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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

34 20 electrodes and presumably also to the stimulated nerve fibers. ECAP amplitude decreases as the recording electrode is moved further away from the stimulating electrode. These functions, while simple to record, tend to be relatively broad and dependent on both the characteristics of the recording electrode and how voltage is conducted along the length of the cochlea (Abbas et al. 2004; Cohen et al. 2004). While it does provide some indication of how current spreads within the cochlea, it is not a direct measure of neural channel interaction. Another method of measuring channel interaction has been called spatial masking or spatial selectivity (Cohen, Richardson, Saunders, & Cowan, 2003; Hughes & Stille, 2010; van der Beek, Briaire, & Frijns, 2012). This is the method we will use to assess channel interaction. Channel interaction functions are recorded by fixing the probe electrode, the recording electrode, and the IPI. The masker electrode is systematically varied across the array. The open circles in Figure 4 are used to plot channel interaction functions recorded from an adult Nucleus 24M user. Three channel interaction functions shown were recorded by fixing the probe on electrode 3, 10 and 17 and varying the masker electrode across the intracochlear electrode array. This method is a bit more complicated because the electrical DR on each of the intracochlear electrodes can vary. It is not always possible or appropriate to use a fixed masker level for all of the masker electrodes. Investigators have used different methods to choose the masker level. In this example, the masker level was fixed at 80% of the electrical DR on each of the individual intracochlear electrodes. Figure 5 shows how variations in the masker electrode location impact ECAP amplitude. Figure 5 has three panels. In this Figure 5-1, the masker and probe are on the same electrode. This results in maximum overlap (interaction) between the group of nerve fibers stimulated by the probe and masker pulses. Trace A shows the ECAP response in the probe-alone condition and trace B is the ECAP response in the maskerplus-probe condition. Trace A-B represents the simplified subtracted ECAP response.

35 21 Because the masker and probe both stimulate the same group of neurons and the IPI is short, there is no response to the probe in trace B. As a result, in the subtraction (Trace A-B), ECAP amplitude is large. Figure 5-2 represents a condition where the masker and probe are presented on different electrodes but where there is some overlap between the neural populations stimulated by the masker and probe pulses. In this example, neurons that are not stimulated by the masker pulse will be able to respond to the probe (see Trace B, figure 5-2). This results in a smaller amplitude ECAP response once the subtraction is completed (Figure 5-2, trace A-B). In the Figure 5-3, when the masker and probe are presented on electrodes that stimulate two independent neural populations, fibers recruited by the probe are not affected by the masker. If there is no overlap between the neural populations stimulated by the masker and probe electrodes, there will be no ECAP once the subtraction is complete. When this method is used, a large amplitude response indicates there is significant interaction between the neural population stimulated by the masker electrode and the neural population stimulated by the probe electrodes. No response indicates that there is little, if any, interaction between the masker and probe electrodes (Abbas et al., 2004; Hughes & Abbas, 2006). This general method has been used in a number of studies to estimate channel interaction in CI users (Cohen et al., 2003; Abbas et al., 2004; Eisen and Franck, 2005; Hughes and Abbas, 2006a,b; Hughes and Stille, 2008; Hughes and Stille, 2010; van der Beek, Briaire, & Frijns, 2012). In this study, we proposed to use this method to assess channel interaction in both pediatric and adult CI users Methods of Quantifying Channel Interaction Several different investigators have attempted to measure spread of current and neural excitation within the cochlea (e.g. Cohen et al, 2003; Abbas et al, 2004; Hughes and Stille, 2010). Wider CI functions are typically interpreted as representing greater channel interaction. However, there is no consensus as to the optimal method of

36 22 quantifying the width of these functions. Cohen et al (2003) defined a model template and performed a least mean squares fit of ECAP channel interaction data to that model. They normalized the resulting curves and the width of the ECAP channel interaction function was calculated at 50% of the maximum peak amplitude. Abbas et al (2004) and Hughes and Abbas (2006) normalized the ECAP amplitudes to the maximum response amplitude obtained for each channel interaction curve that they recorded. Typically, the largest normalized amplitude was obtained when the masker and probe electrodes are the same. They then expressed the width of the channel interaction function as the number of electrodes between the two points on either side of the peak that resulted in a normalized amplitude of 75%. They selected a normalized amplitude of 75% to calculate width of these functions because this was lowest normalized amplitude value that allowed them to estimate the width of the channel interaction functions for all subjects and for all stimulation levels. More recently, van der Beek et al (2012) used 60% of the peak amplitude to calculate the number of electrodes as the width of channel interaction. This criterion allowed them to obtain as many curves as possible and also to measure differences between distinctive profiles across the electrode array in their study. Theoretically, we might expect masking will be the strongest when the masker and probe electrodes are the same and will become weaker when the masker moves away from the probe. In addition, we might expect that the shape of the ECAP masking function would be symmetric about the probe electrode. However, asymmetric channel interaction functions have been reported (Abbas et al, 2004; Eisen and Franck, 2005; Hughes & Abbas, 2006). Generally, more channel interaction was observed for maskers located more apical to the probe. Asymmetric channel interaction has been interpreted as a consequence of uneven patterns of surviving neurons or non-uniform current spread. A single metric, such as those described by Cohen and Abbas are not able to describe asymmetries or differences in the shape of the channel interaction function either across subjects or across electrodes within a subject.

37 23 Eisen and Franck (2005) used an analysis of the channel interaction function that could accommodate the function s limited resolution and at the same time allow a direct comparison among the electrode arrays with disparate inter-electrode separations. They plotted channel interaction functions as cumulative ECAP amplitude versus distance from the apical end of the array in millimeters. Interaction was then quantified as the distance along the electrode array between the points at 30% and 70% of the maximum cumulative ECAP amplitude. The authors argued that this method could be used directly to compare between different array designs. In 2008, Hughes re-analyzed the data they published earlier (Hughes and Abbas, 2006). This time, ECAP amplitude was normalized to the single highest amplitude of all ECAPs across all of the electrodes tested in each subject. A metric they named the ECAP separation index was defined as the sum of difference in normalized amplitude across all of the masker electrodes for channel interaction functions measured from two different probe electrodes. The larger the ECAP separation index, the greater the separation between two probe electrodes and the less the channel interaction occurs. When this method of quantifying channel interaction was used, a significant positive correlation between channel interaction and electrode pitch ranking was found while use of the simpler method of quantifying the width of channel interaction at 75 % of the normalized amplitude did not yield a significant correlation to pitch ranking. Hughes (2008) suggested that this may be simply because the width measure does not take into account the shapes of the function while the brain may be able to use differences in shape of these functions to discriminate pitch. In this study, we will use a method similar to that described by Hughes and Abbas (2006) to characterize channel interaction. Specifically, we will normalize the ECAP amplitudes to the maximum response amplitude obtained for channel interaction curve and compute the average the normalized amplitudes for all of the active electrodes across

38 24 the electrode array. We use the term channel interaction index to describe that metric. It is essentially a measure of average area under the curve Effect of Probe and Masker Levels on Channel Interaction Functions Factors that can affect the degree of channel interaction include the stimulus level used for the probe and/or masker pulses. Several studies have explored how the choice of probe and/or masker level impact the shape and width of the channel interaction function recorded from Nucleus CI recipients using ECAPs. Generally, these studies have produced mixed results. Eisen and Franck (2005) found increasing probe level resulted in increased width of the channel interaction function for a group of 27 pediatric CI users. 16 subjects used the Clarion CII cochlear implant and 11 subjects used the Nucleus 24 device. In the Eisen and Franck (2005) study, the interaction functions were measured at the three probe levels 2, 3, and 4 db above ECAP threshold and at three different probe locations along the electrode array (basal, middle and apical probe). Masker and probe levels were fixed at equal current levels for the Nucleus subjects and masker was fixed 32 ua higher than the probe stimulus level for the Advance Bionics Clarion subjects. Their results showed that channel interaction functions became broader as probe intensity was increased. In line with Eisen and Franck (2005), Hughes and Stille (2010) also reported a significant effect of probe level on width of channel interaction functions. These investigators measured channel interaction for probes presented at 70%, 80% and 90% of the behavioral DR for basal, middle and apical probe electrodes with masker levels the same as the probe levels in nine Advance Bionics and nine Nucleus adult CI users. Their results showed that higher stimulus levels produced broader channel interaction functions. They found it was often difficult to measure level effects on channel

39 25 interaction functions for listeners with small behavioral DRs or for individuals whose ECAP thresholds were very close to their maximum behavioral comfortable level. In contrast, Cohen et al (2003) reported little effect of stimulation level on the width of channel interaction functions when the probe and masker levels were equal and between 50 % and 80% of the loudness at C level. Four Nucleus 24M and three Nucleus 24R adult subjects participated in this study. A more recent study by van der Beek et al (2012) also indicated the widths of channel interaction functions were not significantly different when the probe and masker levels were at the low, medium and high intensity levels. They measured channel interaction functions by fixing the masker electrodes and varying probe electrodes at the levels that ranged from 0.6 to 1.2 ma in 31 pediatric and adult CI users using Advanced Bionics HiRes 90K cochlear implants with the HiFocus 1J electrode array. The authors pointed out that all of the measurements were performed when the patients were under general anesthesia during surgery and even the low level used was in the upper range of the electrical DR found in normal clinical M-levels. Their results may have been related to some extent, to the methodological differences in this study. That is, noise artifact in the operation room could potentially contaminate the ECAP recordings and the three levels chosen were all in the upper range of M-levels where channel interaction functions might reach a plateau. While neither van der Beek (2012 ) or Cohen et al (2003) showed significant effects of stimulus level on the width of channel interactions for group data, both investigators reported finding individual cases where increased stimulus level resulted in wider channel interaction functions. Abbas et al (2004) measured channel interaction functions in 12 Nucleus 24M and five Nucleus 24R adult CI users by fixing the probe electrode level 10 programming units below the maximum comfort level (C level) and holding the masker level at C level, 10 and 20 programming units less than C level. The results showed channel interaction widths increased with increased masker levels while the probe level was fixed. Hughes and Stille (2010) also found significant masker level effects. In their study, channel

40 26 interaction functions were measured when masker electrode was set at 80% of the DR and another softer level. They observed higher masker levels resulted in larger ECAP amplitudes and broader channel interaction function. In this study, the channel interaction functions will be obtained by fixing the probe and masker levels at 60-80% of the behavioral DR. Pilot data suggests that most subjects have measurable neural responses for all 11 masker electrodes used at 60-80% of the behavioral DR. This level range was chosen as it is comparable to levels used in previous studies. 2.4 The Impact of Electrode Design or Anatomic Differences on ECAP Growth and Channel Interaction Functions Several different factors could influence the electrode-neural interface and resulting neural activation patterns in CI users. Some factors may be related to design of the intracochlear electrode array. For example, the distance between the electrode contacts and the modiolus of the cochlea. It is also possible that anatomic factors could impact the electrode-neural interface. These factors may include things like the location of the stimulable neural tissue (e.g. peripheral processes vs cell bodies or axons) inside the cochlea (e.g. Sheperd et al., 1993), the location and extent of fibrous and/or bony tissue growth around the electrode array (e.g. Kawano et al., 1998), and the density or total number of surviving auditory neurons in the cochlea (e.g. Nadol et al., 2001). All of these factors could combine to influence the effective distance between the electrode contact and the stimulable neural element. Any of these factors, whether they are related to design of the intracochlear array or are related to cochlear structure, could impact ECAP-based measures of threshold, slope of the ECAP growth function, channel interaction and therefore might be expected to differ in populations who present with

41 27 etiologies that create congenital hearing loss versus populations that present with acquired hearing loss. Pediatric CI users generally have congenital sensorineural hearing loss. Adult CI recipients have a range of etiologies but most of those who opt for cochlear implantation are post-lingually deafened. It seems reasonable that differences in etiology of deafness between these two groups might result in systematic differences in channel interaction and/or growth of ECAP amplitude as a function of stimulation level. The following sections review studies describing impact of these factors on these basic response properties of the auditory nerve response to electrical stimulation. The sections below provide a brief review/overview of literature that addresses each of these factors Location of the Electrode Array within the Cochlea There is evidence in the literature that the distance between the intracochlear electrode and the modiolar wall can impact the ECAP and/or EABR thresholds as well as slope of the ECAP or EABR growth functions. Most of these studies have used animal models. For example, in 1993 Shepherd, Hatsushika, and Clark reported the effect the electrode location had on EABR threshold and growth functions in ten adult cats. In this study, ten cats who were deafened by Kanamycin and aminooxyacetic acid. 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. The magnitude of the hearing loss in these cats varied widely and histology showed different patterns of surviving spiral ganglion cells and peripheral processes. EABR responses were recorded using a stimulating electrode placed at four different locations within the cochlea: along the outer wall, near the modiolus, close to the spiral ganglion and directly underneath basilar membrane near 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 electrode is close to viable auditory

42 28 neurons and stimulation levels are low, current spread in the cochlea will be minimized and the number of additional neurons activated for each increment in stimulation level will be fairly small resulting in the shallow growth functions observed. Conversely, electrodes located further from the viable neurons require the use of higher current 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 result is higher EABR thresholds and steeper growth functions. Two years later, Frijns et al (1995) used a computational model of the electrically implanted guinea pig cochlea to address neural excitation and the influence of the electrode location. Their results were consistent with the findings of Sheperd et al. (1993) and showed that both excitation thresholds and slopes of the EABR or ECAP growth function depend strongly on the location of the stimulating electrode relative to the surviving neurons in the cochlea. In 2000, Cords et al reported that insertion of the electrode positioner resulted in shallower EABR growth functions and lower electrical thresholds. This was independently corroborated in other animal studies by Donaldson et al. (2001) and Young et al., (2001). In patient trials, Cohen et al. (2001) performed psychophysical measurements in one patient implanted with a standard array and three patients implanted with the Nucleus CI22 device fitted with a developmental pre-curved arrays. The developmental array was molded to conform approximately to the shape of the inner wall of the scala tympani and was held straight with a specially designed insertion tool. They used radiographs to confirm the pre-curved electrode arrays lay closer to the inner wall of the scala tympani than the standard array. Consistent with the animal data described previously, they showed that the pre-curled electrode array resulted in reduced thresholds, MCL, and increased DRs.

43 29 In a later study, Saunders et al. (2002) correlated psychophysical measures of threshold 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. Cohen et al. (2003) reported the widths of masking functions obtained with ECAPs for basal, middle and apical probe electrodes on three CI24R and four CI24M users. Their results suggest less channel interaction for the CI24R users, indicating the width of masking functions was significantly correlated with the distance of the electrode band from the modiolus. Another study by Hughes and Abbas (2006) examined ECAP channel interactions and behavioral thresholds in five CI24M and five CI24 R users. The results also showed significantly less channel interaction for CI24R users but no significant difference in thresholds. Van Weert et al (2005) studied Nucleus CI users. They obtained NRT measures in the operating room from a group of 14 adults who were undergoing CI surgery to implant the Nucleus CI24R (CS) Contour electrode. This electrode array is pre-curved but comes with a stylet that holds it straight during insertion. Stylet removal allows the electrode to curl into a location near the modiolar wall of the scala tympani. In this study, NRT measures were performed intra-operatively, both before and after stylet removal. They demonstrated that removal of the stylet had no significant effect on the ECAP threshold or slope. But the channel interaction functions for electrodes in the basal and apical portions of the electrode array were narrower after the stylet was removed. Advanced Bionics Corp also showed advantages of pre-curved electrode arrays. Firszt et al. (2003) used evoked potential measures to examine the effect of electrode location within the cochlea in humans tested in the operating room. They compared wave V of EABR before and immediately after placement of a silastic electrode positioner in 13 adult and 12 pediatric Clarion HiFocus CI recipients. They reported that moving the

44 30 electrode array closer to the modiolus by inserting the positioner resulted in decreased EABR wave V thresholds and increased ABR wave V amplitudes for suprathreshold stimuli. Eisen and Franck (2004) measured ECAP growth functions in 16 pediatric subjects using the Clarion HiFocus electrode array. They reported ECAP thresholds were lower with than without the positioner in children, a finding that supported a closer proximity between the electrodes and excitable neural elements with the positioner. However, they did not find difference on the slope of ECAP growth functions between with and without positioner. Gordin et al. (2009) tested 115 children, divided into three groups: CI24M, CI24R and CI24 RE. They reported that ECAP thresholds for CI24RE device were significantly lower as compared with those of CI24M and CI24R groups. They proposed that the improved thresholds for CI24RE may be due to the less traumatic insertion method used with the advance off stylet CI24RE array. A very recent study measured impedance and ECAP thresholds for different CI generations of the Nucleus CI system (Telmeasani and Said, 2015). Responses were recorded from apical, middle and basal sites for 10 Nucleus CI24RE and 23 Nucleus CI422 CI pediatric users. This study reported ECAP thresholds were significantly higher in CI422 users than CI24RE users but only at basal sites. The authors took this as direct consequence of a peri-modiolar electrode versus a lateral wall electrode. Finally, researchers at the University of Utah developed new arrays of penetrating microelectrodes for direct neural stimulation. The use of penetrating electrodes minimizes the distance between the electrodes and the nerve even further (Badi et al, 2002; Hillman, 2003). The Utah Electrode Array (IEA) is a three-dimensional, siliconbased microelectrode array with the potential ability to implant up to 100 electrodes directly in the auditory nerve. Middlebrooks and Snyder (2007) recorded responses from the central nucleus of the inferior colliculus and compared a conventional multichannel

45 31 scala tympani electrode and an intra-neural electrode array in cats. The data showed thresholds for intra-neural stimulation were significantly lower than for scala tympani stimulation. In addition, the use of intra-neural stimulation resulted in less channel interaction between electrodes. These electrodes are not yet in use with commercial cochlear implant systems. Generally, closer proximity between the CI electrode array and the spiral ganglion cells has been achieved by pre-curved electrode arrays in an attempt to achieve lower thresholds and reduce current spread that may results in channel interaction Fibrous Tissue and New Bone Formation The insertion of a CI electrode array can damage the inner ear (e.g. Nadol, 2006). One of the pathologic changes that can occur is the formation of fibrous tissue and/or new bone in the cochlea. In animal models, a fibrous tissue sheath and new bone formation has been observed to form around the implanted electrodes (Walsh & Leak- Jones, 1982). Histopathological studies of temporal bone specimens obtained from patients who had been implanted during life (Linthicum et al, 1991; Zappia et al, 1991; Nadol et al, 2001; Nadol and Eddington, 2004; Li et al 2007; Somdas et al, 2007) also show fibrous tissue and new bone formation. Both processes are considered to be chronic inflammatory responses and the process is often termed fibrous encapsulation (Xiang et al, 2006). Shepherd et al (1994) measured electrode impedance in kittens who had been implanted with an intracochlear electrode array. They reported finding higher impedance values for electrodes in areas of the cochlea with moderate amounts of tissue growth compared to other electrodes located in areas of the cochlea where there was only mild tissue growth. They also found EABR responses recorded using bipolar intracochlear stimulation exhibited large increases in response amplitude as a function of time postimplant. They suggested a fibrous tissue response may have altered the current

46 32 distribution within these cochleae resulting in more effective stimulation and larger response amplitudes. Grill and Mortimer (1994) implanted four-electrode arrays in adult cats and measured tissue resistivity in vivo. They reported similar findings. That is, formation of the encapsulation tissue resulted in a significant increase in the resistivity of the tissue around the array and this change in resistivity was sufficient to change the shape and magnitude of the electric field generated by chronically implanted electrodes. A cat experiment of Clark et al. (1995) and a guinea-pig experiment by Charlet de Sauvage et al. (1997) both showed a correlation between changes in intracochlear electrode impedance and the degree of tissue growth around the electrode. The change in electrode impedance can result in change of current spread. Furthermore, Charlet de Sauvage et al (1997) also reported an increase in impedance correlated with an increase in compound action potential amplitude. In a temporal bone study of five patients implanted with a Nucleus 22-channel cochlear implant, Kawano et al. (1998) found that the psychophysical thresholds (Tlevels) were elevated and comfortable levels were lower in areas of the cochlea where there was evidence of new bone and fibrous tissue formation. Although not measured, these changes in perceptual DR are likely accompanied by changes in slope of the ECAP or EABR growth functions. In 2001, Hughes et al. published one of the few studies exploring changes in electrode impedance as well as the threshold and slope of the ECAP growth function over time for both pediatric and adult Nucleus CI24M users. They report results collected during the first 24 months of device usage. They found that for pediatric CI users, electrode impedance increased over time for electrodes in the basal, middle and apical region of the cochlea. However, this trend toward increased electrode impedance was limited to the basal electrodes only for adult CI users. Hughes et al. (2001) proposed that this difference in the way the impedance characteristics changed over time in pediatric

47 33 and adult CI users 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 these changes in electrode impedance, Hughes et al. (2001) also found that ECAP thresholds remained fairly stable over time but that the slope of the ECAP growth functions became progressively steeper for pediatric CI users. It was unchanged for adult CI users. They again hypothesized that increased slope of the ECAP growth functions over time could be the result of changes in electrical current fields in the cochlea caused by fibrous tissue formation and the differences between adults and children that they noted could reflect more aggressive fibrous tissue growth and bone formation in children compared with adults. 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 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. Like Hughes et al., Brown et al (2010) also suggest that congenitally deaf children who receive a CI may develop more fibrous tissue than post-lingually deafened adult CI users. While both Brown et al. (2010) and Hughes et al. (2001) report data that may indicate there are differences in the way current flows in the cochlea of children and adults, there is very little histologic evidence to support that assumption. It has been

48 34 shown that wounds in children and young adults often heal quickly with excessive scarring than adults (Ottole and Mellerio, 2010). Burton et al (1994) investigated the effects of cochlear implantation on skull growth fibrous tissue and bone growth over time in young monkeys who had been implanted. They found the formation of fibrous tissue in each implanted monkey and they also mentioned that it has been the observation of experienced pediatric otolaryngologists that the capacity of bony growth is significantly greater in children than in adults and greater in younger children compared with older children. Shepherd et al. (1994) reported an increased fibrous tissue and bony growth following chronic electrical stimulation in neonatally deafened kittens. However, several years later, Coco et al. (2007) reported results of a similar study conducted on adult cats. They did not find the same kind of changes that Shepherd et al (1994) reported and concluded that the young deafened cochleae may be predisposed to a more vigorous tissue growth in response to cochlear implantation and electrical stimulation. Fibrous tissue and new bone formation could, in turn, alter the current fields within the cochlea and change the electrode impedance measures. Additionally, growth of fibrous tissue could also create more distance between the electrode contact and residual auditory nerve fibers in the modiolus of the cochlea leading to changes in ECAP threshold, growth and/or channel interaction measures. Researchers have used variations in the electrode design to achieve differences in placement of the electrode relative to the stimulable nerve fibers. If there are systematic differences between children and adults, the same electrode placement would yield differences between these two groups Spiral Ganglion Cell Survival Spiral ganglion cells (SGCs) are the first neurons in the auditory system. In the normal organ of Corti, the hair cells are in synaptic contact with the peripheral processes of the SGCs and the central processes of the SGCs send auditory information to the brain.

49 35 SGCs are direct target for electrical stimulation by CIs, therefore the status of SGCs is a critical factor in CI performance outcomes. It is possible that damage to the Organ of Corti caused by insertion of the intracochlear electrode array of the CI could lead to the loss of hair cells and the cessation of afferent inputs to the auditory system. Studies have shown that SNHL can cause significant retrograde degeneration of the SGCs in both animal models (Spoendlin,1975; Shepherd et al., 1994) and human (Otte et al., 1978; Nadol et al., 1989). Spoendlin and Schrott (1990) suggested that retrograde degeneration initiated at the periphery progresses at a rapid rate in humans. Furthermore, other human studies reported the number of remaining SGCs far exceeded the number of residual peripheral processes (Suzuka and Schuknecht, 1988, Nadol et al, 1990), suggesting that spiral ganglion cells may survive losses of their peripheral processes. Leake and Hradek (1988) found that these peripheral changes later result in demyelination and reduction in soma area, demyelination of the central axon, and ultimately SGC death. It is expected that uneven and poor neural survival at the sites of excitation would compromise the spread of excitation, resulting in more channel interaction. The studies above demonstrate that how the placement of electrode array and/or difference in etiology across subjects can affect ECAP growth and channel interaction functions. One of the goals of this study is to systematically explore and characterize ECAP threshold, growth and channel interaction function in a group of post-lingually deafened adults and children who were born with congenital hearing loss. If there are functional differences in the cochlear of congenitally deaf children and post-lingually deafened adults, one might expect those differences to affect channel interaction and potentially performance with the device.

50 36 CHAPTER 3 METHODS 3.1 Participants A total of 77 subjects participated in this study. This total included 20 subjects (Nine adults and 11 children) who used CI24M CI, 27 subjects (16 adults and 11 children) who used CI24R CI, 17 subjects (eight adults and nine children) who used the CI24RE CI, and 13 adults who used the Nucleus CI422. All were underwent cochlear implant surgery at the University of Iowa Hospitals and clinics between 1996 and They all had normal cochlear anatomy and full electrode insertions. The adult study participants were considered to be post-lingually deafened and had used their CI s for a minimum of six months prior to participating in this study. The pediatric study participants were thought to be congenitally deaf since birth, and received their CI before five years of age. At the time they participated in this testing, the pediatric participants were all between the ages of five and 14 years. All of the study participants were considered to be full time CI users and were familiar with standard methods of estimating threshold and maximum comfortable levels used to program the speech process of the CIs. More detailed demographic information about individual study participants is included in Table General Procedures Initially, electrode impedance measures were obtained for each subject using Custom Sound EP software (version 3.0). Common ground impedance values were used in this study. Electrodes that were shorted or had abnormally high impedance were noted and not used either for stimulation or recording purposes. Behavioral measures of threshold and DR were then obtained using the low rate biphasic pulse train required for evoked potential testing. Theses stimuli were generated via Custom Sound EP (version 3.0). This software was used both to control stimulation

51 37 levels used to estimate behavioral measure of threshold and maximum comfort level and to record ECAPs. A single Freedom speech processor interfaced with a standard Nucleus programming pod was used to evaluate the study participants who were old enough perform this task. The stimulus used for behavioral testing was a 500 msec burst of biphasic current pulses presented in a monopolar stimulation mode at a rate of 80 Hz. Individual pulses in the pulse train were cathodic leading, charge-balanced and 25 μsec/phase. One 500 msec burst was presented per second. For each subject who is old enough to perform this task, measures of their electrical DR were obtained for electrodes 1, 4, 6, 8, 10, 11, 15, 17, 19 and 22 using an ascending method of adjustment procedure. Initially, the pulse train was presented at a very low stimulation level and slowly increased. Study participants were asked to indicate when they first heard the sound (T-level) and when they considered the sound to be loud but not uncomfortable (C-level) in a clinical loudness scale from 0 (no sound) to 10 (too loud) (advanced Bionics, 2004). This procedure was repeated until consistent T-levels and C-levels were obtained two times. The stimulation level was increased in steps of two current units (CUs) for participants with DR smaller than 25 CU; steps of five CUs were used for individuals with larger DRs. Once the 10 electrodes were tested individually, linear interpolation was used to estimate T-levels and C-levels for the remaining electrodes in the intracochlear electrode array and the behavioral DR (C-level minus T-level) for each electrode was calculated. Each study participant was then asked to sit in a comfortable chair and to relax, read, or watch captioned TV while the neural telemetry measures were obtained. Study participants were instructed to indicate if any of the stimuli used were too loud or otherwise uncomfortable. Breaks were offered as necessary. The whole procedure took two hours. All of these procedures were approved by the University of Iowa Human Subjects Committee and informed consent or assent was obtained prior to participation.

52 ECAP Growth Functions Stimulation and Recording Procedures ECAP growth functions were measured for two different electrodes using the Neural Telemetry software (version 3.1) for CI24M and CI24R devices and the Custom sound EP (version 3.0) for CI24RE and CI422 devices. One basal electrode and one apical electrode were selected. Typically, the electrodes used were electrodes 6 and 17 in the Nucleus array. If either of those electrodes had an abnormal electrode impedance, exhibited limited loudness growth or was deactivated in the subject s everyday MAP, an electrode close to these two electrodes was selected. An ECAP growth function is a plot of how amplitude of ECAP response changes as a function of stimulation level. In this study, we specify level in clinical programming CUs that are commonly used to program the speech processor of the Nucleus device. ECAP growth functions were measured by fixing the masker at or just below the subject s behavioral C-level. A pair of biphasic current pulses (referred to here as a masker and a probe pulse) were presented to the same electrode separated by 500 µsec. A recording electrode typically located two electrodes apical relative to the stimulating electrode was selected and the ECAP was measured using a gain of 60 db and a delay of approximately 100 µsec between the offset of the probe pulse and the initiation of sampling. Typically each recording was based on an average of at least 50 stimulus presentations. At low levels or in cases where ECAP amplitudes were very small, as many as 100 stimulus presentations were used. The whole process was repeated twice, once for an apical electrode and once for a more basal electrode. Figure 2 shows a series of ECAPs recorded as the probe level was changed from 215 CL to 195 CL. The ECAP consists of single negative peak (N1) followed by a less prominent positive potential (P2). The N1 peak typically has a latency of less than 0.5 ms. ECAP amplitude decreases as level of the probe is decreased. If the recordings obtained

53 39 at the higher stimulation levels were contaminated by artifact, the recording delay or electrode was modified slightly. In some cases, the amplifier gain was decreased. These modifications were based on a protocol outlined previously by Abbas et al. (1999) that describes methods of optimizing ECAP morphology Data Analysis ECAP waveforms were analyzed off-line using custom-designed MATLAB software program. The N1 and P2 peaks were identified, latency of each peak was measured and the difference in voltage between the N1 and P2 peaks was computed. For each series of ECAP recordings, visual detection thresholds were identified and defined as the lowest probe level eliciting a repeatable waveform. Amplitude of the ECAP response was plotted as a function of stimulation level and linear regression analysis was used to compute slope of the ECAP growth function. The different devices evaluated had different noise floors. The noise floor of the CI24M and CI24R CIs is approximately 15 µv. The noise floor of the CI 24RE and 422 users is approximately 5 µv. ECAP amplitudes lower than these levels were not included in the linear regression analysis. Similarly response recorded at high stimulation levels where the ECAP growth function that exhibited significant saturation was also typically excluded from the regression analysis. (see figure 6) ECAP Channel Interaction Functions Stimulation and Recording Procedures The method used to assess channel interaction in this study was to fix the probe electrode and stimulus level and to record the change in ECAP amplitude observed while the masker electrode was systematically varied across the electrode array. This is a method similar to one described by Hughes & Stille in 2010.

54 40 In this study, the same two electrodes used to record ECAP growth function were also used to measures channel interaction. In order to record the channel interaction function, a probe pulse was presented to a single electrode. The level of the probe was fixed. The recording electrode used varied depending on the position of the masker electrode. A recording electrode two electrodes apical to the probe electrode was used when the electrode selected to be used for the masker pulse as basal relative to the probe electrode. A recording electrode two electrodes away from the probe in a basal direction was used when the electrode selected for use for the masker pulse was apical relative to the probe electrode. In some cases, a recording electrode located three electrodes away from the stimulating electrode was necessary to avoid saturation of the recording amplifier. Additionally, for CI24R CIs, electrodes 12, 14 and 16 were not typically used as masker electrodes because Hughes M.L (2006) showed that use of these electrodes were used to record an ECAP, the response morphology was typically very poor. Typically, the largest response amplitudes are obtained when the same electrode is used for the masker and probe pulses. ECAP amplitude decreases as the masker electrode is moved away from the probe. If the probe and masker levels are too low, it is difficult to measure the width of the channel interaction function. As a result, probe levels were chosen to be the highest current levels where artifact free ECAPs with amplitudes could be obtained, greater than 15 µv for CI24M and CI24R devices and 5 µv for CI24RE and CI422 devices. In most cases this was achieved using probe levels that were between 80 and 100% of the subject s behavioral DR. In some cases, channel interaction functions were assessed using probe levels as low as 60% of the subject s DR. The masker stimulus was always presented at the same percentage of the DR as the probe electrode for the masker electrode. The presentation order of the masker electrodes was randomized. This procedure follows one outlined by Hughes & Stille, 2010.

55 41 Typically the same gain and recording delays used for the ECAP growth functions were also used for the ECAP channel interaction measures. 100 sweeps used to record the ECAPs were used to construct the channel interaction function. The whole process was repeated twice, once for a probe electrode near the basal end of the electrode array and once for a more apical electrode Data Analysis ECAP waveforms were analyzed off-line using custom-designed MATLAB software program. The N1 and P2 peaks were identified, latency of each peak was measured and the difference in voltage between the N1 and P2 peaks was computed. Amplitude of the ECAP response was plotted as a function of masker electrode. Figure 7 shows a series of ECAPs recorded as masker electrode was systematically varied across the electrode array but while the probe electrode and probe current level was fixed. In this example the probe electrode is electrode 6, the probe level is fixed at 80% of the DR and the recording electrode is electrode 8 for masker electrodes between electrode 1 and 6 and electrode 4 for masker electrodes between electrode 6 and 22. Averaged ECAPs for electrode 6 was used as electrode 6 was measured 2 times at different recording electrodes. In this case, the masker is presented at 80% of the DR for measured behaviorally from the masker electrode. Clearly, as the spatial separation between the masker and probe electrodes increases, the ECAP amplitude decreases. When the masker and probe were presented on the same electrode 6, the largest response amplitude was obtained. Fig 8A and 8C show channel interaction functions from an adult CI24R and an adult CI24M subjects. The channel interaction functions were constructed by plotting the amplitude of the ECAP as masker electrode is varied. In Figure 8B and 8D, ECAP amplitude is normalized relative to the single highest amplitude across the electrode array. Several different methods have been used to quantify channel interaction. Those methods

56 42 were reviewed in the previous chapter. In this study, we compute a channel interaction index (CII). The CII was defined as the average normalized ECAP amplitude based on recordings obtained from all of the active electrodes. Deactivated electrodes were excluded from the calculation. Generally, the wider these functions are, the bigger the CIIs are. Wider channel interaction functions and bigger CIIs indicate more channel interaction is occurring. The channel interaction function is wider in figure 8C than that in figure 8A while CIIs are larger in figure 8D than that in 8B, which indicates more channel interaction occurred in the CI24M adult subject.

57 43 Table 1. Summary of Key Differences between CI24M, CI24R, CI24RE & CI422. Device Year Introduced Electrode Design CI24M 1998 Straight Full bands Placement of electrode array Near lateral wall NRT Noise Floor Electrode Contact Area 15 µv mm 2 Inter- Electrode Spacing 0.75 mm CI24R 2000 Pre-curled Half bands Near modiolus 15 µv mm 2 0.7mm at basal to 0.6 mm at apical CI24RE 2005 Pre-curled with Softtip Half bands Near modiolus 5 µv mm 2 0.8mm at basal to 0.4 mm at apical CI Straight Half bands Near lateral wall 5 µv mm to 0.95 mm *The table is adapted from Patrick et al., (2006), Cochlear Nucleus published information and personal communication with Cochlear Nucleus representatives.

58 44 Table 2. CI24M Subject Demographic Data ID Age (yrs) Sex Ear Reported Etiology Age at IS (yrs) M2 68 F L Unknown 51 M4 72 M L Unknown 58 M15 82 F R Infection 69 M27 62 F L Autoimmune SNHL 39 M35 77 M R/L Hereditary 68 M42 52 F L Hereditary 41 M51 58 F L Hereditary 43 M54 63 F R Unknown 51 M58 69 F L Meniere's disease 59 CM1 9 F L Marshall's syndrome 54m CM3 6 F R Hereditary 24m CM9 5 F R Usher's syndrome 18m CM12 7 M R Enlarged Vestibular Aqueduct 41m CM13 13 M R Unknown 31m CM14 7 M R Meningtis 14m CM20 8 M L Unknown 61m CM22 4 F R Unknown 18m CM27 13 F R Unknown 18m CM34 13 F R Unknown 24m CM39 5 M L Hereditary 38m

59 45 Table 3. CI24RSubject Demographic Data ID Age (yrs) Sex Ear Reported Etiology Age at IS (yrs) R3 49 M L Unknown 45 R13 76 F R Unknown 66 R16 79 F L Hereditary 69 R19 19 F R Hereditary 17 R21 71 F R Unknown 68 R22 77 M R Hereditary 70 R32 38 F L Hereditary 38 R34 65 F R Unknown 65 R36 48 M R/L Unknown 46 R46 78 M R Unknown 76 R48 56 M L Unknown 54 R55 76 F R Unknown 73 R70 65 F R Unknown 58 R72 50 F R Kearn-Sayre syndrome 49 R75 61 M L Unknown 59 R82 80 M R Unknown 80 CR10 11 M L Unknown 20m CR12 14 M L Hereditary 15m CR13 9 F L Unknown 17m CR16 12 M L Unknown 50m CR17 6 F L Unknown 17m CR21 10 M R Hereditary 13m CR40 9 F R Waardenburg syndrome 13m CR44 5 M R Unknown 10m CR50 9 M L Unknown 28m CR68 9 M L Hereditary 15m CR72 10 M R Unknown 46m

60 46 Table 4. CI24RE Subject Demographic Data ID Age Sex Ear Reported Etiology Age at IS (yrs) E11 84 M R Meniere disease 127 E40 50 M R/L Unknown 44 E54 76 M L Unknown 69 E55 57 F L Unknown 64 E58 57 M L Unknown 50 E69 37 F R Meningtis 96 E97 69 M L Unknown 66 E99 56 M R/L Unknown 54 CE1 14 F L Unknown 60m CE24 10 M R/L Unknown 36m CE32 13 M R Unknown 50m CE41 10 F L Unknown 58m CE54 9 M R Unknown 15m CE38 7 M R Waardenburg syndrome 11m CE F R Hereditary 48m

61 47 Table 5. CI422 Subject Demographic Data ID Age (yrs) Sex Ear Reported Etiology Age at IS (yrs) S7 64 F L Head trauma 63 S8 74 F L Hereditary 73 S9 65 M R Meniere's disease 64 S12 65 F R Meniere's disease 63 S17 27 F R/L Unknown 25 S19 40 M L Unknown 38 S20 59 F L Unknown 59 S23 74 F L Hereditary 72 S24 55 F L Autoimmune SNHL 54 S26 60 F R Meniere's disease 59 S32 54 M R Hereditary 53 S33 72 M R Unknown 71

62 Figure 1. the Forward-Masking Subtraction Method. (Adapted from Abbas et al. 2004). 48

63 Figure 2. ECAP Waveforms and ECAP Growth Function. The left figure shows ECAP waveforms recorded using stimulation levels ranging from CL. The asterisk indicates threshold. The right figure shows the resulting ECAP growth function. 49

64 Amplitude (µv) 600 Fixed Masker 400 Linked Masker 100 µv µv Probe Current Level Fixed Method EAP Threshold (programming units) Fixed Method Slope (µv/programming unit) Linked Method EAP Threshold (programming units) A r = B 10 r = Linked Method Slope (µv/programming unit) Figure 3. Comparison between the Linked and Fixed Masker Methods. The left figure was adapted from Abbas et al., (1999). Open symbols show a growth function obtained using the linked masker method and filled symbols show a growth function obtained using fixed masker method. Graphs A and B on the right are reprinted from Hughes et al., (2001). These two scatter plots compare results obtaining using the fixed and linked masker methods. Data points in panel A represent ECAP thresholds. Panel B shows the maximum slope of the growth functions obtained using the fixed versus linked methods. The dark solid line represents results of linear regression analysis.

65 51 Amplitude ( V) CI 24M elec CI 24M elec.10 Amplitude ( V) Amplitude ( V) CI 24M elec Recording or Masker electrodes Recording electrode Masker eletrode Figure 4. Comparison of Spatial Spread Function and Channel Interaction Function. Spatial spread functions (filled circles) were obtained by changing the position of the recording electrode, and channel interaction functions (open circles) were obtained by changing the position of masker electrodes from an adult CI24M user. The stimulation level was fixed at 80% of behavioral DR.

66 Figure 5. Effect of Changing Masker Electrode Position on ECAP response. In the figure 5-1, masker and probe are on the same electrode, which yields a maximum ECAP response in the subtracted trace (A-B). Gray ovals represent hypothetical current fields. Bolded lines represent stimulated fibers. In the figure 5-2, masker and probe are on different electrodes partially overlapped, which yields a smaller subtracted ECAP response. In the figure 5-3, masker and probe are widely spaced and no ECAP is recorded (Adapted from Hughes & Abbas, 2006). 52