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1 University of Iowa Iowa Research Online Theses and Dissertations Spring 2016 The effect that design of the Nucleus Intracochlear Electrode Array and age of onset of hearing loss have on electrically evoked compound action potential growth and spread of excitation functions Li-Kuei Chiou University of Iowa Copyright 2016 LIKUEI CHIOU This dissertation is available at Iowa Research Online: Recommended Citation Chiou, Li-Kuei. "The effect that design of the Nucleus Intracochlear Electrode Array and age of onset of hearing loss have on electrically evoked compound action potential growth and spread of excitation functions." PhD (Doctor of Philosophy) thesis, University of Iowa, Follow this and additional works at: Part of the Speech Pathology and Audiology Commons

2 THE EFFECT THAT DESIGN OF THE NUCLEUS INTRACOCHLEAR ELECTRODE ARRAY AND AGE OF ONSET OF HEARING LOSS HAVE ON ELECTRICALLY EVOKED COMPOUND ACTION POTENTIAL GROWTH AND SPREAD OF EXCITATION FUNCTIONS by Li-Kuei Chiou 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 May 2016 Thesis Supervisor: Professor Carolyn J Brown

3 Copyright by Li-Kuei Chiou 2016 All Rights Reserved

4 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 Li-Kuei Chiou has been approved by the Examining Committee for the thesis requirement for the Doctor of Philosophy degree in Speech and Hearing Science at the May 2016 graduation. Thesis Committee: Carolyn J Brown, Thesis Supervisor Paul J Abbas Marlan Hansen Lenore Holte Jacob Oleson

5 To Yusheng Chiu, my deaf and talented brother ii

6 BIG THANKS to the following people: ACKNOWLEDGMENTS Carolyn Brown is not only my super advisor but also my life mentor. She has helped me go through ups and downs through this process. It is amazing that she completed this impossible mission that she finally kicked me out of the school. Paul Abbas has provided invaluable research feedback and excellent pizza and bread. Christine Etler, Viral Tejani, Rachel Scheperle, and Julie Jeon are the best lab team and friends who have given me priceless assistance and support. Barb Gienapp, Sue Dunn, Megan Asklof, and Lisa Stille are my lovely coworkers who have offered me mental support and boosted confidence in myself. My husband and my daughter have been so tolerant of a too-busy wife and mom. Committee members have been a valuable resource. My project would not have been possible without the study participants. Financial support for this project was provided by the National Institutes of Health, National Institute on Deafness and Other Communication Disorders under award P50DC iii

7 ABSTRACT The purpose of this study was to investigate how design changes in Cochlear Nucleus cochlear implants (CIs) (CI24M, CI24R, CI24RE and CI422) affected electrode impedance and ECAP measures, and to determine if these design changes affected postlingually deafened adults and children with congenital hearing loss in a similar way. Results of this study showed that electrode impedance was inversely related to the area of the electrode contacts in the array: lowest for the full-banded CI24M CI and highest for adults who used the CI422 device which has the smallest electrode contacts of all four devices. The noise floor of the NRT system likely plays a significant role in the finding that CI users with older devices (the CI24M, and CI24R CIs) had higher ECAP thresholds than individuals with the CI24RE electrode array. The position of the electrode array in the cochlea was also found to have a significant effect on ECAP measures. CI users with modiolar hugging (the CI24R and CI24RE CIs) electrode arrays were found to have lower ECAP thresholds than CI users whose electrode arrays were seated more laterally in the cochlear duct (e.g. the CI24M and CI422 implants). The position of the electrode contacts relative to the modiolus of the cochlea was found to be related to slope of the ECAP growth functions. The lowest slopes were found in CI24RE users. It also had a significant impact on the width of the channel interaction function. Electrode arrays seated further from the modiolus have significantly more channel interaction than electrode arrays that hug the modiolus of the cochlea. Differences between results recorded from post-lingually deafened adults and children with congenital hearing loss were minimal. The difference only reflected on the ECAP slopes. Slopes in children with congenital hearing loss were significantly steeper than those recorded from adults. This may indicate that children with congenital hearing loss may have better neural survival than adults with acquired hearing loss. In conclusion, the results of the current study show evidence of the effects of variations in design and function of the implanted components of the Nucleus CI. Perhaps iv

8 the most significant finding from the current data set is that electrode arrays located closer to the modiolus of the cochlea have lower thresholds and exhibit less channel interaction than electrode arrays that are positioned more laterally. An argument could be made that lower stimulation levels and less channel interaction may result in better outcomes and/or longer battery life. For CI candidates who do not have significant residual acoustic hearing, the CI24RE implant might be a better choice than the more recently introduced CI422 electrode array. v

9 PUBLIC ABSTRACT Since the Nucleus cochlear implant (CI) was first introduced into clinical practice in the mid-1980 s, there have been several changes in the design of the intracochlear electrode array and in the neural response telemetry (NRT) system used to record electrically evoked compound action potentials (ECAP). ECAPs are the most direct measure of the peripheral auditory system that available today. The purpose of this study was to assess the impact that these changes (CI24M, CI24R, CI24RE and CI422) had on electrode impedance and on ECAP measures in both post-lingually deafened adults and children with congenital hearing loss. These results demonstrate that variation in design and function of the implanted components of the Nucleus CI are not without consequences. The most significant finding from the current data set is that children CI users may have better neural survival than adult users. Also, electrode arrays located closer to the modiolus of the cochlea have lower thresholds and exhibit less channel interaction than electrode arrays that are positioned more laterally. There is no data to suggest that a lateral wall placement of the electrode array is linked to poorer performance on measures of speech perception, however, an argument could be made that changes in electrode design that result in greater channel interaction could potentially have a negative rather than positive impact on performance and, for example, use of a more modiolar hugging design might be preferable for CI candidates who do not have significant residual acoustic hearing. Specifically, the CI24RE implant might be a better choice than the more recently introduced CI422 electrode array if hearing preservation is not an issue. vi

10 TABLE OF CONTENTS LIST OF TABLES... ix LIST OF FIGURES...x LIST OF ABBREVIATIONS... xi CHAPTER 1 INTRODUCTION The Relationship between Electrode Array Design and Responsiveness to Electrical Stimulation Effect That Differences in Cochlear Anatomy May Have on Responsiveness to Electrical Stimulation Differences between Individuals with Congenital Versus Acquired Hearing Loss The Purpose of This Study...10 CHAPTER 2 REVIEW OF THE LITERATURE Overview of Changes in the Nucleus Electrode Array and Telemetry Systems (1997 to 2012) Nucleus CI24M Cochlear Implant Nucleus CI24R Cochlear Implant Nucleus CI24RE Cochlear Implant Nucleus CI422 Cochlear Implant ECAP Growth Functions ECAP Channel Interaction Functions Methods of Quantifying Channel Interaction Effect of Probe and Masker Levels on Channel Interaction Functions The Impact of Electrode Design or Anatomic Differences on ECAP Growth and Channel Interaction Functions Location of the Electrode Array within the Cochlea Fibrous Tissue and New Bone Formation Spiral Ganglion Cell Survival...34 CHAPTER 3 METHODS Participants General Procedures ECAP Growth Functions Stimulation and Recording Procedures Data Analysis ECAP Channel Interaction Functions Stimulation and Recording Procedures Data Analysis...41 CHAPTER 4 RESULTS Individual Data ECAP Growth Function ECAP Channel Interaction Function Mean Trends Electrode Impedance...58 vii

11 4.2.2 ECAP Threshold ECAP Slope Channel Interaction Functions...62 CHAPTER 5 DISCUSSION Electrode Impedance ECAP Growth Functions ECAP Channel Interaction Functions Age Effect Conclusions...83 REFERENCES...85 viii

12 LIST OF TABLES Table 1. Summary of Key Differences between CI24M, CI24R, CI24RE & CI Table 2. CI24M Subject Demographic Data...44 Table 3. CI24RSubject Demographic Data...45 Table 4. CI24RE Subject Demographic Data...46 Table 5. CI422 Subject Demographic Data...47 Table 6. Results of Linear Mixed Model Analysis ix

13 LIST OF FIGURES Figure 1. the Forward-Masking Subtraction Method Figure 2. ECAP Waveforms and ECAP Growth Function Figure 3. Comparison between the Linked and Fixed Masker Method Figure 4. Comparison of Spatial Spread Function and Channel Interaction Function Figure 5. Effect of Changing Masker Electrode Position on ECAP Response Figure 6. Different ECAP Amplitude Criteria for Devices with Different Noise Floor Figure 7. ECAP Waveforms for Channel Interaction Measures...54 Figure 8. Channel Interaction Function Figure 9. Individual ECAP Growth Functions Figure 10. Individual Channel Interaction Functions Figure 11. Effect of Device Type, Electrode Position and Age group on Electrode Impedance Figure 12. Effect of Device Type, Electrode Position and Age group on ECAP Thresholds Figure 13. Effect of Device Type, Electrode Position and Age group on ECAP Slopes Figure 14.. Effect of Device Type, Electrode Position and Age group on CII Figure 15. Mean Normalized Channel Interaction Functions for CI24M and CI24R Devices in Adults and Children Figure 16. Mean Normalized Channel Interaction Functions for CI422 and CI24RE Devices in Adults x

14 LIST OF ABBREVIATIONS Auditory Brainstem Response Channel Interaction Index Cochlear Implant Current Unit Dynamic Range Electrically Evoked Auditory Brainstem Response Electrically Evoked Compound Action Potential Electrode Interpulse Interval Initial Stimulation Masker-probe Interval Milliamperes Milliseconds ABR CII CI CU DR EABR ECAP E IPI IS MPI ma ms MicroVolts µv MicroSecond µs Monopolar Most Comfortable Level Neural Response Telemetry Spiral Ganglion Cell U.S. Food and Drug administration MP MCL NRT SGC FDA xi

15 1 CHAPTER 1 INTRODUCTION Cochlear implants (CI) have become the treatment of choice for both adults and children with severe-to-profound sensorineural hearing loss. The speech processor of the CI samples the acoustic environment and transforms the acoustic signal into a series of electrical pulses that stimulate the auditory nerve fibers in the cochlea. Neural information is then transmitted normally through the auditory system to the cortex. Success with a multichannel CI is contingent upon many factors. One factor that is likely to impact outcome with a CI is the ability of the device to stimulate discrete subpopulations of auditory nerve fibers and in so doing, to form independent neural channels of stimulation. The extent to which that is possible depends on the number of intracochlear electrodes that the implanted electrode array has and the spacing of those electrodes. Clearly, performance with a multichannel CI is better than performance with a single channel CI (Gantz et al., 1988; Rubinstein & Miller, 1999). However, two electrodes that are located very close to each other may stimulate the same population of neurons. This phenomenon is termed channel interaction. Increasing the number of intracochlear electrodes or decreasing the spacing of those electrodes can result in greater channel interaction and may limit overall performance. For example, there is evidence in the literature to suggest that speech recognition fails to improve with more than 8 to 10 intracochlear electrodes (Fishman, Shannon, & Slattery, 1997; Fu, Shannon, & Wang, 1998; Friesen, Shannon, Baskent, & Wang, 2001). This finding seems to support the contention that increasing the number of electrode contacts and/or decreasing the spacing between electrodes might limit the number of independent neural channels of stimulation and potentially adversely affect performance. A second factor that could influence the number of independent channels of stimulation that can be achieved is the size and orientation of the electrode contacts and

16 2 how the electrode array is located in the cochlea. More specifically, how close the implanted electrodes are to the surviving auditory nerve fibers. In the 1990 s, cochlear implants marketed by Cochlear Corporation featured intracochlear electrode arrays that had full-banded contacts mounted on a straight electrode carrier. The electrode array was designed to lie along the lateral wall of the scala tympani. In 2005, the Nucleus CI24RE electrode array was introduced. This device was designed to hug the modiolus of the cochlea and featured half banded electrode contacts oriented toward the modiolus on a pre-curled silastic carrier. The idea behind this design change was that positioning the electrode contacts closer to the auditory neurons would result in lower stimulation levels and less channel interaction. Recently, there has been a trend toward the development of electrode arrays that can be inserted with as little trauma as possible into the cochlea. The result has been the introduction of electrode arrays such as the Nucleus CI422 that are thinner, flexible and are not pre-curled. These electrode arrays are designed to be inserted with minimal trauma into the cochlea often via the round window rather than a cochleostomy. It seems reasonable to assume that these changes in electrode design could also influence how current spreads in the cochlea and, in turn, affect stimulation thresholds, the size of the electrical dynamic range (DR) as well as channel interaction measures. A third factor that could influence performance with a CI is related to cochlear anatomy. For example, how much channel interaction occurs is likely to depend on anatomic factors like the relative density and location of surviving spiral ganglion cells (SGCs) as well as the presence or absence of fibrous tissue growth in the cochlea. Both factors are likely to vary across and within individuals, may change over time and may be different in adults with acquired sensorineural hearing loss versus children born with hearing impairment. Again, it seems reasonable to assume that factors could contribute, at least in part, to the wide variance in post-implant performance that is routinely

17 3 observed (Gantz et al., 1988; Parkin & Parkin, 1994; Sarant et al., 2001; Finley et al., 2008). 1.1 The Relationship between Electrode Array Design and Responsiveness to Electrical Stimulation This study explores how changes in the design of the intracochlear electrode array of the Nucleus CI system, marketed by Cochlear Ltd. (Sydney, Australia), impact the response of the auditory nerve to electrical stimulation. The specific devices that we compare include the Nucleus CI24M, CI24R, CI24RE and CI422 cochlear implants. Device differences are summarized briefly here but in more detail in the next chapter. The CI24M device was introduced in It featured an electrode array that was full banded and designed to lie along the lateral wall of the cochlea. The CI24R and CI24RE CIs were introduced in 2000 and 2005 respectively. Both had 22 intracochlear electrodes but they were half-banded and were mounted on a pre-curled silastic carrier that was designed to hug the modiolar wall of the cochlea. In addition, the CI24RE CI was equipped with a low-noise floor amplifier used to measure electrically evoked compound action potentials. In 2012, the CI422 electrode array was introduced. This electrode array again had 22 contacts but they were smaller than those used previously and the array itself is straight and thin. Like the original CI24M device, the CI422 electrode array is designed to lie along the lateral wall of the cochlea. There have been previous studies that have explored the effect that the electrode design has on perceptual factors like stimulation threshold, DR and channel interaction. For example, Cohen et al. (2001) performed psychophysical measurements in three patients implanted with CI22 device pre-curved arrays and one patient implanted with a standard array. They showed that the modiolar hugging electrode array resulted in reduced threshold and most comfortable level (MCL), increased DR, and better electrode discrimination. Saunders et al. (2002) correlated psychophysical measures of threshold

18 4 and comfortable levels to distance of the electrode from the modiolus in Nucleus 24 implant users. They found that, at the time of initial stimulation, users of the CI24R device, which lies closer to the modiolus, had significantly lower thresholds than users of the CI24M device, which lies along the outer wall of the cochlea. Two years later, Firszt et al. (2003) used evoked potential measures to examine the effect of electrode location within the cochlea. They compared wave V of EABR before and immediately after placement of a silastic electrode positioner in twenty-five Clarion HiFocus users. Moving the electrode array closer to the modiolus of the cochlea and the surviving SGCs resulted in decreased EABR wave V thresholds and increased ABR wave V amplitudes for supra-threshold stimuli. Collectively, the results of these studies suggest that changes in the design of the intracochlear electrode array have the potential to impact ECAP threshold, rate of growth with increasing stimulation levels and peripherally based measures of channel interaction. 1.2 Effect That Differences in Cochlear Anatomy May Have on Responsiveness to Electrical Stimulation It is also likely that neural survival varies across CI users. Differences in the number of surviving nerve fibers or distribution of these fibers across the cochlea could also impact ECAP growth and/or channel interaction measures. Electrically evoked auditory potentials have long been used to try to estimate neural survival and channel interaction in CI users. For example, Smith and Simons (1983) recorded EABRs in cat ears with different degrees of neural degeneration. No EABRs were recorded in cats with complete loss of SGCs. Cats with more surviving neural cells typically had steeper EABR growth functions. They concluded that measures of EABR amplitude and/or slope of the EABR growth function could serve as a predictor of the number of surviving SGCs. Lusted et al (1984) also demonstrated that the slope of growth function of the EABR is proportional to the quantity of SGCs in the stimulated cat cochlea. In 1990, Hall

19 5 analyzed wave I of the EABR recorded from deafened rats and also demonstrated that slope of the EABR growth function was directly correlated with the number of surviving SGCs. Miller, Abbas, & Robinson, (1994) measured EABR growth functions from deafened guinea pigs and reported finding a significant correlation between slope of the EABR growth function and number of surviving SGCs. More recently, Shinohara et al., (2002) reported finding a correlation between EABR thresholds measured from chemically deafened guinea pigs and the density of surviving SGCs. The conclusion reached by these investigators was that steeper growth functions for wave I of the ABR or the ECAP would be expected in ears with more surviving auditory nerve fibers adjacent to the stimulating electrode. While slope of the ECAP or EABR growth function may be related to the number of surviving SCGs in a specific cochlea, it may also be related to the distance between the electrode contact and the point where auditory neuron is activated. For example, Shepherd, Hatsushika, and Clark (1993) compared electrode location to EABR growth functions recorded from in ten adult cats. In this study, the period between deafening and data collection was varied from four months to three years in order to allow time for the degeneration of SGCs to occur. Hearing loss in these cats ranged from normal to profoundly deaf and histology showed that the cats had different patterns of surviving spiral ganglion cells and peripheral processes. EABR responses were recorded using an electrode placed at four different locations within the cochlea: along the outer wall, near the modiolus, close to the spiral ganglion and underneath the peripheral processes. They found a clear reduction in EABR threshold and significantly more shallow EABR growth functions when the stimulating electrode was near the peripheral processes compared to any of the other three locations. They interpret their findings to suggest that when the stimulating electrode is close to the surviving auditory neurons and stimulation levels are low, current spread in the cochlea is minimal and the number of additional neurons activated for each increment in stimulation level is fairly small resulting in the shallow

20 6 growth functions observed. Conversely, electrodes located further from the stimulable neural tissue require the use of higher stimulation levels to reach threshold. At these higher stimulation levels, current spread in the cochlea is greater and the number of neurons recruited for each increment in stimulation level is larger. This results in higher thresholds and steeper growth slopes. Cochlear modeling studies (Frijns, de Snoo, & Schoonhoven, 1995) have also shown that excitation thresholds and growth slopes depend on electrode site. The model predictions were in good agreement with the experimental results by Sheperd et al. (1993). Finally, human temporal bone studies have shown that the pattern of neuron survival can vary among individuals, even for individuals with the same degree of hearing loss (Kawano, Seldon, Clark, Ramsden, & Raine, 1998; Nadol, 1990a; Zimmermann, Burgess, & Nadol, 1995). Surviving SGCs may be damaged and the degree of damage can vary across subjects and across time. Typically, the peripheral processes degenerate first, followed by the cell body and then the remainder of the nerve fiber (Nadol, 1990b). Previously, a group of investigators measured ABRs in experimental mice with peripheral myelin deficiency (Zhou, Assouline, Abbas, Messing, & Gantz, 1995). Their histological examination revealed that there was myelin deficiency of the auditory nerve fibers that were accompanied by a loss of peripheral processes and a loss of spiral ganglion cell bodies. They reported shallower slope of the ABR growth functions and elevated thresholds in mice with severe myelin deficiency and/or substantial loss of nerve fibers (Zhou, Assouline, Abbas, Messing, & Gantz, 1995). For CI users, loss of SGCs or significant atrophy of peripheral processes within the cochlea could increase the distance between the stimulable neural tissue and the electrode and that, in turn, could affect the ECAP or EABR growth function. Rattay, Leao, & Felix, (2001) used computer modeling to demonstrate that neurons with lost peripheral processes need higher stimulus currents because their excitable structures are located farther away from the electrode contacts.

21 7 We know that both behavioral and physiologic measures can change over time (Hughes et al., 2001; Henkin et al., 2003). Those changes could be due, at least in part, to changes in how current flows within the cochlea. For example, the degree to which the electrode array is encapsulated by fibrous tissue or new bone growth can change during the initial months following implantation. Clark et al (1995) reported finding a positive correlation between the growth of tissue around the electrode array and electrode impedance in cats. Fibrous tissue or new bone growth has also been observed in human temporal bone specimens obtained from CI users (Kawano et al, 1998; Nadol et al., 2001). These anatomic changes could modify the paths of current flow and alter both ECAP threshold and the way neurons are recruited as stimulation level is increased. One might speculate that fibrous tissue or new bone growth may result in increased distance between the electrode contacts and the modiolus of the cochlea and this in turn could lead to increased thresholds and steeper ECAP growth functions. Collectively, the results of these studies suggest that anatomic differences exist across subjects and may also impact ECAP threshold, the slope of the ECAP growth function and peripherally based measures of channel interaction. 1.3 Differences between Individuals with Congenital Versus Acquired Hearing Loss CIs are routinely used both for children born with congenital hearing loss and for adults who acquire their hearing loss after they learn to speak. It seems likely that the pathophysiology of deafness in these two groups will not be the same. Very few studies have reported differences in peripherally generated auditory evoked responses recorded from pediatric CI users who have been deaf since birth and post-lingually deafened, adult CI users. Hughes et al. (2001) measured changes in electrode impedance as well as the threshold and slope of the ECAP growth functions recorded from both pediatric and adult CI24M cochlear implant users over a 24 month period following insertion of the

22 8 electrode array. They found that for pediatric CI users, electrode impedance increased over time for electrodes in the basal, middle and apical region of the cochlea, whereas this trend toward increases in electrode impedance over time was limited to the basal electrodes only for adult CI users. Hughes et al. (2001) proposed that this impedance change may have resulted from fibrous tissue or new bone growth in the cochlea and that this phenomenon may affect the whole cochlea for pediatric CI recipients but may be limited to the base of the cochlea in adults. In addition to changes in electrode impedance, Hughes et al. (2001) found also that threshold remained fairly stable but that the slope of the ECAP growth functions was steeper for pediatric CI users than it was for adult CI users. They hypothesized that this finding is consistent with the assumption that children may have more fibrous tissue growth and bony formation than adults, resulting in different current flow pathways within the cochlea. More recently, Brown et al. (2010) examined long-term changes in ECAPs for Nucleus CI users. These investigators measured the ECAP threshold and slope over a period of up to 96 months after initial stimulation. They studied both pediatric and adult CI recipients who used both the Nucleus CI24M and CI24R cochlear implants. ECAP threshold and slope measures were found to be stable over time, but like Hughes et al. (2001), Brown et al. (2010) also showed that children who used either the CI24M or CI24R cochlear implants had significantly steeper ECAP growth functions than adults. Additionally, the pediatric CI users had slightly higher ECAP thresholds than the adults. Brown et al. (2010) propose that this observation higher ECAP thresholds and steeper slopes could be a reflection of a systematic difference in distance between the intracochlear electrodes and the site of stimulation within the cochlea for children and adults. Brown et al. (2010) describe two different theories for why this might occur. First, congenitally deaf children who receive a CI may develop more fibrous tissue than post-lingually deafened adults and as a result the current fields within the cochlea could

23 9 be altered such that there is effectively more distance between the stimulating electrode contact and the point on the auditory nerve where stimulation occurs. An alternate explanation may be that pediatric CI users have fewer or shorter surviving peripheral processes than adults. Neither the Hughes et al. (2001) nor the Brown et al. (2010) studies provide evidence that allows us to evaluate which hypothesis is correct. Do pediatric CI users have steeper ECAP growth functions than adults because they have more fibrous tissue in their cochlea or because they have fewer or shorter surviving peripheral processes? One way to distinguish between these two hypotheses may be by using the ECAPs to measure channel interaction at the auditory periphery from both pediatric and adult CI users. ECAPs are traditionally measured using a two-pulse forward masking paradigm. Two biphasic current pulses termed a masker and probe pulse are introduced. These two pulses are separated by a short interpulse interval (IPI). If the IPI is short enough, neurons that respond to the masker will be refractory and will not be able to respond to the probe. If the masker and probe are applied to the same electrode, there will be maximal overlap between the population of neurons responding to the probe and the masker and because of the subtraction used to minimize electrical artifact, the ECAP amplitude will be large. When the masker and probe are applied to different electrodes, there will be less neural overlap between the populations of neurons stimulated by the masker and by the probe and the ECAP amplitude will be smaller. Channel interaction functions are graphs showing amplitude of the ECAP as a function of masker electrode for a fixed probe electrode. If current is spreading widely across the cochlea, we would expect that these channel interaction functions will be broad. If current flow is more restricted, channel interaction functions should be narrower.

24 The Purpose of This Study The primary goal of this study is to investigate how changes in cochlear implant design affect electrode impedance and measures of ECAP threshold, growth and channel interaction. A secondary goal is to contrast results obtained from adults who were postlingually deafened with results obtained from children who have been deaf since birth. Our focus is on CIs marketed by Cochlear Ltd. (Sydney, Australia). The specific devices that we compare include the Nucleus CI24M, CI24R, CI24RE and CI422 cochlear implants. Our first goal is to test several specific hypotheses that we have regarding how changes in the intracochlear electrode array have impacted measures of the electrically evoked compound action potentials recorded using neural telemetry software. These hypotheses are summarized below. 1. Because electrode impedance is inversely related to the size of the electrical contact, we hypothesize that the CI24M and CI24R implants will have lower average electrode impedance values than the CI24RE or CI422 device, both of which have smaller electrode contacts. 2. Devices with a higher noise floor (CI24M and CI24R) will have higher ECAP thresholds than those with a lower noise floor (CI24RE and CI422). 3. Electrode arrays that are seated closer to the modiolus of the cochlea (i.e., the CI24RE and CI24R CIs) will have lower ECAP thresholds, shallower ECAP growth functions and less channel interaction than similar measures recorded from individuals who use devices where the electrodes are located along the lateral wall of the cochlea (i.e., the CI24M and CI422 CIs). Our second goal is to compare measures of ECAP threshold, growth and channel interaction in children who have been deaf since birth with similar results obtained from

25 11 post-lingually deafened adults. We hypothesize that there may be systematic differences between the cochleae of children with congenital hearing loss compared to adults with acquired losses. For example, children who were born deaf have more fibrous tissue growth in their cochlea than adults. Unfortunately, there is no way to assess directly the amount of fibrous tissue growth that has occurred in a specific cochlea following cochlear implantation. However, if the growth of fibrous tissue in the cochlea alters current flow patterns, we would expect it to also affect ECAP growth and channel interaction measures. Therefore, in this study we report comparisons between ECAP growth and channel interaction functions recorded from post-lingually deafened adults and children with who have been deaf since birth. ECAPs are the most direct measure of the peripheral auditory system that available today and we hypothesize that if fibrous tissue reactions are more robust in children with congenital hearing loss than they are in adults who lose their hearing later in life, the ECAP growth functions recorded from children with congenital hearing loss may be steeper and the channel interaction functions wider than similar measures recorded from post-lingually deafened adults. While there is evidence in the literature to suggest that both the location and design of the electrode array may impact neural telemetry measures and while we can find evidence in the literature that there are differences between adult and pediatric CI users, this study will be unique in that it will address both factors (electrode design and population) systematically and expand our understanding of how the response of the auditory nerve (more specifically, ECAP threshold, growth and channel interactions measures) to electrical stimulation. Such information could impact future design changes and should provide evidence to help inform decisions about which electrode array to select for a prospective cochlear implant recipient.

26 12 CHAPTER 2 REVIEW OF THE LITERATURE This chapter starts with a brief description of how the intracochlear electrode arrays and telemetry systems in the Nucleus CI have evolved. That is followed by an overview of how the neural telemetry system of the Nucleus CI works and how it can be used to record ECAP growth and channel interaction functions. Finally, a review of published literature is included that describes how differences either in the design of the intracochlear electrode array or differences in cochlear anatomy affect these measures of peripheral neural response to electrical stimulation. 2.1 Overview of Changes in the Nucleus Electrode Array and Telemetry Systems (1997 to 2012) The intracochlear electrode array of all of the Nucleus 24 CIs have 22 platinum electrodes designed to be inserted into the scala tympani. Electrode 1 is the most basal electrode and 22 is the most apical. The Nucleus 24 CI also has two extra-cochlear reference electrodes. One is a ball or rod shaped electrode (MP1) positioned under the temporalis muscle. The other is a plate electrode (MP2) located on the receiver/stimulator package. They also are equipped with a telemetry system which allows radio frequency pulses from the internal electronics to be sent back out to the externally worn coil. This telemetry system can be used to monitor electrode integrity or to record ECAPs. The telemetry system used to record the ECAP is called the Neural Response Telemetry (NRT). The NRT system allows clinicians to stimulate one of the intracochlear electrodes relative to one of the extra-cochlear grounds and then to record the neural response from a second electrode relative to the second ground electrode (Abbas et al., 2000; Brown et al., 2000; Saunders et al., 2002). The intracochlear array and the electronic components used with the NRT system have evolved over the years and are described briefly below and summarized in Table 1.

27 Nucleus CI24M Cochlear Implant The Nucleus CI24M electrode array was introduced in 1998 and featured 22 full band electrodes. The electrode contacts are mounted on a silastic carrier and the width of that silastic carrier tapers off from the basal to the apical end. The surface area of each electrode contact on the CI24M device also decreases systematically in a basal to apical direction. Electrode contacts are equally spaced 0.75 millimeters apart along the length of the electrode array. The silastic carrier is straight and flexible. It is designed to lie along the lateral surface of the scala tympani. The tapering design facilitates insertion and accommodates the changes in diameter of the scala tympani (Saunders et al., 2002). The CI24M cochlear implant was the first Nucleus CI that had NRT capabilities. The amplifier on the electrode chip had a noise floor of approximately 15 µv when used with a gain of 60 db (Patrick et al., 2006). The NRT system is designed to record a series of 16 samples after the probe pulse is presented using a maximum sampling rate of 10 khz Nucleus CI24R Cochlear Implant In 2000, the CI24R was approved by FDA. This device has 22 half-banded electrode contacts mounted on a pre-coiled silastic carrier. A stylet wire inserted into the silicone carrier keeps the electrode array in a straight position before insertion. During the insertion process, the stylet is removed and the electrode array curls toward the modular wall and moving the electrode contacts closer to the target neural elements (Saunders et al., 2002). The idea behind this modiolar hugging design of the CI24R array was to help minimize the amount of current spread away from target spiral ganglion cells. Temporal bone studies have confirmed that the Nucleus CI24 Contour electrode array can be placed in a peri-modiolar position (Balkany, Eshraghi, & Yang, 2002; Richter et al., 2001; Tykocinski et al., 2001). Inter-electrode spacing varies from 0.7 millimeters at the

28 14 base and 0.6 millimeters at the apex to maintain equal radial distance relative to the modiolus. The NRT system used with this device was the same as that used with the CI24M CI. The amplifier on the electrode chip had a noise floor of approximately 15 µv at the amplifier gain setting of 60 db (Patrick et al., 2006). The NRT is designed to record a series of 16 samples after each stimulus pulse, with a maximum sampling rate of 10 khz Nucleus CI24RE Cochlear Implant In 2005, the CI24RE electrode array was introduced to clinical practice. The implanted electronic components were redesigned such that the amplifier used for NRT had a lower noise floor than was used in previous cochlear implants. The noise floor of the CI24RE device was estimated to be approximately 5 µv at the amplifier gain of 60 db (Patrick et al., 2006) and it could sample intracochlear voltages at a rate of approximately 20 khz. Like its predecessor, the CI24RE device was also half banded and modiolar hugging. It was also inserted using a stylet. The CI24RE differed from CI24R electrode array in that it included a soft tip at the most apical end of the electrode array that was described by the manufacturers as a design change that might limit insertion trauma Nucleus CI422 Cochlear Implant In 2012, Cochlear introduced the CI422 electrode array. The Nucleus CI422 straight array uses the same electronic receiver stimulator package as the CI24RE device. The electrode contacts in this electrode array, however, are smaller with surface areas ranging from 0.19 to 0.14mm. Like the CI24M device, the intra-cochlear electrodes are mounted on a straight silastic electrode carrier but the dimensions of this silastic carrier are smaller than those used in previous versions of the Nucleus CI system. The smaller dimensions and straight electrode design have been viewed as a way to reduce trauma when it is inserted into the cochlea. This electrode array is designed to be fully inserted

29 15 into the cochlea either through a cochleostomy or via the round window in subjects with either no or very limited residual hearing or partially inserted in subjects with more residual low frequency hearing. Skarzynski et al. (2010), who studied 22 temporal bones implanted with the CI422 electrode array, found very little insertion trauma for partial insertions and only slightly more for fully insertions. 2.2 ECAP Growth Functions ECAPs were first measured in Ineraid CI users (Brown, Abbas, & Gantz, 1990). They are recordings of the synchronous response of multiple auditory nerve fibers to electrical stimulation. The Ineraid device used a percutaneous connection between the speech processor and the implanted electrode arrays that made recording ECAPs from an intracochlear electrode possible. The Ineraid device was never FDA approved for marketing in the US and Smith and Nephew Richards stopped manufacturing it in In 1997, Cochlear Corporation introduced the Nucleus CI24M cochlear implant. This was the first CI system that could be used to record ECAPs without a percutaneous connection. The bidirectional telemetry capabilities made it possible to measure both electrode impedance and ECAPs (Abbas et al., 1999; Dillier et al., 2002). Today, most commercially available CIs are similarly equipped. ECAPs provide a measure of how the auditory nerve responds to electrical stimulation. Recording ECAPs using the neural telemetry system does not require active participation on the part of the subject or application of recording electrodes. The close proximity of the recording electrode to the auditory nerve trunk results in a good signal to noise ratio making sleep or sedation unnecessary. Additionally, because it is a measure of the peripheral auditory system, ECAPs are not affected by maturation, attention or other cognitive factors. All of these factors make them ideal for pediatric applications. The ECAP is composed of a single negative peak often labeled N1 followed by a positive peak labeled P2. ECAP amplitude is defined as the difference in voltage between

30 16 the N1 and P2 peaks. ECAP amplitudes range from tens of microvolts up to a millivolt. The latency of N1 is typically less than 0.4 ms. Short latency neural responses to electrical stimulation are often contaminated by electrical artifact (van den Honert and Stypulkowski, 1986). Brown, Abbas, & Gantz, (1990) developed a forward-masking subtraction method to reduce stimulus artifact in the recordings. This method of reducing stimulus artifact contamination is widely used to record the ECAP with the Nucleus programming software and has been well studied (e.g. Chapter 7, Hughes, 2012). The forward-masking subtraction method is illustrated schematically in Figure 1. It exploits the refractory properties of the auditory nerve. A series of pulses are presented to one electrode and a second intracochlear electrode is used for recording. Initially, a single biphasic current pulse (the probe ) is presented. The response that is recorded, shown in Figure 1A, consists of both stimulus artifact and neural response. A series of two biphasic pulses (a masker and a probe ) separated by a short time are then presented. The time between the two pulses is called the masker-probe interval (MPI) or interpulse interval (IPI). The recording obtained in this condition, shown in Figure 1B, contains stimulus artifact and neural response to the masker as well as probe artifact. If the MPI is short enough, neurons responding to the masker will be refractory and presumably no neural response to the probe will be recorded. Figure 1C shows the third condition. A single pulse (a masker) is presented resulting in a recording consisting of both neural response and the masker stimulus artifact. Finally, a control condition is recorded that allows measurement of switching artifact associated with the presentation of the probe stimulus (Figure 1D.). These four stimulating conditions are interleaved in the average and the NRT software computes a series of subtractions off-line: A-(B-(C- D)). The final waveform shows the result of the subtraction procedure: a neural response to the probe stimulus with minimal artifact contamination. This method of using forward masking to minimize stimulus artifact is the default recording method used in Cochlear Corporation s NRT software.

31 17 Figure 2 shows an example of an ECAP growth function. Amplitude of the ECAP response is plotted as a function of probe level expressed in clinical programming units. In this figure, the line represents the results of linear regression analysis. Two different metrics are used to quantify ECAP growth functions: slope and response threshold. ECAP growth functions have been recorded using two different methods. The first method involves fixing the masker at a high stimulation level and then varying the level of the probe. The second method links the masker and probe levels together, typically with the masker slightly higher than the probe and systematically varies both. Abbas et al. (1999) and later Hughes et al (2001) reported direct comparisons between the two methods. Abbas et al. (1999) included data from 26 adult, Nucleus 24M CI users. Hughes et al. (2001) reports results from 9 adult, Nucleus 24M CI users. While the Hughes et al. (2001) study found no difference in the two methods, Abbas et al. (1999) reported finding that the fixed method resulted in slightly larger ECAP amplitudes at low stimulation levels and this resulted in slightly lower thresholds compared to similar measures obtained using the linked method (See, Figure 3). Generally, these differences were small and in clinical practice the linked method is often used with pediatric populations where maximum comfortable stimulation levels may not be easy to obtain. Several different methods have been used to determine ECAP threshold. One method is described as visual detection. Visual detection thresholds are judgments made by the audiologist at the time the ECAP growth function is recorded. The ECAP visual detection threshold is the lowest current level at which the tester can identifies that a response is present and repeatable. This is one of the most widely used methods in clinical practice. ECAP growth functions can also be used to estimate threshold. The growth function is recorded and linear regression analysis is used to determine the equation for the line that best fits the recorded data. The equation for that line is then used to

32 18 determine the slope of the ECAP growth function and to determine the current level that results in an ECAP with an amplitude of 0 µv. This is the technique used with NRT software available from Cochlear Corporation. ECAP thresholds based on linear regression are often lower than those based on simple visual detection. However, ECAP growth functions are not always well fit by a linear curve. Some show evidence of saturation at high current levels. They can also exhibit two stages of growth that include a shallow tail at low stimulation levels and steeper growth at higher stimulation levels (Botros et al, 2007). This is a common observation when ECAP growth functions are recorded from individuals using new CI systems like the CI24RE or Nucleus 422 CIs which both have a lower noise floor than was available with the earlier CI24M and CI24R devices. Clearly, using linear regression to fit a nonlinear growth function can lead to errors in estimated ECAP thresholds. In 2000, Brown et al estimated ECAP thresholds by using a third technique they refer to as cross-correlation analysis. This is an offline procedure. With this approach, a clear ECAP obtained at supra-threshold levels is used as a template. ECAP responses recorded at lower stimulus levels are scaled to match with the template and cross correlation analysis was used to compare low level responses with the supra-threshold template. ECAP threshold was defined as the stimulation level where the correlation coefficient dropped to 0.8. Hughes et al (2000) reported that ECAP thresholds determined using correlation technique agreed well with visual detection thresholds in 20 children using Nucleus 24 devices. Finally, AutoNRT is software that Cochlear Corporation developed in order to more rapidly and automatically estimate ECAP thresholds across the electrode array. AutoNRT uses a statistical algorithm to analyze the recorded waveforms, optimize the recording parameters and automatically determine threshold (Botros, et al. 2007; van Dijk et al. 2007). Van Dijk et al. (2007) found that AutoNRT thresholds do not differ

33 19 significantly from those determined visually by expert observers. This software is widely used in clinical practice. In this study, we propose to record growth functions using the linked masker method. Maskers will be fixed at a level slightly higher than the probe and systematically varied across the listener s DR. The slope of ECAP growth function will be determined by using linear regression analysis for ECAPs with amplitudes greater than approximately 15 µv and 5 µv (the noise floor of the NRT system with the Nucleus CI24M and CI24RE devices) and below a point where inspection of the growth function reveals evidence of saturation. ECAP thresholds will be determined using visual detection techniques. 2.3 ECAP Channel Interaction Functions In addition to recording thresholds and growth functions, ECAPs have also been used to assess spread of excitation in the cochlea. There are different ways to do that. One approach is to fix the location of the stimulating electrode and systematically vary the recording electrode across the electrode array (Cohen, Saunders, & Richardson, 2004; Hughes & Stille, 2010; van der Beek, Briaire, & Frijns, 2012). Various terms like spatial spread of excitation, and scanning have been used to describe this approach to measuring spread of excitation across the cochlea (Cohen, Richardson, Saunders, & Cowan, 2003; Abbas, Hughes, Brown, Miller, & South, 2004; van der Beek, Briaire, & Frijns, 2012). In this document we will refer these functions as spatial spread functions. The filled circles in Figure 4 show an example of a spatial spread functions recorded from a Nucleus CI24M user. A series of three spatial spread of excitation functions were recorded by fixing the masker and probe on a basal electrode (e3), a middle (e10) and an apical electrode (e17). For each function, the masker and probe levels were held constant, and the recording electrode was systematically changed. Note that the largest ECAP amplitudes are measured when the recording electrode is close to the stimulating