Manifestations of Cochlear Events in the Auditory Brain-stem Response and Its Clinical Applications

3.21 Manifestations of Cochlear Events in the Auditory Brain-stem Response and Its Clinical Applications J D Durrant, University of Pittsburgh, Pittsburgh, PA, USA ª 2008 Elsevier Inc. All rights reserved.

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Glossary acoustic click Sound stimulus – a brief transient – that is composed of most audible frequencies, produced by exciting an earphone with a brief direct-current pulse (e.g., 100 ms duration for a bandwidth of nearly 10 kHz). auditory brainstem response (ABR) Electrical potential derived via computer averaging to extract a sensory (auditory) signal evoked by the applied (sound) stimulus, generated by the auditory nerve and brainstem auditory pathways (namely, pontine level). cochlear mechanics Sum of hydromechanical events of the cochlea (auditory portion of the inner ear) involved in the transduction of sound. frequency-following response (FFR) Variation of the auditory brainstem response elicited by tone bursts and whose waveform follows the waveform of the stimulus. frequency-specific Characteristic of sound stimuli whose energy is largely concentrated around a particular frequency. latency Time delay between the onset of a stimulus and the onset of a given wave of a stimulusevoked potential. masking A stimulus used to obscure/eliminate a sensory response evoked by another (probe or target) stimulus.

place encoding mechanism Effect of cochlear mechanics such that the displacement maxima occur at a place specific to the stimulus frequency and wherein high-frequency maxima tend to occur toward the base, and low-frequency maxima toward the apex. threshold In sensory physiology and psychology, the concept that there is a stimulus magnitude that is just adequate to reliably excite a response (e.g., action potential, sensory-evoked potentials like the auditory brainstem response, behavioral response such as pushing a button, etc.). tone burst Sinusoidal pulse, formed by abruptly turning on and off a sine wave. traveling wave The wavelike motion peculiar to the cochlea by which sound energy is efficiently coupled to the basilar membrane and travels along this structure from the cochlear base toward the apex, reaching a maximum at a place according to the sound’s frequency. vertex (Cz) Location on the scalp at the top of the head, frequently used as a recording site for sensory-evoked potentials like the auditory brainstem response. whole-nerve action potential (AP) Compound action potential of the auditory (VIII cranial) nerve in response to sound stimulation, thereby a population response of first-order auditory neurons.

The auditory brainstem response (ABR) is a compound neural potential recorded from the scalp. Obtaining the ABR requires computer signal averaging to extract this 0.5 ¼ mV signal from background electrical noise. The ABR comprises a series of waves falling within the first approximately 10 ms of bioelectrically generated response to the onset of sound

(Figure 1(a)), representing in turn the initial stages of activation of the auditory nervous system. This signal has found extensive clinical use via four major applications (see reviews by Hall, III, J. W., 1991; Durrant, J. D. and Ferraro, J. A., 1999; Goldstein, R. and Aldrich, W. M., 1999). The first is neurodiagnostic testing wherein the waveform and/or timing of the 359

360 Manifestations of Cochlear Events in the Auditory Brain-stem Response

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Latency (ms) Figure 1 (a) The auditory brainstem response (ABR) is recorded between electrodes placed on or near the vertex (Cz) of the head and the ear (earlobe, mastoid, ear canal, or deeper). Enhancement of the diminutive wave I recorded at the scalp’s surface can be accomplished by combining ABR recording with electrocochleography (ECochG), using an electrode deep in the ear canal or on the tympanic membrane (TM). Here, even the cochlear summating potential is detected, along with a more prominent N1 component of the whole-nerve action potential (AP). A third electrode, at nasion, completes the electrode montage for electrical grounding and safety of the subject. The stimulus (stim) derives from exciting the earphone with a brief direct-current pulse, delivering energy essentially at all frequencies shaped by the transducer’s frequency response. The ABR component waves are labeled by Roman numerals (according to Jewett, D. L. and Williston, J. S., 1971). (b) A strictly surface recording method (vertex to mastoid) was used to record ABRs in response to sinusoidal pulses of various frequencies, as indicated. The dashed line traces the latency shift associated with effectively shifting the place of stimulation from near the cochlear base (high frequencies) to near the apex (low frequencies). (c) Tone-burst responses were aligned according to wave-V latency and summated to produce the stacked ABR (panel: stacked TB (tone burst)), reducing the untoward effects of traveling-wave dispersion (panel b) and dramatically improving ABR magnitude compared to that elicited by the broadband, unfiltered click (panel: unmarked click).

ABR waves are evaluated to detect neural blockage from space-occupying lesions, demyelinating diseases, etc. The second is newborn hearing screening which takes advantage of the strong correlation between ABR detection levels and behavioral hearing thresholds, plus the ability to record ABRs in sleeping/sedated patients, even premature infants. The third application is hearing threshold estimation which combines the advantages of ABR testing for newborn screening with the use of frequency-specific stimuli to estimate the audiogram (the pattern of hearing loss across frequency) in young pediatric, mentally handicapped, and other difficult-to-test subjects. The last application, intraoperative monitoring, capitalizes on most of the features above to

provide a test keenly sensitive to conditions adverse to neural conduction in peripheral nerve and pontine-brainstem structures; monitoring the status of the ABR can help to minimize damage from neurosurgical procedures. It may be asked, ‘‘What is such a topic as the ABR doing as follow-up to a chapter on cochlear function?’’ The short answer is that the ABR is actually a misnomer; the first two waves of the ABR derive from responses of the VIII nerve. Generally recorded between metal electrodes placed near the top of the head (vertex) and the stimulated ear (Figure 1(a)), the first barrage of electrical activity registered is nothing more than the N1 component of the whole-nerve action potential (AP). Indeed, using an

Manifestations of Cochlear Events in the Auditory Brain-stem Response

electrode deep in the ear canal or on the tympanic membrane enhances the AP (Figure 1(a)) and may reveal stimulus-related cochlear potentials, such as the summating potential (SP) – a method known as electrocochleography (ECochG). ECochG can also be performed using a needle electrode to penetrate the tympanic membrane, resting on the promontory (lateral wall of the cochlea, near the niche of the round window). The other potential that can be recorded is the cochlear microphonic. The SP and AP have been found useful for the differential diagnosis of Meniere’s disease, characterized by a condition known as cochlear hydrops. In hydrops cases, the SP tends to be exaggerated in absolute magnitude or relative to the AP, perhaps reflecting asymmetrical mechanical biasing of the cochlear partition and/or biochemical effects due to this condition. Figure 1(a) illustrates another application of ECochG, combined with ABR recording (Durrant, J. D., 1986), to enhance wave I of the ABR, as this wave may be easily obscured by peripheral hearing loss. After the VIII nerve traverses the highly dense and electrically insulating temporal bone (specifically, the petrous pyramid), a second electrical wave develops as the nerve exits in the cerebellopontine angle, en route to the brainstem (Moller, A. R., 1994; Martin, W. H. et al., 1995). This too is a manifestation of activity of the VIII nerve, that is the first-order neurons of the auditory pathway. Consequently, not until the third wave is the ABR truly a brainstem response; this and later waves are registered more prominently by the vertex (Cz) electrode (Figure 1(a)). The longer and less obvious answer, regarding relevance of the ABR here, is that its nuances are strongly determined in the auditory periphery, despite the fact that waves III–V (Figure 1(a)) are generated in the pons between the dorsal–ventral cochlear nucleus complex and the inferior colliculus (Scherg, M. and von Cramon, D., 1985; Moore, J. K., 1987; Durrant, J. D. et al., 1994). The representation of stimulus onset in the discharge patterns of auditory neurons is quite robust regardless of neuron type (Kiang, N. Y. S., 1975). Thus, the onset of the stimulus excites a high spike-discharge rate such that this feature of the primary-neural discharge pattern is prevalent throughout the auditory pathways. The several waves of the ABR are readily attributable to the sequential connectivity of the nerve and brainstem pathways which provide a combination of axonal (propagation) and synaptic delays at each major nucleus (Scherg, M. and von Cramon, D.,

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1985; Moore, J. K., 1987). Consequently, the activity at each level of the pathway will be passed on to the next, as in a relay race. The result is a multiphasic compound neural response of several milliseconds duration. As conventionally tested, a simple wideband stimulus, called the acoustic click, is used to elicit the ABR. As such, the ABR may be considered as the impulse response of the combined VIII-nerve and brainstem systems. The input sound approximates an ideal impulse (a very brief transient). The click is created by exciting the earphone transducer with a brief direct-current pulse, typically 100 ms in duration (Figure 1(a)), providing equal power at all frequencies up to nearly 10 000 Hz (see Durrant, J. D. and Lovrinic, J. H., 1995 for review of underlying principles). Consequently, the output signal (waves of the ABR) is expected to reflect activity representing a broad frequency range, if, in fact, the frequency content of the input stimulus was well encoded by the hearing organ. The preceding chapter has established that, indeed, it should have been, but through the rather special transform effected by traveling-wave mechanics. The brainstem thus sees the outside world through the VIII nerve, which, in turn, sees the world through an array of variably tuned narrow-band filters produced by the place-encoding mechanism of the basilar membrane and the outer hair cells. Recall that, by this mechanism, the basilar membrane is not excited all at once, rather the traveling-wave motion is propagated with finite speed from the base toward the apex. The result is that the different best-frequency regions are excited sequentially, progressing from high- (basal) to low-frequency (apical) places. Due to cochlear mechanics, the AP reflects activity at most audible frequencies in response to the simple (unfiltered) click, yet not instantaneously. Consequently, the click waveform (or its frequency content) is not obvious in the recorded signal. In other words, the AP (ABR wave I) does not mimic the input signal. True, it still is brief, roughly 1 ms in duration and thus is itself a transient. In contrast, it would take several milliseconds of activity to represent the entire cochlear response, again due to traveling-wave propagation. In VIII-nerve activity alone this would outlast the entire click-evoked ABR! So where did the rest of the activity go? Well, this same encoding mechanism, by virtue of the cochlear propagation delay, as well as filtering properties of the cochlear hydromechanics, causes phase dispersion. Activity from the base, where the traveling-wave velocity is high and the propagation delay

362 Manifestations of Cochlear Events in the Auditory Brain-stem Response

(and thus phase dispersion) is minimum, dominates the recorded response, yielding the robust but temporally compact wave observed. In contrast, activity from more apical regions tends to cancel out. Still, an appropriate masking technique (use of interfering noise of different cut-off frequencies) or frequencyspecific stimuli (use of sinusoidal pulses (tone bursts)) can be used to isolate more apical places of excitation. The same approach can be taken with the entire ABR (which suffers the same fate as the AP, accounting for its own compactness), as shown in Figure 1(b). Note the shifting latency (delay from the start of the stimulus), namely increasing latency as frequency of the stimulus decreases. Recombining the frequencyor place-specific responses, while compensating for the traveling-wave delays (stacked TB ABR in Figure 1(c)), produces a substantially greater magnitude of response (Philibert, B. et al., 2003). Interestingly, stimulus intensity also has a dramatic and related effect (Figure 2(a)). As stimulus intensity decreases, not only does the response magnitude

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decrease (as expected), but the peaks of the earlier/ smaller waves disappear, and the waves occur at progressively longer latencies. This results from a combination of effects, including a basic neural effect – the characteristic increase of latency with decreasing stimulus intensity (Kiang, N. Y. S., 1965), and a cochlear mechanical effect – progressively fewer neurons excited on the tails of their turning curves (Ozdamar, O. and Dallos, P., 1976). The latency-intensity tradeoff is the hallmark of auditory-evoked responses. Given such pervasive influence of cochlear mechanics on the ABR, it seems likely that traveling-wave velocity could be estimated using ABR latency measures, as indeed is the case (e.g., see Donaldson, G. S. and Ruth, R. A., 1993). This entirely noninvasive clinical tool thus permits the examination of cochlear function in intact humans and other animals. With all this attention to place-frequency encoding, what about time synchrony? In fact, a high degree of synchrony of neural discharge is essential

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Figure 2 Illustration of typical effects of level of the acoustic-click stimulus (a), peripheral auditory pathology (b, c), and retrocochlear lesion on the auditory brainstem response (ABR). a, Normal ABR recorded at click hearing levels indicated: just at/above hearing threshold of the acoustic click stimulus, and several levels above, yielding at 70 and 90 dB hearing level full complements of waves. b, Simulated flat conductive loss, typical of middle-ear disease, leading merely to simple attenuation of the stimulus, i.e., the 90 dB response corresponds to the 70 dB, and the detection level of the response is elevated. c, Simulated high-frequency sensory loss, yielding similar effects to the conductive loss at low levels but by 90 dB, in this case, an essentially normal amount of activity is recruited due, in part, to basalward spread of excitation. d, Actual responses from a case of acoustic tumor which, in this case, had virtually no adverse effects on the usual tests of hearing, yet causing a clear delay in neural conduction in the VIII nerve (indicated by prolongation of the I–III interpeak interval). DNT, did not test; nHL, normal hearing level.

Manifestations of Cochlear Events in the Auditory Brain-stem Response

for a good ABR. Stimuli with relatively long rise times yield poor responses (Hecox, K. et al., 1976). The click is highly effective, not only because of its broad bandwidth, but also its abruptness. Subtle timing cues, in fact, are readily evident in the ABR, for example, the slight time difference between condensation (C) and rarefaction (R) polarity stimuli – stimuli initiated with a push versus a pull on the eardrum. The result in the average subject is that there is a subtle, yet measurable, difference in waveform and latency between the C- and R-evoked ABRs (see Durrant, J. D. and Ferraro, J. A., 1999). This follows from the fact that the excitatory phase of stimulation in the cochlea is basilar membrane movement (displacement and velocity) going from scala tympani to the scala vestibuli (Dallos, P. and Durrant, J. D., 1972); this motion corresponds to R. Still more compelling is the extent to which phase synchrony can be expressed in the ABR under appropriate recording conditions. Returning to Figure 1, inspection of the ABR reveals a pseudosinusoidal waveform. It may not be too surprising, then, that short sinusoidal pulses can be used to drive this feature to produce a frequency-following response (FFR) that more-or-less mimics the stimulus waveform (e.g., see Ananthanarayan, A. K. and Durrant, J. D., 1992). The FFR responses are most robust in the mid-frequency range of hearing, roughly 500–2000 Hz, the upper range being consistent with the upper limit of the most efficient phase locking of single auditory neurons (the lower limit perhaps reflects the general deterioration of the ABR at low frequencies, as low-frequency stimuli have inherently slower onsets. In general, the ABR is not quite as robust/distinctive when elicited below 1000 Hz; e.g., see Kiang, N. Y. S., 1965; Joris, P. X. et al., 1994a; 1994b). This temporal synchrony is robust enough that the FFR can be used to study encoding of complex stimuli, most notably vowels of speech (Krishnan, A., 2002). So complete is this reflection of cochlear events, that yet another manifestation of cochlear function, that is, nonlinearity (e.g., intermodulation distortion products), is also expressed in FFR activity (Pandya, P. K. and Krishnan, A., 2004). To outline this of clinical correlation, a few examples of applications and related concepts will be worthwhile. The most basic manifestation of cochlear function is hearing sensitivity. While it certainly takes the rest of the auditory pathways to provide the sense of hearing and related conscious/voluntary responses, as sampled via conventional (behavioral) audiometry, it is well established that the limits of

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hearing sensitivity are determined by the peripheral auditory system. It was noted earlier that a common application of the ABR is found in newborn hearing screening and hearing threshold estimation in young children and others incapable of participating in the standard (behavioral) clinical test. This application enjoys broad utility, providing reliable screening for hearing impairment and threshold estimation often to within an accuracy of 10 dB, as illustrated in Figure 2(a). Such results, in practice, are usually obtained while the subject is asleep naturally or under sedation or general anesthesia. This is possible because the generators of the ABR are below the inferior colliculus and strongly driven by the peripheral nerve, as revealed above. In many pediatric patients, a common problem of hearing is fluid in the middle ear which attenuates sound delivered to the inner ear and causes changes in the ABR (see Figure 2(b)). Hearing loss in the population at large, however, is most often caused by loss of hair-cell function, frequently limited to the higher frequencies. This also causes deterioration in the ABR. However, moderate or less severe losses may be overcome with increasing stimulus intensity due to basalward spread of excitation from the traveling wave, which may finally overcome the impaired thresholds of more basal or high-frequency neurons (Figure 2(c)). Consequently, the ABR may be used to explore/define such losses and the nuances of their effects. The latency-intensity relationship, specifically, can help predict hearing loss type (conductive versus sensory) and degree. At the same time, such peripheral effects must be fully appreciated before retrocochlear neural influences can be confidently deduced. This brings the discussion to another major application of ABR testing, that of differential diagnosis (see Durrant, J. D. and Ferraro, J. A., 1999, for review). The effects of a common space-occupying retrocochlear lesion (the acoustic tumor) also is illustrated in Figure 2. In this case, the compression of the VIII nerve by the tumor appears not to significantly affect hearing sensitivity, at least not as clinically tested, yet the lesion has clear impact on the ABR. The delay between waves I and III is consistent with the site of lesion, i.e., blockage of VIII-nerve conduction. Over the past decade, the clinical importance of the ABR for detection of such tumors has diminished with advancements in imaging. However, Don M. et al. (1997) have shown that, by using an approach similar to that represented in Figures 1(b) and 1(c) (i.e., stacked ABR analysis),

364 Manifestations of Cochlear Events in the Auditory Brain-stem Response

the ABR can be enhanced, providing a more thorough test of VIII-nerve function, that is, not merely the higher-frequency response elicited via the unfiltered click (Don, M. et al., 1997; Philibert, B. et al., 2003). Interestingly, the basic stimulus-analysis paradigm of the stacked-ABR test was developed over four decades ago for the purpose of breaking down the click-evoked AP into its (equivalent) component frequency bands (Teas, D. C. et al., 1962). The method represents the results of the much more tedious and invasive analysis of single-unit-response measurement along the nerve trunk well (Kiang, N. Y. S., 1975), again reflecting propagation events along the cochlear partition. Lastly, the acoustic-tumor example also demonstrates the basis for use of the ABR in intraoperative monitoring, in this case the possible compression of the VIII-nerve or more central fiber tracts during neurosurgery. In summary, cochlear events are strongly manifested in, and determine many characteristics of, the ABR. While a powerful and sensitive clinical tool for investigating or ruling out retrocochlear pathology and objective hearing screening, ABR recording is an equally valuable investigative tool in the evaluation of peripheral auditory sensorineural events.

References Ananthanarayan, A. K. and Durrant, J. D. 1992. The frequency following response and the onset response: evaluation of frequency specificity using a forward masking paradigm. Ear Hear. 13, 228–232. Dallos, P. and Durrant, J. D. 1972. On the derivative relationship between stapes displacement and cochlear microphonics. J. Acoust. Soc. Am. 52, 1263–1265. Don, M., Masuda, A., Nelson, R., and Brackmann, D. 1997. Successful detection of small acoustic tumors using the stacked derived-band auditory brain stem response amplitude. Am. J. Otol. 18, 608–621. Donaldson, G. S. and Ruth, R. A. 1993. Derived band auditory brain-stem response estimates of traveling wave velocity in humans. I. Normal-hearing subjects. J. Acoust. Soc. Am. 93, 940–951. Durrant, J. D. 1986. Combined ECochG-ABR versus conventional ABR recordings. Semin. Hear. 7, 289–305. Durrant, J. D. and Ferraro, J. A. 1999. Short-Latency Evoked Potentials: Electrocochleography and Auditory Brainstem Response. In: Contemporary Perspectives in Hearing Assessment (eds. F. Musiek and W. Rintlemann), pp. 197–242. Allyn-Bacon. Durrant, J. D. and Lovrinic, J. H. 1995. Bases of Hearing Science, 3rd edn. Williams & Wilkins.

Durrant, J. D., Martin, W. H., Hirsch, B., and Schwegler, J. 1994. 3CLT ABR analyses in a human subject with unilateral extirpation of the inferior colliculus. Hear. Res. 72, 99–107. Goldstein, R. and Aldrich, W. M. 1999. Evoked Potential Audiometry. Allyn and Bacon. Hall, J. W. III, 1991. Handbook of Auditory Evoked Responses. Allyn and Bacon. Hecox, K., Squires, N., and Galambos, R. 1976. Brainstem auditory evoked responses in man. I. Effect of stimulus rise– fall time and duration. J. Acoust. Soc. Am. 60, 1187–1192. Jewett, D. L. and Williston, J. S. 1971. Auditory-evoked far fields averaged from the scalp of humans. Brain 94, 681–696. Joris, P. X., Carney, L. H., Smith, P. H., and Yin, T. C. 1994a. Enhancement of neural synchronization in the anteroventral cochlear nucleus. I. Responses to tones at the characteristic frequency. J. Neurophysiol. 71, 1022–1036. Joris, P. X., Smith, P. H., and Yin, T. C. 1994b. Enhancement of neural synchronization in the anteroventral cochlear nucleus. II. Responses in the tuning curve tail. J. Neurophysiol. 71, 1037–1051. Kiang, N. Y. S. 1965. Discharge Patterns of Single Fibers in the Cat’s Auditory Nerve. MIT Press. Kiang, N. Y. S. 1975. Stimulus Representation in the Discharge Patterns of Auditory Neurons. In: The Nervous System – Vol. 3: Human Communication and Its Disorders (ed. E. L. Eagles), pp. 81–96. Raven Press. Krishnan, A. 2002. Human frequency-following responses: representation of steady-state synthetic vowels. Hear. Res. 166, 192–201. Martin, W. H., Pratt, H., and Schwegler, J. W. 1995. The origin of the human auditory brain-stem response wave II. Electroencephalogr. Clin. Neurophysiol. 96, 357–370. Moller, A. R. 1994. Neural Generators of Auditory Evoked Potentials. In: Principles and Applications in Auditory Evoked Potentials (ed. J. T. Jacobson), pp. 23–46. Allyn and Bacon. Moore, J. K. 1987. The human auditory brain stem as a generator of auditory evoked potentials. Hear. Res. 29, 33–43. Ozdamar, O. and Dallos, P. 1976. Input–output functions of cochlear whole-nerve action potentials: interpretation in terms of one population of neurons. J. Acoust. Soc. Am. 59, 143–147. Pandya, P. K. and Krishnan, A. 2004. Human frequencyfollowing response correlates of the distortion product at 2F1-F2. J. Am. Acad. Audiol. 15, 184–197. Philibert, B., Durrant, J. D., Ferber-Viart, C., Duclaux, R., Veuillet, E., and Collet, L. 2003. Stacked tone-burst-evoked auditory brainstem response (ABR): preliminary findings. Int. J. Audiol. 42, 71–81. Scherg, M. and von Cramon, D. 1985. A new interpretation of the generators of BAEP waves I–V: results of a spatiotemporal dipole model. Electroencephalogr. Clin. Neurophysiol. 62, 290–299. Teas, D. C., Eldrege, D. H., and Davis, H. 1962. Cochlear responses to acoustic transients: an interpretation of whole nerve action potentials. J. Acoust. Soc. Am. 34, 1438–1459.

Further Reading Burkard, R. F., Don, M., and Eggerment, J.J (eds.) 2007. Auditory Evoked Potentials: Basic Principles and clinical Application Lippincott Williams & Wilkins.