The origin of short-latency transient-evoked otoacoustic emissions

Transcription

1 University of Iowa Iowa Research Online Theses and Dissertations Fall 2013 The origin of short-latency transient-evoked otoacoustic emissions James Douglas Lewis University of Iowa Copyright 2013 James Lewis This dissertation is available at Iowa Research Online: Recommended Citation Lewis, James Douglas. "The origin of short-latency transient-evoked otoacoustic emissions." PhD (Doctor of Philosophy) thesis, University of Iowa, Follow this and additional works at: Part of the Speech and Hearing Science Commons

2 THE ORIGIN OF SHORT-LATENCY TRANSIENT-EVOKED OTOACOUSTIC EMISSIONS by James Douglas Lewis A thesis submitted in partial fulfillment of the requirements for the Doctor of Philosophy degree in Speech and Hearing Science in the Graduate College of The University of Iowa December 2013 Thesis Supervisor: Assistant Professor Shawn S. Goodman

3 Graduate College The University of Iowa Iowa City, Iowa CERTIFICATE OF APPROVAL PH.D. THESIS This is to certify that the Ph. D. thesis of James Douglas Lewis has been approved by the Examining Committee for the thesis requirement for the Doctor of Philosophy degree in Speech and Hearing Science at the December 2013 graduation. Thesis Committee: Shawn S. Goodman, Thesis Supervisor Paul J. Abbas Ruth A. Bentler Lenore A. Holte Christopher W. Turner

4 To Kelli & Emelia. ii

5 Listen to this, O Job, Stand and consider the wonders of God. Do you know how God establishes them, And makes the lightning of His cloud to shine? Do you know about the layers of the thick clouds, The wonders of one perfect in knowledge, You whose garments are hot, When the land is still because of the south wind? -Job 37:14-17 iii

6 ACKNOWLEDGEMENTS Thanks to Shawn Goodman who first welcomed me into his lab back in 2006 when we were both just beginning in the department. I am now happy to call Shawn both a mentor and friend. Shawn taught me how to program, think critically, seek answers, and ask questions. He has been an example of one who cares about his work and wants to make a meaningful contribution to the field of hearing science. Thanks to Paul Abbas, Ruth Bentler, Lenore Holte, and Chris Turner who, along with Shawn, served on my dissertation committee. Each of these individuals has made significant contributions to my development both as a researcher and clinical audiologist. I want to extend my gratitude to Rachel Stanziola and Brittany James who worked with me to collect the data presented in this thesis. Over 80 hours of data were collected during the final month of the semester thanks to these two. I d also like to thank the Executive Council for Graduate and Profession Students at the University of Iowa who generously provided the funding to complete the experimental work described in the following pages. Thanks also to my parents, Doug and Christine. Two things stand out to me as I think of them. First, they are the hardest working people I know. Second, everything they touch is made better. If I possess even the slightest measure of these qualities it is because of my dad and mom. My wife Kelli deserves greatest thanks. Her devotion has never been contingent on my success but, rather, something that is always present and can be relied upon even in the midst of failure or disappointment. I can t really imagine going through the Ph.D. program without my wife. She has brought me so much joy and happiness, without which I m not sure how long I would have lasted. Kelli has never yielded her support or been lacking in encouragement for me over these past few years. I m glad to be moving-on with her by my side. iv

7 ABSTRACT Bandpass filtered transient-evoked otoacoustic emission (TEOAE) waveforms are composed of short-latency (SL) and long-latency (LL) portions. The LL portion has latency consistent with generation through linear coherent reflection at the tonotopic place on the basilar membrane. The short-latency (SL) portion occurs earlier in time and exhibits less compressive growth. Several mechanisms have been hypothesized to explain generation of the SL portion, including 2 f 1! f 2 intermodulation distortion and coherent reflection basal to the tonotopic place. Two experiments were designed to examine the generation mechanism and generation location of the SL portion. Experiment 1 tests the hypothesis that the SL portion results from low-side, cubic intermodulation distortion. Experiment 2 determines the region along the basilar membrane at which the SL portion of the TEOAE is generated. The null hypothesis that the SL portion of the TEOAE is generated through lowside, cubic intermodulation distortion requires stimuli with broad frequency content. Stimulus energy at different frequencies ( f 1 and f 2 ) is presumed to interact simultaneously across the cochlear partition, generating a distortion-source OAE. To test this hypothesis, OAEs were evoked using 2 khz tone-bursts with durations spanning the time-frequency continuum between a click and a pure tone. As tone-burst duration increases, stimulus energy at the primary frequencies ( f 1 and f 2 ) decreases and the input to any nonlinear distortion source is reduced. Accordingly, if generated through 2 f 1! f 2 distortion, the magnitude of the SL portion of the TEOAE was expected to decrease as tone-burst duration increased. Results were inconsistent with generation of the SL portion through intermodulation distortion. As tone-burst duration increased, the SL portion remained present in the TEOAE. The presence of the SL portion influenced the leveldependency of TEOAE latency and magnitude to the same extent across all tone-burst durations. v

8 The region of generation along the cochlear partition of the SL portion has implications for the mechanism through which it is generated. Generation through lowside, cubic intermodulation distortion ( 2 f 1! f 2 ) would occur near the f 2 tonotopic place. If generation is through coherent reflection, a generation region basal to that of the tonotopic place is hypothesized. To determine the cochlear region where the SL portion is generated, TEOAEs were evoked by 2 khz tone-bursts in the presence of different suppressor stimuli. The amount of suppression induced by each suppressor on the OAE was measured, and the suppressor frequency causing greatest suppression of a given portion of the TEOAE was interpreted as corresponding to that portion s generation place along the basilar membrane. For analysis purposes, the SL portion was divided into two SL time-windows (SL1 and SL2). The LL portion of the TEOAE was maximally suppressed by a 2.07 khz tone, consistent with generation at the tonotopic place. Both SL components were generated basal to the tonotopic place. The later-occurring SL portion of the TEOAE (SL1) was generated between 1/4-1/3-octave basal to the tonotopic place while the earlier-occurring SL portion (SL2) was generated 3/5-octave basal to the tonotopic place. The generation region of the SL1 portion of the TEOAE was too apical to be consistent with generation through 2 f 1! f 2 distortion. Although the generation region of the SL2 portion was what would be expected for a 2 f 1! f 2 distortion-source OAE, the latency was too early. Generation of both SL portions may be explained through basal linear coherent reflection. Per this mode of generation, the SL1 and SL2 portions of the TEOAE each likely mirror the underlying mechanics at different regions along the cochlear partition. vi

9 TABLE OF CONTENTS LIST OF TABLES...ix LIST OF FIGURES...x LIST OF ABBREVIATIONS...xii INTRODUCTION...1 CHAPTER I. MECHANICS OF THE COCHLEA Passive Cochlear Mechanics The Cochlear Amplifier Active Cochlear Mechanics...8 II. OTOACOUSTIC EMISSIONS OAE Classification OAEs and Cochlear Mechanics Generation Mechanisms Underlying Theories Generation of DPOAEs Generation of SFOAEs Generation of TEOAEs The Long-Latency TEOAE The Short-Latency TEOAE...25 III. EXPERIMENT 1: THE EFFECT OF TONE-BURST DURATION ON THE SHORT-LATENCY TEOAE Introduction Methods Subjects Signal Generation and Data Acquisition Measurement and Analysis of TEOAEs Stimuli Calibration Analysis Results TEOAE Envelopes TEOAE Latency-Intensity Functions...43 vii

10 3.3.3 TEOAE Input-Output Functions Discussion Generation Mechanism of the SL TEOAE Origin of TEOAE envelope morphology...57 IV. EXPERIMENT 2: TWO-TONE SUPPRESSION OF SL AND LL PORTIONS OF THE TEOAE Introduction Methods Subjects Signal Generation and Data Acquisition Measurement and Analysis of TEOAEs Stimuli Calibration Analysis Results Tone-Burst Suppressor Condition Pure Tone and Noise-Burst Suppressor Conditions Discussion SL and LL Portions of the TEOAE Generation Regions of the TEOAE Generation Mechanisms of the TEOAE Relation of TEOAEs to BM Mechanics Cochlear Compression Basal Shift in the Peak of the Traveling Wave Implications for Ears with SNHL V. SUMMARY AND CONCLUSIONS SL and LL Portions of the TEOAE Growth and Latency Behavior Proposed Mechanisms of Generation Experimental Work to Determine the Origin of the SL TEOAE Experiment Design and Analysis Results Discussion Experiment Design and Analysis Results Discussion Conclusions and Future Directions REFERENCES viii

11 LIST OF TABLES Table 3.1. Table 3.2. Mean latencies (ms) ± 1 standard deviation (ms) for each tone-burst duration and level. 62 Mean magnitudes (db SPL) ± 1 standard deviation (db) for each tone-burst duration and level. 63 ix

12 LIST OF FIGURES Figure 3.1. Figure 3.2 Figure 3.3 Figure 3.4 Figure 3.5 Figure 3.6 Figure 3.7 Figure 3.8 Time- and frequency-domain representations of the 2 khz tone-burst stimuli. 64 Empirical distribution functions used to determine SNR criterion. 65 TEOAE envelopes for three subjects across different levels and tone-burst durations. 66 TEOAE envelopes for three subjects across different levels and tone-burst durations. 67 Latency-intensity functions for each tone-burst stimulus for all 12 subjects. 68 The effect of temporal interaction between the SL and LL components on the 24-cycle TEOAE latency calculation. 69 Group latency-intensity functions for each tone-burst stimulus. 70 Input-output functions for each tone-burst stimulus for all 12 subjects. 71 Figure 3.9 Group input-output functions for each tone-burst stimulus. 72 Figure 3.10 Figure 4.1 Figure 4.2 Figure 4.3 Figure 4.4 Simulation results for the multiple component model to explain TEOAE envelope morphology. 73 Probe- and suppressor-stimulus paradigm used to evoke the suppressed TEOAE. 106 Illustration of the technique used to specify the timewindows corresponding to different-temporal portions of the TEOAE. 107 TEOAE envelopes measured for different level tone-bursts in the tone-burst suppressor condition. 108 TEOAE envelopes measured for different level tone-bursts in the tone-burst suppressor condition. 109 x

13 Figure 4.5 Figure 4.6 Figure 4.7 Figure 4.8 Figure 4.9 Figure 4.10 Figure 4.11 Level-series illustration of the different-temporal portions of the TEOAE for the tone-burst suppressor condition, collapsed across all subjects. 110 Mean input-output, slope-intensity, and latency-intensity functions for the different-temporal portions of the TEOAE and the total TEOAE. 111 Contour plots showing the effect of different frequency suppressors on the TEOAE. 112 Contour plots showing the effect of different frequency suppressors on the TEOAE. 113 Mean iso-level suppression curves for the different-latency portions of the TEOAE and the total TEOAE. 114 Slope-intensity functions for the SL2, SL1, and LL portions of the TEOAE compared to those derived from measurements at proportional locations on the BM. 115 Input-output functions for the LL, SL1, and SL2 portions of the TEOAE compared to those at proportional locations on the basilar membrane. 116 xi

14 LIST OF ABBREVIATIONS BLN band-limited noise BM basilar membrane CEOAE click evoked otoacoustic emission CF characteristic frequency CP cochlear partition cspl bandwidth compensated sound pressure level db decibel DPOAE distortion product otoacoustic emission EEOAE electrically evoked otoacoustic emission FFT Fast Fourier transform FIR finite impulse response HL hearing level Hz hertz IHC inner hair cell IO input-output khz kilohertz LCR linear coherent reflection LL long-latency m meters mm millimeters ms millisecond xii

15 NLD nonlinear distortion OAE otoacoustic emission OHC outer hair cell PC personal computer pspl peak sound pressure level PSR probe-to-suppressor ratio RMS root-mean-square SFOAE stimulus frequency otoacoustic emission SL short-latency SL1 short-latency (occurring later-in-time) SL2 short-latency (occurring earlier-in-time) SL3 short-latency (occurring earliest-in-time) SNHL sensorineural hearing loss SNR signal-to-noise ratio SOAE spontaneous otoacoustic emission SPL sound pressure level SSOAE synchronous spontaneous otoacoustic emission TBOAE tone-burst evoked otoacoustic emission TEOAE transient evoked otoacoustic emission xiii

16 1 INTRODUCTION Ototacoustic emissions (OAEs) are sounds generated within the cochlea and transmitted through the middle ear to the ear canal. This thesis is concerned with the generation of one specific type, transient-evoked otoacoustic emissions (TEOAEs). Specifically, the generation mechanism and the generation location within the cochlea are examined. Chapter I provides a brief introduction to the passive and active mechanics of the cochlea. Chapter II examines the relationship between OAEs and cochlear mechanics, with emphasis on the generation mechanisms of the most commonly measured OAEs: distortion product (DPOAEs), stimulus frequency (SFOAEs), and transient-evoked (TEOAEs). Within the discussion of TEOAE generation mechanisms, attention is directed toward those mechanisms that may account for the short-latency portion of the emission. Two potential generation mechanisms are introduced, intermodulation distortion and basal reflection. Chapter III describes the experimental work carried out for this thesis to determine whether intermodulation distortion or basal reflection is the more likely generator of the short-latency portion of the TEOAE. Related to the generation mechanism is the generation location along the cochlear partition. Chapter IV describes the experimental work performed to identify the generation location of the short-latency portion of the TEOAE. A summary of the findings of this thesis and ideas for future research are presented in Chapter V. When an acoustic stimulus is presented to the healthy cochlea, soft sounds, known as OAEs, can be measured in the ear canal. OAEs are generated within the cochlea and provide insight into the mechanics of the cochlea. The generation of OAEs within the cochlea is dependent on the cochlear amplifier; a biological process by which cochlear vibration is enhanced, resulting in increased behavioral auditory sensitivity and frequency discrimination. OAEs arise as a byproduct of the amplification process; therefore the measurement of OAES provides an indirect and noninvasive means to examine cochlear

17 2 mechanics and cochlear health in humans. However, realization of the full utility of OAEs likely depends on an accurate understanding of how and where they are generated. There is still much to be learned about the various types of OAEs. This thesis focuses on understanding how and where TEOAEs are generated. As the name implies, TEOAEs are evoked by temporally short stimuli including acoustic impulses, or clicks, and tone-bursts. Given their transient nature, the spectral bandwidths of these stimuli are broad. Upon presentation to the cochlea, TEOAEs are evoked across an equally broad frequency range. In other words, the TEOAE contains multiple frequency components. When evoked by a low-level stimulus, each frequency component is generated near its tonotopic place along the cochlear partition. Evidence for generation at the different tonotopic places is revealed by the time delay, or latency, of the different frequency components in the TEOAE. As the frequency of the TEOAE decreases, the associated latency exponentially increases. The latency of a given frequency in the TEOAE approximates the round-trip travel time required for propagation of the cochlear traveling wave to its characteristic frequency location and back to the middle ear. In this thesis, TEOAE energy with this delay behavior is referred to as the long-latency (LL) portion of the TEOAE. When evoked by a moderate- to highlevel transient stimulus, each frequency in the TEOAE also contains energy at much shorter latencies. In this thesis, this earlier-occurring energy is referred to as the shortlatency (SL) portion of the TEOAE. The growth rates of the LL and SL portions are different. The magnitude of the LL portion of the TEOAE grows very compressively as stimulus level increases. In contrast, the SL portion grows less compressively, with growth rates approaching unity (1 db/db). Both the mechanism and place of generation for the SL portion are poorly understood. Given its short latency and the broad excitation of the cochlear partition caused by transient stimuli, intermodulation distortion has been proposed as the likely

18 3 generation mechanism. An alternative mode of generation may be through coherent reflection from a location basal to the tonotopic place. Experiment 1 was designed to test the hypothesis that the SL portion of the TEOAE is generated through intermodulation distortion. This was done by exploiting the presumed dependency of the SL portion on stimulus energy at two specific frequencies, f 1 and f 2. In this experiment, TEOAEs were evoked by 2 khz tone-bursts of different lengths, from very short, click-like bursts to relatively long bursts that begin to approximate pure tones. As tone-burst duration increases, the bandwidth of the stimulus narrows and the spatial excitation of the cochlear partition induced by the stimulus at frequencies f 1 and f 2 decreases. Accordingly, if the SL portion of the TEOAE is generated through intermodulation distortion, its magnitude should become smaller as the tone-burst increases in duration. The alternative hypothesis, generation through basal reflection, predicts contrasting behavior. If generated through basal reflection, the SL portion depends primarily on the level of stimulus energy at the tone-burst center frequency (2 khz, in this case) and should therefore remain unchanged in amplitude as the tone-burst duration increases and bandwidth becomes increasingly narrow around 2 khz. Experiment 2 was designed to identify the region along the basilar membrane where the SL portion of the TEOAE is generated. Two-tone suppression was utilized to localize the regions along the basilar membrane contributing to generation of the different latency portions of the TEOAE. TEOAEs were evoked by 2 khz tone-bursts in the presence of different suppressor stimuli that spanned a range of frequencies both higher and lower than 2 khz. Although the main goal of this experiment was not to determine the generation mechanism but rather the generation place, the results were anticipated to provide either support for or against generation through intermodulation distortion. As a final note about the format of this thesis, Experiment 1 (Chapter III) and Experiment 2 (Chapter IV) were each written with an eye towards publication as stand-

19 4 alone papers in peer reviewed journals. Therefore, in the context of this thesis, these two chapters contain some overlapping and redundant content, particularly with regard to portions of the background and methodology.

20 5 CHAPTER I MECHANICS OF THE COCHLEA Natural auditory perception of sound depends on the functions of the external, middle, and inner ears. The external ear (pinna and ear canal) collects, amplifies, and directs acoustic energy to the tympanic membrane where it is transduced into mechanical vibrations. Within the middle ear these vibrations are amplified by the ossicles as they are directed toward the inner ear where they will become fluid pressure waves. The amplification provided by the ossicles is necessary to minimize the impedance mismatch between air and the cochlear fluids. Stapes vibration against the oval window of the cochlea completes the impedance matching process and gives rise to the cochlear traveling wave across the cochlear partition (CP). The vibration of the CP will eventually result in deflection of the stereocilia of the inner hair cells (IHCs) and be transduced to electrical impulses that are interpreted by the central auditory system. Facilitating the transduction process are the outer hair cells (OHCs). The OHCs work as biological amplifiers and increase the response of the CP to an acoustic stimulus. The action of the OHCs is restricted to the region along the CP corresponding to the frequency of the acoustic stimulus. Accordingly, only the forces acting upon a subset of the sensory IHCs are amplified. At low stimulus levels, the contribution of the OHCs to the cochlear response is significant and the mechanics are said to be active. In contrast, at high stimulus levels, or in the presence of sensorineural hearing loss (SNHL), the contribution from the OHCs to the cochlear response is diminished and the cochlea is characteristic of a passive system. 1.1 Passive Cochlear Mechanics Békésy s measurements of CP displacement were the first to demonstrate the concept of a cochlear traveling wave (von Békésy, 1947; 1949; 1953). In response to the motion of the stapes against the oval window, a pressure gradient is induced across the

21 6 perilymphatic scalae. As a result of the pressure differential between scalae, the CP (basilar membrane and organ of corti) becomes displaced and vibrates at the frequency of stapes motion. The amplitude and phase lag (relative to stapes motion) of CP displacement is not constant across the partition s length. Amplitude gradually increases until a maximum is reached at a given spatial location on the CP, the characteristic frequency (CF) location; beyond this region displacement rapidly diminishes. Phase lag similarly increases until CP displacement diminishes. It is this longitudinal pattern of increasing CP displacement and phase lag that describes the cochlear traveling wave. The location along the CP where the traveling wave s displacement is greatest depends on the frequency of stapes vibration. Békésy demonstrated that as the stimulating frequency increases, the location of maximum displacement along the CP shifts basally. This observation has resulted in the formulation of frequency-place maps describing the tonotopic arrangement of the CP (Greenwood, 1961; 1990). The tonotopic organization of the CP is a direct consequence of the partition s graded impedance. Compared to its apex, the base of the basilar membrane is relatively thick and narrow resulting in very low compliance and impedance that is stiffness dominated. As the distance from the stapes increases, the basilar membrane decreases in thickness but increases in width. This effectively increases the compliance of the cochlear partition while maintaining nearly constant mass. As a result, impedance becomes mass dominated. It is this change in impedance from the cochlear base to apex that causes each location along the partition to have a unique resonant frequency. Békésy s traveling waves were characteristic of a highly damped response in that the peak of the wave was relatively broad and poorly localized along the CP. These data conflicted with neural tuning curves and behavioral frequency discrimination (Shower & Biddulph, 1931; Evans, 1972; 1975), both of which demonstrated high degrees of tuning. It has since been demonstrated that although Bekesy s measurements were accurate, they were not representative of the traveling wave induced by low-level tones in a living

22 7 cochlea (Rhode, 1971; Sellick et al., 1982; Johnstone et al., 1986; Rhode, 2007). Békésy s measurements, which were made in dead (or physiologically compromised) cochleae using high-level tones (130 db SPL), characterized the passive mechanics of the cochlear partition. 1.2 The Cochlear Amplifier The traveling wave in the healthy cochlea is shaped by the action of the cochlear amplifier, a coin termed by Davis (1983) to refer to the mechanism through which the damping forces of the cochlear fluids are overcome (Neely & Kim, 1983; for review see de Boer, 1996 and Neely & Kim, 2008). The existence of a similar mechanism was originally proposed by Gold (Gold & Pumphrey, 1948; Gold, 1948) during the same time as Békésy s original measurements. Gold suggested that it was inaccurate to think of the cochlea as simply a passive detector of sound energy. Shortly after Kemp s initial discovery of evoked otoacoustic emissions (OAEs; Kemp, 1978), Kemp (1979a) and Wilson (1980) both reported that some OAEs occurred spontaneously and could not be explained by a passive cochlea. It is now well established that the displacement of the CP is a result of both passive and active mechanisms, the latter of which are associated with the cochlear amplifier. The OHC is the likely structure through which the cochlear amplifier enhances the CP response. For instance, loss of the OHCs is known to reduce behavioral sensitivity and frequency selectivity while at the same time causing abnormal loudness growth, all of which are mediated through the action of the cochlear amplifier (discussed below). Moreover, the OHC is electromotile presumably through the membrane protein prestin (Zheng et al., 2000; Liberman et al., 2002; Cheatham et al., 2004; Dallos et al., 2008; Santos-Sacchi et al., 2006), such that depolarization shortens the cell while hyperpolarization lengthens the cell (Brownell et al., 1985). The forces generated by these length changes have been shown to be sufficient to overcome the damping forces of

23 8 the cochlear fluids and amplify the CP response (Iwasa and Chadwick, 1992). Accordingly, the OHC is widely considered to be the location of the cochlear amplifier. The action of the cochlear amplifier occurs within a feedback system whereby cochlear partition displacement activates the amplifier and is adjusted by the amplifier (Patuzzi & Robertson, 1988; Hubbard 1993; Geisler, 1998). In short, lateral displacement of the OHC stereocilia by the motion of the CP induces current flow within the OHC (either positive or negative, depending on the direction of ciliary deflection). The current generates a voltage potential across the basolateral membrane of the OHC, which then causes conformational changes to the motor protein prestin, either lengthening or shortening the OHC. The forces generated by the OHC length changes act upon the cochlear partition to reduce the damping of the cochlear fluids and amplify displacement. The current generated through ciliary deflection has been modeled by saturating nonlinearities including the hyperbolic tangent and Boltzmann functions (Weiss & Leong, 1985; Kros & Richardson, 1992; Lukashin & Russell, 1998; Bian et al., 2002). The receptor potential generated by this current is therefore also nonlinear. As a result of this nonlinearity, the forces generated through OHC length changes saturate at higherlevels of stimulation (Santos-Sacchi, 1992; Evans and Dallos, 1993; for review see Patuzzi, 1996). Furthermore, as the stimulation level increases, the forces generated by the OHCs become less effective in overcoming the damping forces of the cochlear fluids. In other words, the gain provided by the cochlear amplifier decreases as input level increases. 1.3 Active Cochlear Mechanics Measurements of CP displacement in living cochlea establish the role of the cochlear amplifier in auditory perception. In the healthy cochlea, displacement of the CP is amplified by db, relative to stapes displacement, for low-level inputs (Robles et al., 1986; Gorga et al., 2003; Rhode, 2007). The gain provided by the cochlear amplifier can thus account for behavioral detection of very soft sounds. Moreover, the

24 9 low-level gain provided by the amplifier is restricted to a narrow region at and immediately basal to the CF location. The result is partition displacement that is highly localized to a specific spatial location that depends on the frequency of stimulation. The tuning afforded by this localized amplification is similar to that of auditory neurons (Robles et al., 1986; Khanna & Leonard, 1986; Ruggero et al., 1997; Ren & Nuttall, 2001) and is likely the origin of behavioral frequency discrimination. The level and frequency dependent gain provided by the cochlear amplifier results in compressive growth of CP displacement (Rhode, 1971; Rhode, 1978; Sellick et al., 1982; Johnstone et al., 1986; Ruggero et al., 1997; Rhode, 2007). Accordingly, the healthy cochlea is nonlinear. In addition to compression, some of the other nonlinear behaviors exhibited by the cochlea include biasing (Sellick et al., 1982; Patuzzi et al., 1984; Bian et al., 2002), two-tone suppression (Geisler et al., 1990; Cooper & Rhode, 1992), and generation of distortion (harmonic or intermodulation; Robles et al., 1991; Patuzzi, 1996; Rhode, 2007). Cochlear nonlinearity is most pronounced at and near the CF location where the contribution from the cochlear amplifier is greatest (de Boer, 1983a; 1983b). Compression at the CF place has been shown to occur for input levels as low as 0 db SPL (Rhode, 2007). Other data is more consistent with near linear growth at the CF place for input levels up to ~ 40 db SPL (Ruggero et al., 1997). As the input level increases beyond 40 db SPL, compression becomes increasingly pronounced with growth rates between db/db (Ruggero et al., 1997; Rhode, 2007). Compression also occurs at spatial locations basal to the CF place; however, the amount of compression is reduced. By approximately 1/2-octave basal, basilar membrane growth is nearly linear (Ruggero et al., 1997; Robles & Ruggero, 2001). As stimulus level increases, the forces generated by the OHCs are insufficient to overcome the energy loss associated with the traveling wave approaching its resonance place. In other words, the mechanics shift from active to increasingly passive. As a result, the peak of the traveling wave shifts basally (Ruggero et

25 10 al., 1997; Recio et al., 1998) to regions just beyond the resonance place. The amplitude of the peak continues to grow but at less compressive rates than those for lower stimulus levels. Accordingly, the interplay between mechanics presumably accounts for the broad dynamic range over which perception occurs (~120 db; for review see Oxenham & Bacon, 2003). In summary, the sound induced vibrations of the cochlear partition are a combination of passive and active mechanics. The active mechanics are attributable to the action of the cochlear amplifier in the OHCs and result in cochlear nonlinearity. This nonlinearity is beneficial to audition and allows for detection of very soft sounds, discrimination between similar sounds, and perception of sound across a broad range of levels. Although the active mechanics of the living cochlea in human are unobservable due to the invasiveness of the measurements, a byproduct of the active mechanism, OAEs, can be used to provide far-field insight into human cochlear processing.

26 11 CHAPTER II OTOACOUSTIC EMISSIONS In 1978 David Kemp demonstrated that the cochlea generates an echo when presented with an acoustic stimulus (Kemp, 1978). In his original work, Kemp presented acoustic impulses to the ear and observed that the decay of the ear canal pressure response was not monotonic. Rather, several milliseconds after stimulus cessation a small pressure peak was evident that was not present in either a coupler or ears with middle ear pathology. He hypothesized that the echo, or otoacoustic emission (OAE), was a byproduct of Gold s active mechanism (Gold, 1948) within the cochlea and that the OAE could provide insight into cochlear mechanics. The discovery of OAEs measured in the absence of external acoustic stimulation, spontaneous otoacoustic emissions (SOAEs), provided further support of an active cochlea (Kemp, 1979a; Wilson, 1980). Since the earliest discoveries by Kemp and later, Wilson, OAEs have garnered considerable interest. OAEs are now viewed as being byproducts of the cochlear amplifier. The relation between OAEs and active cochlear mechanics (reviewed below) has been an area of special attention since measures including single-nerve fiber recordings and interferometer measures of basilar membrane vibration are invasive and unattainable in humans. If OAEs, which are non-invasive, objective measurements and easily measured in humans, provide equivalent information, then greater knowledge of the underlying mechanisms responsible for human audition may be realized. Such knowledge would certainly be beneficial in the diagnosis of and differentiation between hearing pathologies. Prior to further discussion of OAEs and cochlear mechanics it is worthwhile to review the different types of OAEs. 2.1 OAE Classification The current naming conventions used to classify OAEs is somewhat ambiguous. At the broadest level, OAEs can be either evoked by external stimuli (evoked OAEs) or

27 12 can arise spontaneously (Kemp, 1979a; Wilson, 1980). There are two types of spontaneously generated OAEs including SOAEs and synchronous-spontaneous OAEs (SSOAEs). The former were defined above and are found in approximately 60-80% of all healthy ears (Martin et al., 1990; Talmadge et al., 1993; Penner & Zhang, 1997). SSOAEs are emissions that are elicited by acoustic stimulation but then may persist up to hundreds of milliseconds after stimulus cessation before decaying. Both SOAEs and SSOAEs may originate from instability in the active feedback mechanism (Gold, 1948; Camalet, 2000; Sisto et al., 2001; Martin et al., 2001) and/or the creation of standing waves within the cochlear cavity (Kemp, 1979a; 1979b; Talmadge & Tubis, 1993; Shera, 2003). Evoked OAEs can be elicited by either electrical stimuli (EEOAEs; Hubbard & Mountain, 1983; Ren & Nuttall, 1996) or acoustic stimuli. Acoustically-evoked OAEs have traditionally been classified according to characteristics of the stimulus. The most commonly used stimuli are short transients or long pure tones. Emissions evoked by relatively short-duration stimuli may be referred to generally as transient-evoked OAEs (TEOAEs). They may also be given more specific names, such as clicked-evoked OAEs (CEOAEs) when the stimuli are acoustic impulses (clicks) or tone-burst OAEs (TBOAEs) when the stimuli are short, ramped tone bursts. Emissions evoked by relatively long-duration sinusoidal stimuli are referred to as stimulus frequency OAEs (SFOAEs) when the stimulus is a single tone or distortion-product OAEs (DPOAEs) when the stimuli are pairs of tones. Of course, acoustically-evoked OAEs can be elicited by any acoustic stimulus, including those that fall somewhere in between short transients and long pure tones. For example, frequency glides have been explored as stimuli (Neumann et al., 1994; Kalluri & Shera, 2013), as have long bursts of white noise (Maat et al., 2000). In this thesis, some of the stimuli used to elicit OAEs are of medium length, falling in between the

28 13 space between short transients and long tones. In all of these cases, the traditional naming classification system based on stimulus type is not particularly useful. More recently, an attempt was made to reclassify OAEs based on their generation mechanisms (Shera & Guinan, 1999). According to this classification scheme, SFOAEs and TEOAEs are considered reflection-source emissions since they are thought to arise through reflection of the forward-moving traveling wave off impedance irregularities along the basilar membrane (discussed further in subsequent sections). In contrast to SF and TEOAEs, DPOAEs are classified both as a reflection-source and a distortion-source OAE. DPOAEs contain two components (discussed further in subsequent sections); the distortion-source component is generated through nonlinear distortion in the cochlear mechanics and the reflection-source is generated through the same mechanism as SF and TEOAEs. Unfortunately, this classification scheme has proved less useful than initially hoped, because some OAEs appear be generated by more than one mechanism, depending on stimulus level. Further, referring to all OAEs as being one of two types does not give enough information about how they were elicited. At this time, it appears that the practice of classifying OAEs by the eliciting stimuli will continue, with the addition of specifying generation mechanism when that information is deemed useful. 2.2 OAEs and Cochlear Mechanics The association between OAEs and the cochlear amplifier and, therefore, active cochlear mechanics, is attested to through the observation that OAEs are either diminished or absent in ears with sensorineural hearing loss (SNHL; Probst et al., 1987; Collet et al., 1989; Smurzynski et al., 1990). Correlation between the behavioral audiogram and OAE magnitude has also been demonstrated and implicates OAEs as frequency specific indicators of cochlear amplifier integrity (Collet et al., 1991; Boege & Janssen, 2001; Mertes & Goodman, 2013). Unfortunately, attempts to predict threshold from OAEs have shown limited success (Avan et al., 1991; Hussain et al., 1998; Dorn et al., 1999; Gorga et al., 2003). The limited utility of OAEs in predicting threshold may

29 14 result from several factors. First, there is evidence that the OAE of a particular frequency (TEOAE, SFOAE, or DPOAE) is generated across a broad region of the basilar membrane (Siegel et al., 2005; Johnson et al., 2007; Withnell et al., 2008; Goodman et al., 2011; Moleti et al., 2013; Martin et al., 2013) and; therefore, the OAE may not be as frequency-specific of a measure compared to behavioral threshold. Second, behavioral threshold reflects both peripheral and central auditory processing. In contrast, OAEs, as typically measured, likely reflect only the integrity of the OHC. In light of the limitations in predicting hearing loss from OAEs, the clinical utility of OAEs has been relegated to the detection of hearing loss in infants, young children, and other individuals who are unable to perform more advanced behavioral measures. Despite the limited usefulness of evoked OAEs in predicting auditory threshold, OAEs are able to provide insight into various aspects of active cochlear mechanics. For instance, the tonotopic organization of the cochlear partition is demonstrated by OAE latency (the occurrence in time of the OAE relative that of the evoking stimulus). As the frequency of the evoking stimulus increases, the latency of the OAE decreases (Kemp, 1978; Wilson, 1980; Norton & Neely, 1987; Tognola et al., 1997; Shera & Guinan, 2003; Sisto et al., 2007). The decrease in OAE latency is consistent with the traveling wave propagating longer distances across the cochlear partition as frequency decreases. OAE latency has also been used as a measure of cochlear tuning (Shera et al., 2002; Shera & Guinan, 2003; Moleti & Sisto, 2003). If the cochlear partition (CP) is modeled as a series of minimum-phase, bandpass filters (Zweig, 1976), the bandwidth of each filter will be inversely proportional to its group delay. In cases of SNHL, damage to the OHCs (or the organ of Corti, more generally speaking) results in a decrease in the amount of gain afforded by the cochlear amplifier and the bandwidths of the cochlear filters increase. OAEs reflect this loss of tuning in that OAE latencies in ears with SNHL tend to be shorter than latencies in ears with normal hearing (Konrad-Martin & Keefe, 2005; Keefe, 2012; see Don et al., 1998). In addition to depending on the integrity of the

30 15 cochlear amplifier, cochlear gain is also level dependent such that greatest gain is provided for low-level stimuli. As stimulus level increases, the gain provided by the cochlear amplifier decreases and the excitation pattern along the CP broadens (Ruggero et al., 1997; Rhode & Recio, 2000; Rhode, 2007). Not unexpectedly, the latency of OAEs evoked by low-level stimuli is longer than that of OAEs evoked by higher-level stimuli (Neely et al., 1988; Schairer et al., 2006; Sisto & Moleti, 2007). OAE magnitude has been used to assay active mechanics including cochlear amplifier gain and tuning. This has been achieved through OAE suppression experiments and the formulation of OAE tuning curves (Brass & Kemp, 1993; Abdala et al., 1996; Abdala, 2001; Gorga et al., 2003; Gorga et al., 2011; Keefe et al., 2008). When two tones are presented to the cochlea the displacement at each tone s characteristic frequency (CF) location is suppressed by the presence of the other tone (Geisler et al., 1990; Ruggero, 1992; Ruggero et al., 1992; Geisler & Nuttall, 1997). Suppression is greatest in the region of active mechanics at and immediately basal to the tonotopic place (de Boer, 1983a; 1983b; Brass and Kemp, 1993; Killan et al., 2012). OAE amplitude is similarly subject to the effects of suppression and has been used to examine the effect of SNHL on cochlear tuning. For instance, OAE tuning curves have been measured in ears with normal hearing and ears with hearing loss. The latter demonstrate reduced cochlear gain compared to the former and are consistent with diminished action of the cochlear amplifier (Gorga et al., 2003). Yet another aspect of active mechanics that may be examined from OAEs is the nonlinear growth of CP displacement. Similar to the CP response, OAE magnitude increases nonlinearly with stimulus level (Grandori, 1985; Probst, et al., 1986; Dorn et al., 2001; Schairer et al., 2003). At low stimulus levels the OAE grows nearly linearly. As stimulus level increases, the growth of the OAE becomes increasingly compressive. This basic pattern of linear transitioning into compressive growth resembles that of the CP at a

31 16 given measurement location in response to its CF (Robles, et al., 1986; Ruggero et al., 1997; Rhode & Recio, 2000). The potential usefulness of measuring OAEs to assay active cochlear partition mechanics depends on an accurate understanding of how and where the OAE is generated. A well-known example of this is illustrated by using DPOAEs versus SFOAEs to predict hearing loss at a given frequency. Although the frequency of these OAEs might be identical, 2 khz for instance, they are generated at different locations along the cochlear partition. The 2 khz DPOAE is generated near the 3.1 khz spatial location while the 2 khz SFOAE is generated near the 2 khz spatial location. Accordingly, it would be inaccurate to try to predict the 2 khz behavioral threshold using a 2 khz DPOAE. Despite the large body of research concerning the generation mechanisms and locations of OAEs, knowledge gaps still exist. The following sections review what is known regarding the generation mechanisms of OAEs and highlights inconsistencies in the literature. Many of these inconsistencies can be traced to incomplete understanding of the generation of TEOAEs and SFOAEs and form the basis for the experiments described in the following chapters. 2.3 Generation Mechanisms Underlying Theories The two most common theories of OAE generation are linear coherent reflection (LCR) and nonlinear distortion (NLD; Zweig & Shera, 1995; Shera & Guinan, 1999). LCR depends on the presence of randomly distributed impedance irregularities across the basilar membrane. In other words, the basilar membrane is not smooth but rough. As the cochlear traveling wave moves along the cochlear partition, it encounters the impedance discontinuities and portions of the wave are reflected back toward the stapes. Majority of these backscattered wavelets interact destructively with each other due to phase differences; however, wavelets reflected near the peak of the traveling wave interact

32 17 constructively and can be measured as an OAE in the ear canal (Zweig & Shera, 1995). The peak of the traveling wave is optimal for constructive interaction between reflected wavelets because of its large amplitude, broad spatial width, and constant wavelength (for review see Shera & Guinan, 2008). The term place-fixed (Kemp, 1986) is frequently used to refer to the LCR mechanism since the impedance discontinuities responsible for the OAE are a physical characteristic of the basilar membrane. Nonlinear distortion OAE generation is founded upon cochlear nonlinearity. The traveling wave induces distortion at and around the spatial location of its peak where the cochlear response is highly nonlinear. The distortion generates a reverse-traveling wavelet of the same frequency as the evoking stimulus. If the wavelet is of sufficient amplitude, an OAE may be measured in the ear canal. Additionally, if multiple, closely spaced tones are simultaneously presented to the ear, intermodulation distortion occurs, resulting in wavelets at frequencies corresponding to integer combinations of the evoking stimulus frequencies. These wavelets can similarly be measured in the ear canal as OAEs. The term wave-fixed (Kemp, 1986) is frequently used to refer to the NLD mechanism since the OAE is generated by a distortion source induced by the cochlear traveling wave(s). LCR and NLD each predict contrasting phase behavior for the OAE across frequency, so that the phase of the OAE can be used to determine its generation mechanism. The phase behavior of OAEs generated through NLD depends on the cochlea being scaling-symmetric (Rhode, 1971; Zweig, 1976). In a perfectly scalingsymmetric cochlea, the traveling wave rotates through the same number of cycles to reach its CF place, regardless of frequency. Consider two OAEs, P OAE1 and P OAE2, evoked by non-simultaneously presented pure tones, f 1 and f 2 ( f 2 > f 1 ), respectively: The cochlear traveling waves for f 1 and f 2 both rotate through the same number of cycles to their characteristic locations on the basilar membrane (BM), x 1 and x 2, respectively, despite x 1 being a further distance from the cochlear base than x 2. At each site, the

33 18 mechanics are nonlinear and a distortion source OAE is generated. Because the traveling waves for the two tones accumulated the same amount of phase delay by the time they reached their characteristic locations and induced distortion, the generated OAEs also have the same phase,!p OAE1 "!P OAE 2 (Shera & Guinan, 1999). NLD similarly predicts constant phase across frequency for OAEs generated by intermodulation distortion. For two pure tones simultaneously presented to the cochlea, intermodulation distortion occurs at the cochlear location corresponding to maximum overlap of the two tones traveling waves (Hall, 1974; Gaskill & Brown, 1990). The distortion source generates forward and reverse traveling waves. The reverse traveling wave is measured as a distortion-source OAE. If the ratio of the two pure tones is maintained, such that the spatial distance on the basilar membrane is held constant, and the frequencies are swept, the different frequency distortion-source OAEs will have nearly identical phases (Shera & Guinan, 1999; Knight & Kemp, 2001). In contrast to NLD generation, the OAE resulting from coherent reflection does not originate from a source induced by the wave but rather through reflection of the wave off pre-existing irregularities in the BM mechanics. The phase of the emitted emission thus corresponds to the time-delay imposed by the round-trip travel time of the cochlear traveling wave from the stapes to the characteristic frequency spatial location (Shera & Guinan, 1999). Consistent with the tonotopic arrangement of the basilar membrane, the phase of the OAE is expected to rotate rapidly across frequency. The phase predictions of both theories imply different OAE latencies when latency is quantified in terms of group delay (! ),! =! "", Eq. 2.1 "# where! is in seconds and the quantity!"! "" is minus the first derivative of unwrapped phase with respect to radian frequency. Since the phase of the OAE across

34 19 frequency is predicted to be constant for NLD generation, the expected group delay is approximately zero milliseconds,! NLD! 0 milliseconds. In practice, group delay is small, but non-zero due to the cochlea not being perfectly scaling symmetric. In contrast, LCR theory predicts an OAE group delay approximately twice the basilar membrane group delay,! LCR! 2! BM (Shera & Guinan, 1999; Shera & Guinan, 2003; see Shera et al., 2008). Accordingly, the generating mechanism of a particular OAE can be inferred from the phase response Generation of DPOAEs There is general consensus that the DPOAE includes contributions from both NLD and LCR generators (Shera & Guinan, 1999; Talmadge et al., 1999; Knight & Kemp, 2001; Kalluri & Shera, 2001; Konrad-Martin et al., 2001; Long et al., 2008; Vetešník et al., 2009). The observation that the simultaneous presentation of two tones, f 1 and f 2 ( f 2 > f 1 ), causes the generation of a third tone, f DP, necessarily implies a nonlinear mechanism. Nonlinear system theory would suggest that distortion is most pronounced when the input to the underlying nonlinearity is greatest. In the cochlea, this presumably occurs in the region where the traveling waves of the two primary tones maximally overlap near the f 2 tonotopic place (Hall, 1974; Gaskill & Brown, 1990; Martin et al., 1998; Talmadge et al., 1999; Knight & Kemp, 2000; Gorga et al., 2011; but see Martin et al., 1987; Knight & Kemp, 2001; Martin et al., 2013 for nonlinear interactions basal to the f 2 place). The distortion induced at f 2 generates both forward- (toward the cochlear apex) and reverse-traveling (toward the cochlear base) wavelets at various intermodulation frequencies. In mammals, the dominant intermodulation distortion product is 2 f 1! f 2 ( f 2 f 1 =1.22 ). In the case of 2 f 1! f 2 distortion, the reverse-traveling wavelet is transduced into an acoustic pressure in the ear canal and can be measured as an OAE. This particular component of the DPOAE is commonly referred to as a distortionsource OAE, given its nonlinear origin. Consistent with NLD generation theory and a