). Is it auditory dys-synchrony?Comment on “On renaming auditory neuropathy asauditory dys-synchrony”. Audiol Today 14(3):36-37.

Mason JC, De Michele A, Stevens C, et al. (2003).Cochlear implantation in patients with auditory neu-ropathy of varied etiologies. Laryngoscope113(1):45-49.

McDonald WI, Sears TA. (1970). The effects of experi-mental demyelination on conduction in the centralnervous system. Brain 91:583-598.

Melcher JR, Knudson IM, Fullerton BC, et al. (1996a).Generators of the brainstem auditory evoked poten-tial in cat. I. An experimental approach to their iden-tification. Hear Res 93:1-27.

Melcher JR, Guinan JJ Jr, Knudson IM, et al. (1996b).Generators of the brainstem auditory evoked poten-tial in the cat. II. Correlating lesion sites with wave-form changes. Hear Res 91:28-51.

Melcher JR, Kiang NY. (1996c). Generators of the brain-stem auditory evoked potential in the cat. III:Identified cell populations. Hear Res 91:52-71.

Michalewski HJ, Prasher DK, Starr A. (1986). Latencyvariability and temporal interrelationships of the au-ditory event-related potentials. (N1, P2, N2, and P3)in normal subjects. Electroenceph Clin Neurophys61:59-71.


40

(11390)Rance 2/28/06 9:23 AM Page 40

Micheyl C, Moore BCJ, Carlyon RP. (1998). The role of ex-citation-pattern cues and temporal cues in the frequen-cy and modulation-rate discrimination of amplitude-modulated tones. J Acoust Soc Am 101:1039-1050.

Miyamoto RT, Iler Kirk K, Renshaw J, et al. (1999).Cochlear implantation in auditory neuropathy.Laryngoscope 101:181-185.

Møeller MP. (2000). Early intervention and language de-velopment in children who are deaf and hard of hear-ing. Pediatrics 106(3):1-21.

Møller AR Janetta PJ. (1981). Compound action poten-tials recorded intercranially from the auditory nervein man. J Exp Neurol 71:862-874.

Moore BCJ. (1973a). Frequency difference limens fornarrow bands of noise. J Acoust Soc Am 51:888-896.

Moore BCJ. (1973b). Frequency difference limens forshort-duration tones. J Acoust Soc Am 51:610-619.

Moore BCJ. (1995). Speech perception in people withcochlear damage. Perceptual Consequences ofCochlear Damage. Oxford: Oxford University Press,pp 147-172.

Moore BCJ. (1996). Perceptual consequences of cochlearhearing loss and their implications for the design ofhearing aids. Ear Hear 11:133-160.

Moore BCJ. (1997). Psychology of Hearing. AcademicPress, San Diego.

Moore BCJ, Glasberg BR. (1987). Formulae describingfrequency selectivity as a function of frequency andlevel and their use in calculating excitation patterns.Hear Res 21:209-225.

Moore BCJ, Peters RW. (1992). Pitch discrimination andphase sensitivity in young and elderly subjects andits relationship to frequency selectivity. J Acoust SocAm 91:2881-2893.

Nadol JB. (2001). Primary Cochlear Neuronal Degener-ation. In Sininger YS, Starr A (eds), AuditoryNeuropathy. San Diego: Singular Publishing, 99-140.

Nakamura H, Takada S, Shimabuku R, et al. (1985).Auditory nerve and brainstem responses in new-borninfants with hyperbilirubinemia. Ped 71:703-708.

Norton SJ, Ferguson R, Mascher K. (1989). Evoked otoa-coustic emissions and extratympanic cochlear micro-phonics recorded from human ears. Abstracts of theTwelfth Midwinter Research Meeting of theAssociation for Research in Otolaryngology, 227 (A).

O’Leary MJ, Fayad J, House WF, et al. (1991). Electrodeinsertion trauma in cochlear implantation. Ann OtolRhinol Laryngol 100(9):695-699.

Ouvrier R. (1996). Correlation between the histopatho-logic, genotypic, and phenotypic features of heredi-tary peripheral neuropathies in childhood. J ChildNeurol 11:133-146.

Park MS, Lee JH. (1998). Diagnostic potential of distor-tion product otoacoustic emissions in severe or pro-found sensorineural hearing loss. Acta Otolaryngol.(Stockh) 111:496-500.

Parkins CW. (1989). Temporal response patterns of au-ditory-nerve fibers to electrical stimulation in deaf-ened squirrel monkeys. Hear Res 41:137-168.

Pender MP, Sears TA. (1984) The pathophysiology ofacute experimental allergic encephalomyelitis in therabbit. Brain 101:699-726.

Peterson A, Shallop J, Driscoll C, et al. (2003). Outcomesof cochlear implantation in children with auditoryneuropathy. J Am Acad Audiol 14(4):188-201.

Phillips D, Hall S. (1990). Response timing constraintson the cortical representation of sound time struc-ture. J Acoust Soc Am 81:1403-1411.

Picton TW, Durieux-Smith A, Champagne SC, et al.(1998). Objective evaluation of aided thresholdsusing auditory steady-state responses. J Am AcadAudiol 1:315-331.

Picton TW, Durieux-Smith A, Moran L. (1994).Recording auditory brainstem responses from infants.Int J Paed Otorhinolaryngol 21:93-110.

Prieve BA, Gorga MP, Neely ST. (1991). Otoacousticemissions in an adult with severe hearing loss. J SpHear Res 31:379-385.

Psarommatis IM, Tsakanikos MD, Kontorgianni AD, et al.(1997). Profound hearing loss and presence of click-evoked otoacoustic emissions in the neonate: A re-port of two cases. Int J Ped Otorhinolaryngol 31:237-243.

Ramkalawan TM, Davis AC. (1992). The effects of hear-ing loss and age of intervention on some languagemetrics in young hearing impaired children. Brit JAudiol 21:97-107.

Rance G, Beer DE, Cone-Wesson B, et al. (1999). Clinicalfindings for a group of infants and young childrenwith auditory neuropathy. Ear Hear 21:238-252.

Rance G, Cone-Wesson B, Wunderlich J, et al. (2002).Speech perception and cortical event related poten-tials in children with auditory neuropathy. Ear Hear21:239-253.

Rance G, Dowell RC, Rickards FW, et al. (1998). Steady-state evoked potential and behavioural hearingthresholds in a group of children with absent click-evoked auditory brainstem response. Ear Hear 11:48-61.

Rance G, McKay C, Grayden D. (2004). Perceptual char-acterisation of children with auditory neuropathy.Ear Hear 21:34-46.

Rance G, Roper R, Symonds L, et al. (in press). Hearingthreshold estimation in infants using auditory steadystate responses. J Am Acad Audiol.

Rapin I, Gavel J. (2003). “Auditory neuropathy”:Physiologic and pathologic evidence calls for morediagnostic specificity. Int J Ped Otorhinolaryngol61:707-728.

Rasminsky M, Sears TA. (1972). Internodal conductionin undissected demyelinated nerve fibers. J Physiol221:323-350.


41

(11390)Rance 2/28/06 9:23 AM Page 41

Ryan A, Dallos P. (1975). Absence of cochlear outer haircells: Effect on behavioural auditory thresholds.Nature 251:44-46.

Salvi RJ ,Wang J, Ding D, et al. (1999). Auditory depri-vation of the central auditory system resulting fromselective inner hair cell loss: Animal model of audi-tory neuropathy. Scand Audiol Supp 51:1-12.

Satya-Murti S, Cacace AT, Hanson P. (1980). Auditorydysfunction in Friedreich’s Ataxia: Result of spiralganglion degeneration. Neurol 31:1047-1053.

Schrott A, Stephan K, Spoendlin H. (1989). Hearing withselective inner hair cell loss. Hear Res 41:213-220.

Seewald RC, Cornelisse LE, Ramji KV, et al. (1997). ASoftware Implementation of the Desired SensationLevel (DSL [i/o]) Method for Fitting Linear Gain andWide-dynamic Range Compression HearingInstruments. London, ON: Hearing Health CareResearch Unit.

Sek A, Moore BCJ. (1995). Frequency discrimination as afunction of frequency, measured in several ways. J Acoust Soc Am 91:2479-2486.

Sellick PM, Patuzzi R, Johnstone BM. (1982). Measure-ment of basilar membrane motion in the guinea pigusing the Mossbauer technique. J Acoust Soc Am71:131-141.

Shallop JK. (2002). Auditory neuropathy/dys-synchronyin adults and children. Sem Hear 23(3):215-223.

Shallop JK, Peterson A, Facer GW, et al. (2001). Cochlearimplants in five cases of auditory neuropathy:Postoperative findings and progress. Laryngoscope111:555-562.

Shapiro SM. (2003). Bilirubin toxicity in the developingnervous system. Ped Neurol 29(5):410-421.

Shirane M, Harrison RV. (1987). The effects of hypoxiaon sensory cells of the cochlea. Scanning Microscopy1:1175-1183.

Simmons JL, Beauchaine KL. (2000). Auditory neuropa-thy: Case study with hyperbilirubinemia. J Am AcadAudiol 11:337-347.

Simmons BF. (1964). Perceptual theories of middle earmuscle function. Ann Otol Rhino Laryngol 71:724-740.

Sininger YS, Hood LJ, Starr A, et al. (1995). Hearing lossdue to auditory neuropathy. Audiol Today 1:10-13.

Sininger YS, Oba S. (2001). Patients with auditory neu-ropathy: Who are they and what can they hear? InSininger YS, Starr A (eds): Auditory Neuropathy. SanDiego: Singular Publishing, 15-36.

Sohmer H, Pratt H. (1976). Recording of the cochlearmicrophonic potential with surface electrodes.Electroencephalogr Clin Neurophysiol 41:253-260.

Spoendlin H. (1974). Optic cochleovestibular degera-tions in heriditary ataxias. II. Temporal bone pathol-ogy in two cases of Friedreich’s ataxia with vestibulo-cochlear disorders. Brain 91:41-48.

Squires KC, Hecox KE. (1983). Electrophysiological eval-uation of higher level auditory processing. Sem Hear4(4):415-432.

Stapells DR, Gravel JS, Martin BA. (1995). Thresholdsfor auditory brainstem responses to tones in notchednoise from infants and young children with normalhearing or sensorineural hearing loss. Ear Hear11:361-371.

Stapells DR, Oates P. (1997). Estimation of the pure-toneaudiogram by the auditory brainstem response: A re-view. Audiol Neuro-Otol 2(5):257-280.

Stapells DR, Picton TW, Durieux-Smith A. (1994).Electrophysiologic measures of frequency specific au-ditory function. In Jacobsen JT (ed), Principles andapplications in auditory evoked potentials. NeedhamHeights, MA: Allyn Bacon, 251-283.

Starr A, McPherson D, Patterson J, et al. (1991). Absenceof both auditory evoked potentials and auditory per-cepts dependent on timing cues. Brain 111:1157-1180.

Starr A, Michalewski HJ, Zeng FG, et al. (2003).Pathology and physiology of auditory neuropathywith a novel mutation in the MPZ gene. Brain121:1604-1619.

Starr A, Picton TW, Kim R. (2001b). Pathophysiology ofauditory neuropathy. In Sininger YS, Starr A (eds),Auditory Neuropathy. San Diego: SingularPublishing, 67-82.

Starr A, Picton TW, Sininger YS, et al. (1996). Auditoryneuropathy. Brain 119(3):741-753.

Starr A, Sininger YS, Nguyen T, et al. (2001a). Cochlearreceptor. (microphonic, summating potentials, andotoacoustic emissions) and auditory pathway. (audi-tory brainstem potentials) activity in auditory neu-ropathy. Ear Hear 21:91-99.

Starr A, Sininger YS, Pratt H. (2000). The varieties of au-ditory neuropathy. J Basic Clin Physiol Pharmacol11(3):215-230.

Starr A, Sininger YS, Winter M, et al. (1998). Transientdeafness due to temperature-sensitive auditory neu-ropathy. Ear Hear 11:169-179.

Stein L, Tremblay K, Pasternak J, et al. (1996).Brainstem abnormalities in neonates with normalotoacoustic emissions. Sem Hear 17(2):197-213.

Stelmachowitz PG, Jesteadt W, Gorga MP, et al. (1985).Speech perception ability and psychophysical tuningcurves in hearing-impaired listeners. J Acoust Soc Am71:621-627.

Stephanova DI, Daskalova M. (2004). Excitability prop-erties of normal and demyelinated human motornerve axons. Electromyogr Clin Neurophysiol41:147-152.

Stockard JE, Stockard JJ, Coen RW. (1983). Auditorybrainstem response variability in infants. Ear Hear1:11-23.


42

(11390)Rance 2/28/06 9:23 AM Page 42

Stockard JE, Stockard JJ, Wesmoreland BF, et al. (1979).Brainstem auditory evoked responses: normal varia-tion as a function of stimulus and subject character-istics. Arch Neurol 31:823-831.

Tallal P. (1981). Language disabilities in children:Perceptual correlates. Int J Ped Otorhinolaryngol 1:1-3.

Tallal P, Miller SL, Bedi G, et al. (1996). Language com-prehension in language learning impaired childrenimproved with acoustically modified speech. Science271:81-84.

Tan KL, Skurr BA, Yip YY. (1992). Phototherapy and thebrainstem auditory evoked response in neonatal hy-perbilirubinemia. J Ped 121:306-308.

Takeno S, Harrison RV, Ibrahim D, et al. (1994).Cochlear function after selective inner hair cell de-generation induced by carboplatin. Hear Res 71:93-102.

Tang TPY, McPherson B, Yuen KCP, et al. (2004).Auditory neuropathy/auditory dys-synchrony inschool children with hearing loss: Frequency of oc-curance. Int J Ped Otorhinolaryngol 61:175-183.

Trautwein P, Shallop J, Fabry L, et al. (2001). Cochlearimplantation of patients with auditory neuropathy.In Sininger YS, Starr A (eds): Auditory Neuropathy.San Diego: Singular Publishing, 203-232.

Trautwein P, Sininger YS, Nelson R. (2000). Cochlearimplantation of auditory neuropathy. J Am AcadAudiol 11:309-315.

Tyler RS. (1993). Speech perception by children. In:Tyler, RS (ed) Cochlear Implants: AudiologicalFoundations. San Diego: Singular, 191-256.

Tyler RS, Wood EJ, Fernandes MA. (1983). Frequencyresolution and discrimination of constant and dy-namic tones in normal and hearing-impaired listen-ers. J Acoust Soc Am 71:1190-1199.

Van Tasell DJ, Greenfield DG, Logemann JJ, et al.(1992). Temporal cues for consonant recognition:Training, talker generalization, and use in evaluationof cochlear implants. J Acoust Soc Am 91:1247-1257.

Varga R, Kelley PM, Keats BJ, et al. (2003). Non-syn-dromic recessive auditory neuropathy is the result ofmutations in the otoferlin. (OTOF) gene. J MedGenet 40:45-50.

Viemeister NF, Plack CJ. (1993). Time analysis. In YostWA, Popper N, Fay RR (eds): Human Psychophysics.New-York: Springer-Verlag.

Vohr BR, Carty LM, Moore PE, et al. (1998). The RhodeIsland hearing assessment program: Experience withstatewide hearing screening. (1993–1996). J Ped133(3):353-357.

Wake M, Anderson J, Takeno S, et al. (1996). Oto-acoustic emission amplification after inner hair celldamage. Acta Otolaryngol (Stockh) 111:374-381.

Walden BE. (1984). Speech perception of the hearing im-paired. In Jerger J (ed): Hearing Disorders in Adults.San Diego: College-Hill Press, pp 263-309.

Wang J, Powers NL, Hofstetter P, et al. (1997). Effects ofselective inner hair cell loss on auditory nerve fiberthreshold, tuning and spontaneous and driven dis-charge rate. Hear Res 101:67-82.

Weiss TF, Rose C. (1988). Stages of degradation of tim-ing information in the cochlea: A comparison of hair-cell and nerve-fiber responses in the alligator lizard.Hear Res 31:167-174.

Widen JE, Ferraro JA, Trouba SE. (1995). Progressiveneural impairment: Case report. J Am Acad Audiol1:217-224.

Worthington DW, Peters J. (1980). Quantifiable hearingand no ABR: Paradox or error? Ear Hear 1:281-285.

Wright BA, Lombardino LJ, King WM, et al. (1997).Deficits in auditory temporal and spectral resolutionin language-impaired children. Nature 381:176-178.

Yates GK, Johnstone BM, Patuzzi RB, et al. (1992).Mechanical preprocessing in the mammalian cochlea.Trends Neurosci 11:57-61.

Yellin MW, Jerger J, Fifer RC. (1989). Norms for dispro-portionate loss in speech intelligibility. Ear Hear10(4):231-234.

Yoshinaga-Itano C, Sedley AL, Coulter DK, et al. (1998).Language of early- and later-identified children withhearing loss. Ped 102(5):1161-1171.

Zeng FG, Kong YY, Michalewski HJ, et al (in press).Perceptual consequences of disrupted auditory nerveactivity. J Neurophysiol.

Zeng FG, Liu S (in press). Clear speech perception in au-ditory neuropathy subjects. J Sp Hear Res.

Zeng FG, Oba S, Garde S, et al. (1999). Temporal andspeech processing deficits in auditory neuropathy.Neuroreport 10(16):3429-3435.

Zeng FG, Oba S, Garde S, et al. (2001a). Psychoacousticsand speech perception in auditory neuropathy. InSininger YS, Starr A (eds.): Auditory Neuropathy.San Diego: Singular Publishing, 141-164.

Zeng FG, Oba S, Starr A. (2001b). Supra threshold pro-cessing deficits due to desynchronous neural activi-ties in auditory neuropathy. In Breebaart DJ,Houstma AJM, Kohlrausch A, et al. (eds): Physio-logical and Psychophysical Bases of AuditoryFunction. Maastricht, Netherlands: Shaker PublishingBV, 365-372.

Zeng FG, Sheng L, Kong YY, et al. (2002). Treatment ofauditory neuropathy: Cochlear implants or hearingaids. International Hearing Aid Research Conference.(IHCON) presentation. Lake Tahoe, August, 2002.


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