Importance of cochlear health for implant...

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Hearing Research xxx (2014) 1e12

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Hearing Research

journal homepage: www.elsevier .com/locate/heares

Importance of cochlear health for implant function

Bryan E. Pfingst a, *, Ning Zhou a, b, Deborah J. Colesa a, Melissa M. Watts a,Stefan B. Strahl c, Soha N. Garadat a, d, Kara C. Schvartz-Leyzac a, Cameron L. Budenz a,Yehoash Raphael a, Teresa A. Zwolan a

a Department of Otolaryngology, University of Michigan, Ann Arbor, MI, USAb East Carolina University, Greenville, NC, USAc MED-EL GmbH, Innsbruck, Austriad The University of Jordan, Amman, Jordan

a r t i c l e i n f o

Article history:Received 16 May 2014Received in revised form14 August 2014Accepted 16 September 2014Available online xxx

Abbreviations: AAV, adeno-associated viral vector;site mean; BDNF, brain-derived neurotrophic factor; Clevel; CUNY sentences, a sentence test developed aYork; DPI, days post implantation; EABR, electricallyresponse; ECAP, electrically-evoked compound actionthreshold; IHC, inner hair cell; MDT, modulation detpulse integration; N1, first negative potential; NT-3, neneurotrophic factor-3 gene; P2, second positive poneuron; SNR, signal to noise ratio; TI, temporal inthreshold level* Corresponding author. Kresge Hearing Researc

Otolaryngology, University of Michigan, Ann Arbor, M734 763 2292.

E-mail address: [email protected] (B.E. Pfingst)

http://dx.doi.org/10.1016/j.heares.2014.09.0090378-5955/© 2014 Published by Elsevier B.V.

Please cite this article in press as: Pfingst,dx.doi.org/10.1016/j.heares.2014.09.009

a b s t r a c t

Amazing progress has been made in providing useful hearing to hearing-impaired individuals usingcochlear implants, but challenges remain. One such challenge is understanding the effects of partialdegeneration of the auditory nerve, the target of cochlear implant stimulation. Here we review studiesfrom our human and animal laboratories aimed at characterizing the health of the implanted cochlea andthe auditory nerve. We use the data on cochlear and neural health to guide rehabilitation strategies. Thedata also motivate the development of tissue-engineering procedures to preserve or build a healthycochlea and improve performance obtained by cochlear implant recipients or eventually replace the needfor a cochlear implant.

This article is part of a Special Issue entitled <Lasker Award>.© 2014 Published by Elsevier B.V.

1. Introduction

The pioneers of the multichannel cochlear implant have createda wonderful tool that has enabled thousands of hearing impairedindividuals to function almost normally in a hearing world (Clarket al., 1979, 1987; Hochmair-Desoyer et al., 1981; Hochmair et al.,2006; Schindler and Merzenich, 1985; Wilson et al., 1991; Wilsonand Dorman, 2008). At the same time, the cochlear implant haspresented the research community with many interesting chal-lenges, one of the most significant of which is dealing with apartially degraded auditory nerve, the target of cochlear implant

Ad, adenovirus; ASM, across-level, maximum comfortablet the City University of New-evoked auditory brainstempotential; GDT, gap-detectionection threshold; MPI, multi-urotrophin-3 protein; NTF-3,tential; SGN, spiral gangliontegration; T level, detection

h Institute, Department ofI 48109-5616, USA. Tel.: þ1

.

B.E., et al., Importance of coc

stimulation. One of the first challenges we face is understandinghow the condition of the nerve affects cochlear implant functionand howwemight use that understanding to improve the quality ofperception that patients experience using the implant. Thesestudies also motivate efforts to improve the health of the cochleaand the target neural population. Here we review approaches thatour laboratories have used to address this challenge, aided by a richbase of research from other laboratories.

Results from early work relating neural status to performancewith the implant have challenged the basic assumption that thecondition of the auditory nerve is important for speech recognitionwith cochlear implants. Studies of the number of remaining spiralganglion neurons (SGNs) in cadaveric temporal bones fromdeceased patients showed little relationship to cochlear-implantfunction in life (Khan et al., 2005a). In fact in some cases, nega-tive correlations between speech recognition and SGN counts havebeen found (Nadol et al., 2001; Fayad and Linthicum, 2006).However, interpretation of these results is difficult because thereare confounding variables, such as cognitive ability, that cancontribute strongly to speech recognition using the degraded sig-nals delivered by cochlear implants (Heydebrand et al., 2007). Inaddition, the condition of the auditory nerve at the time of deathmight be different from the condition when the subject's ability touse the implant was assessed. In any case, the anatomical status ofthe auditory nerve (e.g., spiral ganglion cell counts and other

hlear health for implant function, Hearing Research (2014), http://

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B.E. Pfingst et al. / Hearing Research xxx (2014) 1e122

anatomical features observable under the light microscope) mightnot be sufficient to characterize the health of the neural populationsince theymight not reveal changes in the sensitivity or conductiveproperties of the nerves in a pathological state.

In the following sections, we review two approaches that wehave taken to evaluate the importance of cochlear health forcochlear-implant function. The first approach (reviewed in Section2) looks at variation in implant function across stimulation sites in amultichannel implant consistent with the assumption that thehealth of the cochlea and auditory nerve varies along the length ofthe cochlea. These studies use within-subject designs, reducingcomplications from confounding across-subject variables such asresponse criteria and cognitive ability. The second approach(reviewed in Section 3) is to directly compare cochlear implantfunction to observed anatomy across animals with a range ofcochlear pathology. We then use functional measures that arecorrelated with cochlear pathology in animals to noninvasivelyestimate the health of the cochlea in humans who have variousdegrees of speech recognition performance. In Section 4, we reviewexperiments designed to test the translation of our experimentalresults to the clinical practice of programming cochlear implantsound-processors, and in Section 5, we discuss biological

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Fig. 1. Modulation detection thresholds (MDTs) as a function of stimulation site for 12 hunumbered 1 to 22 from the basal end to the apical end of the cochlear implant electrode arraan amplitude-modulated pulse train from a non-modulated pulse train. Functions for MDTsmore apical, electrode (filled circles) are shown. Larger negative values indicate better perpanel. Error bars show ranges of values from three estimates at each site. Data are from G

Please cite this article in press as: Pfingst, B.E., et al., Importance of codx.doi.org/10.1016/j.heares.2014.09.009

approaches to improving cochlear health and cochlear implantfunction. Research protocols from our human and animal labora-tories have been reviewed and approved by the University ofMichigan Medical School Institutional Review Board (IRBMED) andthe University of Michigan Committee on the Use and Care of An-imals (UCUCA) respectively.

2. Across-site patterns of implant function in humans

It is clear from post-mortem studies of temporal bones in peoplewho would have been candidates for cochlear implants, as well asthose who had cochlear implants, that pathology along the lengthof the cochlea in the deaf or deaf-implanted ear is not uniform andthat the pattern of pathology along the length of the cochlea differsacross individuals (Hinojosa and Marion, 1983; Khan et al., 2005b).If the pathology has a significant influence on implant function, itfollows that functional responses to cochlear implant stimulationshould differ across stimulation sites along the electrode array inindividual users and across users. The functional response tostimulation of individual electrodes in the cochlear implant can beassessed using psychophysical or electrophysiological measures.For speech signals, which require stimulation of multiple

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man subjects with 22-electrode cochlear implants. Stimulation sites (electrodes) arey. MDTs represent the minimum modulation depth at which a subject can discriminatein quiet (open circles) and in the presence of non-modulated masker on an adjacent,

formance. Across-site mean (ASM) MDTs are shown in the lower right corner of eacharadat et al., 2012.

chlear health for implant function, Hearing Research (2014), http://

B.E. Pfingst et al. / Hearing Research xxx (2014) 1e12 3

electrodes, we can assess the importance of individual stimulationsites by selecting specific sites for the processor map. These ap-proaches are detailed below.

There are now a relatively large number of studies that haveassessed cochlear implant function for each individual electrodealong the length of the cochlear implant electrode array (Zwolanet al., 1997; Donaldson and Nelson, 2000; Pfingst and Xu, 2004;Bierer and Faulkner, 2010; Pfingst et al., 2008; Garadat et al.,2012). These studies reveal several important characteristics: (1)the functional response to electrical stimulation varies appreciablyfrom one stimulation site to the next along the electrode array; (2)the across-site patterns of implant function are different for eachsubject; (3) for a given subject, the across-site patterns are stableover time in most of the cases that have been tested to date; and (4)the across-site pattern in a given subject is not the same for allmeasures.

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Fig. 2. Stability of modulation detection thresholds over time. Data for 10 ears are showModulation detection thresholds were measured at all available stimulation sites at two timpanel. The first and second sets of data are shown in different symbols: open symbols for thethe mean of two measurements at a given timepoint with error bars representing the rangefirst and second timepoints are shown in the uppereright corner of each panel. For these cocorrelated with the means of the two measurements at each site at the second timepoint.

Please cite this article in press as: Pfingst, B.E., et al., Importance of cocdx.doi.org/10.1016/j.heares.2014.09.009

Examples of patterns of across-site variation in modulationdetection thresholds for 12 different subjects are shown in Fig. 1.The variation from one stimulation site to the next is consistentwith the idea that implant function depends on conditions near thestimulating electrodes. Contributions of more central processes,such as the ability of the subject to interpret signals coming fromthe periphery, would be expected to be more uniform acrossstimulation sites compared to contributions of conditions near thestimulation sites. The long term stability of the across-site patterns(Fig. 2) suggests that they are rooted in physical conditions in thecochlea and are not due to random trial-to-trial variations such asvariation in the subject's attentional state. If the functional mea-sures are dependent on conditions near the implanted electrodes, itis reasonable to expect occasional changes at some sites due tochanging conditions in the cochlea (neural degeneration, tissuegrowth, etc.) andwe do occasionally see such changes. However, for

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most of the cases in Fig. 2, the patterns were unchanged from thefirst test to when a second test was done 1.3 to 3.0 years later. It isimportant to note that the initial data in this test for stability wereobtained in subjects who had been using their implants for a longtime. The first data were obtained an average of 4.6 years (range of1.6 to 8.5 years) after implantation. Conditionsmight have been lessstable immediately after implantation.

The fact that the across-site patterns of MDTs and masked MDTsare different for each subject (Fig. 1) suggests that the pattern is dueto pathology or other conditions near the electrodes and not due to

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Fig. 3. Across-site patterns for six psychophysical measures in two subjects (one subject percomfortable level (C level), modulation detection threshold (MDT), modulation detection(masked MDT), gap-detection threshold (GDT), and slope of the multipulse integration funsupra-threshold functions were measured at levels corresponding to 50% of the site's dynaobtained from previous publications from this laboratory. For T levels, C levels and MDTs andand Pfingst, 2011. For MPI slopes see Zhou et al., 2012 or 2014a).


the normal variation in anatomy or physiology as a function ofapical-basal position in the cochlea. We cannot say, based on thesedata, what conditions near the implant are affecting the functionalmeasures. However, we have found that for any given subject, theacross-site patterns for various measures of implant function arenot the same for all measures, suggesting that the underlyingmechanisms differ across measures. Examples of across-site pat-terns for six different measures are shown for two subjects in Fig. 3.Performance that is relatively good at one site on one measuremight be relatively poor at the same site for another measure. For

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column). The measures are from the top absolute detection threshold (T level), maximalthreshold in presence of a masker on the electrode immediately basal to the probection (MPI slopes). All measures were obtained using an MP 1 þ 2 configuration. Themic range. More information about methods used to collect these types of data can bemasked MDTs, see Garadat et al., 2012 or Zhou and Pfingst, 2012. For GDTs see Garadat


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Fig. 4. Examples of a site-selection strategy to test the relevance of MDTs for speechrecognition, based on the study by Garadat et al. (2012). Two 10-electrode processormaps were created: one with 10 of the better-performing sites (red circles in the toppanel) and one with 10 poorer-performing sites (blue circles in the bottom panel). Tomaintain coverage of the full range of place-pitch information, the electrode array(electrodes 2 through 21) was divided into 5 segments and two sites were selectedfrom each segment. Speech recognition, particularly sentence recognition in noise, wasbetter in most subjects when the map with the better-performing sites was used. (Forinterpretation of the references to colour in this figure legend, the reader is referred tothe web version of this article.)


example, for Subject 60's right ear (S60R), modulation detectionthresholds (MDTs) are high (poor) at the most basal stimulationsites (especially site 1), lowest (best) around stimulation site 7, andhighest (poorest) around stimulation site 13. For the same ear, gap-detection thresholds (GDTs) are also high (poor) at site 1 and low(good) around site 8 but they remain low at the more apical siteswhere the MDTs are poor. Thus, the simple notion that one func-tional measure can be used to identify all aspects of cochlear pa-thology is not valid. Reductions in the number of stimulableneurons might affect one functional measure while another func-tional measure might be dependent on temporal properties of thesurviving neurons and be unaffected by fiber density.

Differences in the probable mechanisms underlying variousfunctional measures of implant function can be illustrated bycomparing across-site patterns of response to electrical stimulationusing absolute detection thresholds versus modulation-detectionthresholds. Variables that result in an increase in absolute detec-tion thresholds do not necessarily cause an increase in modulation-detection thresholds. We examined the relationship betweenacross-site patterns of detection threshold levels (T levels) andmodulation-detection thresholds (MDTs) in 12 ears with cochlearimplants. In 8 of the 12 cases, the across-site correlations between Tlevels and MDTs were not statistically significant (p > 0.05) sug-gesting that T levels are not a reliable predictor of MDTs. Thissuggests that the mechanisms underlying high T levels and highMDT levels are not the same.

At least two variables are thought to affect the levels of currentrequired for absolute stimulus detection: distance of the electrodesfrom the neurons (Shepherd et al., 1993) and a second variable suchas the condition of the stimulated population of neurons (Longet al., 2014). The second variable, i.e., what remains after account-ing for the distance of the electrodes from the modiolus, has beenshown to be important for speech recognition (Long et al., 2014). Ina multi-electrode implant it is likely, for example, that elevations indetection thresholds at some of the sites along the length of thecochlea are due primarily to distance from the electrodes to thenerves and elevations at other sites are most influenced by neuralpathology. The latter mechanism might also affect modulationdetection, resulting in high correlations between the twomeasures,but the former, not so much.

The magnitude of across-site variation in absolute detectionthresholds is strongly influenced by the electrode configuration(Pfingst and Xu, 2004; Bierer, 2007). The across-site variation ismuch smaller for monopolar than for bipolar or tripolar configu-rations, suggesting that the degree of current spread near thestimulation site affects the magnitude of threshold variation. Incontrast, the across-site variation in modulation-detection thresh-olds for bipolar stimulation is similar to that for monopolar stim-ulation (Pfingst, 2011). This suggests that the MDTs might be lessdependent on the number of surviving SGNs close to the stimula-tion site and more dependent on temporal- or intensity-encodingproperties of those neurons.

We use site-selection strategies to determine the effects ofcochlear health on speech recognition. Most users of cochlear im-plants require multiple stimulation sites with frequency-specificchannels of information distributed along the tonotopic axis ofthe cochlea in order to achieve reasonable speech perception.However, it is not always advantageous to use all of the availablesites. Speech recognition scores typically increase as a function ofthe number of channels up to at least 8 channels (Friesen et al.,2001) and we have found that some subjects can benefit frommany more channels. We can test the effects of estimated cochlearpathology on speech recognition performance using multichannelspeech processors by selecting sites for the speech processor mapthat we estimate to be good or poor based on a psychophysical or


electrophysiological measure of performance for stimulation of theindividual stimulation sites. An example of such an experiment isillustrated schematically in Fig. 4 and in detail in the paper byGaradat et al. (2012). In this case, the stimulation sites wereselected based on masked modulation detection thresholds (i.e.,MDTs measured in the presence of an unmodulated masker on anadjacent stimulation site). Electrodes 1 and 22 in the 22-electrodearray were excluded and the remaining 20 electrodes were dividedinto 5 four-electrode segments. The two sites from each segmentthat had the lowest (best) MDTs were selected for one processormap and the two sites per segment that had the highest (worst)MDTs were selected for the other map. Dividing the electrode arrayinto 5 segments allowed us to maintain stimulation along thewhole tonotopic axis when selecting high-MDT or low-MDT stim-ulation sites. Testing the high-MDT and low-MDTmaps in the samesubject allowed us to avoid complications by other subject-specificvariables that could make interpretation of across-subject com-parisons difficult. Twelve subjects were tested in this experimentand all 12 showed better speech recognition in noise with the low-MDT map (better modulation detection) than with the high-MDTmap (poorer MDT detection). This suggests that the conditionsnear the stimulating electrodes that yielded high or lowMDTs wereimportant for recognition of speech signals, particularly sentencesin noisy backgrounds.

The magnitude of across-site variation in functional measuresmight be another indication of cochlear pathology. If cochlear


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pathology is minimal, the conditions along the length of the co-chlea are more likely to be uniform. Consistent with this idea, themagnitude of across-site variation in detection thresholds has beenfound to be correlated with speech recognition (Pfingst et al.,2004). This measure is strengthened by correcting for across-sitevariation in distance of the electrodes from the modiolus (Longet al., 2014). However, the correlation could be weakened inacross-subject comparisons due to confounding across-subjectvariables.

The data on across-site patterns of implant function in humansdescribed in this section provided indirect evidence that conditionsin the cochlea near the individual sites of stimulation affect implantfunction, including recognition of speech signals. The data alsosuggest that the conditions affecting function are not the same forall measures of function. However these data do not tell us thespecific conditions that affect each measure. Additional insight intothe relationship between cochlear conditions and implant functioncan be gained from direct comparison of anatomy and cochlearimplant function in animal models.

3. Relation of cochlear health to implant function in animals

One of the advantages of using experimental animal models isthat these experiments provide better control over events occur-ring between the functional assessments and harvesting of thetemporal bones for histological analysis. By better understandingthe relationship between simple functional measures and neuralanatomy near the implant, one can develop non-invasive measuresthat can be used to estimate nerve survival in humans at the timewhen more complex functions such as speech recognition areassessed.

In studying cochlear implant function in animal models, as inhumans, it is important to consider the time course of events afterimplantation. We have consistently found that implant functionassessed at the behavioral and electrophysiological levels is un-stable during the first weeks after implantation (Pfingst, 1990; Suet al., 2008; Watts et al., 2014). Typically, psychophysical andelectrophysiological thresholds rise, sometimes dramatically, dur-ing the first few days after implantation and then slowly recover toreach a relatively stable lower level. A probable contributor to thisinitial fluctuation is an inflammatory response to the implantationand/or to any deafening treatment that preceded implantation. Itcan occur following implantation in a hearing ear. Since SGN cellbodies do not regenerate once they are lost, this rise and recovery ofthresholds is not due to changes in SGN density, though it might bedue to a temporary loss of function or reduction of sensitivity ofSGN cells. In humans these changes are not often seen because thepatients are typically not tested until the prosthesis is activatedseveral weeks after implantation. In any case, it is clearly importantto follow implant function over time until stable before obtainingdata to relate function to SGN survival.

Our research in guinea pigs has focused on two closely-relatedpsychophysical measures (temporal integration; TI and multi-pulse integration; MPI) and two closely-related electrophysiolog-ical measures (ECAP growth functions and EABR growth functions)that are correlatedwith SGN density (Kang et al., 2010; Pfingst et al.,2011, 2014). These measures are based on commonly used clinicalmeasures so they would involve tasks that require little or notraining of the patients. This is in contrast to previously usedmeasures such as MDTs which are too time consuming to use foranalysis of the implant in a busy cochlear implant clinic. In ourguinea pig subjects, the functional measures were assessed in long-term implanted animals after psychophysical and electrophysio-logical responses had stabilized. In these studies various levels ofnerve survival across animals were created using a variety of


procedures and the functional data were collected for electrodeslocated in the lower half of the basal turn. To create a wide range ofnerve survival across animals in this region, a variety of treatmentswere used. Some animals were implanted in a hearing ear. Theimplant insertion created various amounts of damage, but typicallysome IHCs were preserved and SGN preservation ranged frommoderate to very good. Other animals were deafened by cochlearinfusion with neomycin prior to implantation. This typicallydestroyed all hair cells and most supporting cells and resulted inSGN degeneration to low levels within a month after injection. Athird group was deafened with neomycin but then inoculated witha viral vector containing a neurotrophin gene insert. The vectortransfected the mesothelial cells in the scala tympani and upre-gulated production of neurotrophins, which resulted in greater SGNpreservation than in animals receiving neomycin alone. Additionaldetails regarding the neurotrophin gene therapy procedures arereviewed in Section 5.

3.1. Psychophysical temporal integration and multipulse integrationfunctions

Examples of temporal integration (TI) functions (detectionthreshold versus pulse-train duration for fixed-rate pulse trains)are shown in Fig. 5 and quantified in Table 1. As the pulse-trainduration increased up to about 300 ms, thresholds decreased, asis typical in classic temporal-integration experiments (Gerken et al.,1990; Shannon, 1989). In a healthy cochlea that had surviving IHCsand high SGN densities (>70% of normal) near the cochlear implantelectrodes, we found that thresholds decreased as a function ofstimulus duration more rapidly than in cases with poorer nervesurvival (Fig. 5 and Table 1).

Multipulse integration (MPI) functions (detection thresholdversus pulse rate functions for fixed-duration pulse trains) showsimilar characteristics to the TI functions, particularly below300 pps. In both cases, thresholds decrease as the number of pulsesin the stimulus increase, although the underlyingmechanisms varyacross pulse rates (Viemeister and Wakefield, 1991; McKay et al.,2013b; Zhou and Pfingst, 2013). The best correlations with mea-sures of cochlear health were for pulse rates below 1000 pps(Pfingst et al., 2011). In most ears with preserved hearing, survivingIHCs, and SGN densities greater than 70% of normal, thresholdsdecreased as a function of pulse rate with slopes of 1 to 3 dB per


Table 1Relation of functional measures to anatomical measures of cochlear health for 5 guinea pig ears with various degrees of SGN density near the cochlear implant. Spiral ganglioncell densities (column 2) and inner hair cell (IHC) presence (percent of normal; column 3) were assessed in the region of the implant and just apical to the implant. Temporalintegration (TI) slopes (dB/doubling of pulse-train duration; column 4) and psychophysical detection thresholds for single biphasic pulses (column 5) are based on the datashown in Fig. 5. These datawere obtained during a period when the psychophysical datawere relatively stable. Means of three repeated threshold estimates are shown. Slopesfor electrically-evoked compound action potential (ECAP) amplitude-growth functions (column 6) are based on best linear fits to the data shown in Fig. 6. Slopes were fit todata above 100 mV to be above the noise floor. ECAP thresholds (current required to evoke a 100 mV ECAP response; column 7) were calculated from these regression lines. TheECAP data were obtained at about 150 DPI, when slopes and thresholds were relatively stable. Column 8 indicates the symbols used in Figs. 5 and 6.

Subject, earand implant

SGN density(Cells/mm2)

IHC (%) TI slope(dB/doubling)

Psychophysical thresholdfor a single pulse (dB re 1 mA)

ECAP slope(mV/mA)

ECAP thresh. (mA) Symbols

453L1 959 87 �2.17 �16.6 8.47 122 Red circles510L1 714 0 �0.62 �15.2 7.47 100 Orange stars500L1 477 0 �0.58 �22.9 6.88 56 Green squares455R1 145 0 �0.50 �16.8 4.83 123 Blue diamonds454L1 72 0 �0.30 �15.8 1.66 143 Purple triangles


doubling of pulse rate. However, in ears without IHCs and with SGNdensities less than 70% of normal, we found that the MPI functionswere very shallow with slopes less than 1 dB per doubling of pulserate. These conclusions are based on data from 50 animals with alarge range of SGN and IHC survival (Pfingst et al., 2014). It is notclear from the data we have to date if it is the IHCs or the high SGNdensities (or some other variable that we have not yet assessed)that is responsible for the steep MPI and TI slopes. To date, we haveachieved SGN preservation at greater than 70% of normal in guineapigs only when IHCs are present. However, in human subjects whohave no measurable hearing and thus probably have poor IHCsurvival, we find that some stimulation sites do have steep MPIfunctions (Zhou et al., 2012; Zhou and Pfingst, 2014a). Also, frompublished reports we know that human subjects can maintain SGNdensities at high levels for long periods of time in the absence ofIHCs (e.g., Hinojosa and Marion, 1983). Thus, we believe that IHCsare not necessary to achieve steep MPI functions but that otheraspects of cochlear health, such as SGN density, that are supportedin the guinea pig animal model by the presence of IHCs, are theunderlying variables necessary for multipulse integration andtemporal integration. It is important to note however that, in thestudies conducted to date, the anatomical and electrophysiologicalmeasures used to assess cochlear health account for only about 50%of the variance across animals in MPI slopes (Pfingst et al., 2011,2014). Thus it seems that multiple measures of cochlear health, inaddition to SGN density, will be needed to fully understand themechanisms underlying this measure of cochlear implant function.

To determine the relationship between the level of cochlearhealth as assessed by MPI function slopes and cochlear implantfunction as assessed by speech recognition in humans, we used awithin-subject design in people with bilateral cochlear implants.Specifically we tested the hypothesis that the ear differences inspeech recognition in subjects with bilateral cochlear implantscould be predicted by ear differences in the slopes of MPI functions.This design allowed us to estimate cochlear-neural health in thesame test session where speech recognition was measured. By us-ing a within-subjects design, we reduced confounding effects ofacross-subject variables.

We hypothesized that the effects of sparse neural survival onspeech recognition would include reduced resolution of spectralinformation. With sparse neural survival, stimulation of the indi-vidual electrodes would not be as effective at targeting indepen-dent populations of neurons, and this could result in a reducednumber of effective spectral channels and smeared neural repre-sentation of spectral envelopes. The reduced spectral resolutionwould make listening in fluctuating noises particularly challengingbecause the implant users would be less able to segregate the targetspeech signals from the background noise. The smeared neuralrepresentation of spectral information would lead to difficulties


with perceiving speech features that depend on spectral acousticcues.

In 8 bilaterally implanted listeners with different degrees of earasymmetry, we found that the ears with better cochlear health asestimated by the slopes of the MPI functions were also those thatperformed better in sentence recognition in an amplitude-modulated noise background and phoneme recognition at chal-lenging signal to noise ratios (SNRs) (Zhou and Pfingst, 2014a). Themagnitude of ear differences in the MPI slopes also proportionallypredicted the magnitude of the subjects' ear differences in speechreception thresholds (signal to noise ratios required for 50% correctrecognition of CUNY sentences), consonant recognition at 0 dB SNR,and perception of the place of articulation feature of consonants.More interestingly, perception of various consonant sounds thathave distinct spectral correlates was correlated with estimatedneural survival in the corresponding frequency regions accessed bythe implant. It should be noted that these ear differences did notseem to be related to the subjects' duration of experience with thedevice. These findings were consistent with our hypotheses thatcochlear health is important for speech recognition in fluctuatingnoises and perception of spectral cues.

3.2. Objective electrophysiological measures

Several electrophysiological measures of implant function havebeen shown to correlate with nerve survival in animal models.These include electrically-evoked auditory brainstem response(EABR) inputeoutput (growth) functions (Smith and Simmons,1983; Hall, 1990) and various derivatives of electrically-evokedcompound action potential (ECAP) growth functions (Prado-Guitierrez et al., 2006; Ramekers et al., 2014). Fig. 6 shows exam-ples of ECAP growth functions for guinea pigs with various levels ofSGN density in the region of the implant as detailed in Table 1. Incontrast to the psychophysical TI and MPI functions, which weremost effective at distinguishing between very high levels ofcochlear health and all lower levels of health, the ECAP growthfunction slopes are reasonably good at reflecting cochlear healththroughout a large range of SGN densities in the absence of haircells (Pfingst et al., 2014). However, the spiral ganglion cell densitiesaccount for only about 50% of the variance in the ECAP growthfunction slopes. Note that positions of the curves along the abscissa,as reflected in the current required to evoke a 100 mV ECAPresponse (Table 1, column 7), are not predictive of nerve survival,but the slopes (rate of growth as a function of input level; Table 1,column 6) are. We found similar results for electrically-evokedauditory brainstem (EABR) amplitude-growth functions (Pfingstet al., 2014).

We are currently examining ECAP growth functions in humans.Preliminary results indicate that (1) the slopes vary from one


0 25 50 75 100 125 150 175 200 225 250 275

0

500

1000

1500

Stimulus current (uA)

N1

to P

2 am

plitu

de (u

V)

Fig. 6. Examples of ECAP amplitude-growth functions from the same five animals forwhich TI data are shown in Fig. 5. The N1 to P2 ECAP amplitude (mV) was used becauseP1 was usually obscured by stimulus artifact. Growth function slopes, but notthresholds were correlated with the degree of SGN survival as detailed in Table 1.


stimulation site to the next across the electrode array and (2) theacross-site patterns of these slopes are stable over time. Futurework will examine their relationship to various features of speechrecognition. Clinically, ECAP measures are currently used primarilyto estimate appropriate stimulation levels. This is done using ECAPthresholds, which typically correspond roughly to comfortablelistening levels. However the correlations between ECAP thresholdsand behavioral measures of comfortable loudness are variable andthis has limited their clinical utility (Miller et al., 2008). Furtherwork is needed to study the implementation of advanced ECAPmeasures such as amplitude-growth functions or spread-of-excitation measures as these could serve as an efficient, objectivemeans to improve programming if efforts are successful.

4. Potential clinical applications

The current knowledge of how pathology affects cochlearimplant function has motivated studies aimed at improving speechrecognition by using data on the across-site patterns of cochlearhealth in the implanted ear to guide processor fitting. The idea is touse stimulation sites that are in healthier regions of the cochlea andto avoid or rehabilitate sites that are in poorer regions. We refer tothese approaches as “site selection” and “site rehabilitation”strategies.

4.1. Site-selection strategies

One approach for applying functional data to processor fitting isto simply turn off a few sites that have been judged to have poorfunction based on psychophysical or electrophysiological data. Totest the clinical feasibility of this approach, we turned off selectedsites in the processor maps of long-time stable users of cochlearimplants. We compared speech recognition results obtained withthese experimental maps to results obtained with the subjects'everyday-use maps. In one of the first experiments with thisapproach, Zwolan and colleagues created experimental processormaps that contained only stimulation sites that were discriminablefrom neighboring sites. With these maps, 7 of the 9 subjects ob-tained better speech recognition scores on at least one of a varietyof speech recognition tests relative to performance with all stim-ulation sites. In a later experiment (Garadat et al., 2013), we usedmasked modulation detection thresholds (masked MDTs) as thefunctional measure for site selection. To avoid creating large gaps inthe tonotopic map, we divided the electrode array into 5 segments


and turned off only one site in each segment. In this strategy, thebandwidths of the remaining stimulation sites were broadenedafter site removal in order to transmit the complete speech spec-trum. This resulted in better mean performance across all sites inMDTs but by broadening the frequency allocation to each of theremaining channels we slightly reduced the spectral resolution ofthe processor map. We found better speech recognition in noise(correct performance at more challenging signal to noise ratios) inall 12 of the tested subjects compared to performance with theireveryday speech processor map, consistent with the better meanmodulation detection ability. However, we found some negativeeffects on vowel recognition, consistent with the reduced spectralresolution.

The problem of reduced spectral resolution can be avoided inpatients who have bilateral implants. With bilateral implants, fre-quency reallocation might not be necessary because the missingfrequencies at the removal sites in one ear can be represented at thecorresponding stimulation sites in the contralateral ear. Given thatthe spectral information across the two ears is cohesively fusedcentrally, a complete spectrum can be transmitted without havingto compromise spectral resolution, and the overall psychophysicalacuity can be improved at the same time. This dichotic site selectionstrategy was tested in 8 subjects with bilateral implants. Thestrategy effectively improved the subjects' recognition of sentencesand consonants in noise, as well as vowels, relative to the subjects'performance using their everyday map (Zhou and Pfingst, 2012).Despite the fact that the subjects might have different insertiondepths for the two implants, they all demonstrated cohesivespectral fusion of the dichotic signals by reporting hearing onesound from the two implants.

4.2. Site rehabilitation

Instead of removing poorly performing sites, an alternative toimproving overall modulation sensitivity is to improve perfor-mance at the sub-optimal sites by adjusting their stimulation pa-rameters. This site rehabilitation strategy is based on the fact thatmodulation sensitivity improves as a function of stimulation level(Pfingst et al., 2007). In a recent experiment (Zhou and Pfingst,2014b), we increased the stimulation levels at poorly performingsites. The manipulation was hypothesized to improve modulationdetection at the poorly performing sites, which in turn wouldimprove speech recognition. Results from 9 subjects showedsignificantly improved speech reception thresholds using the site-specific level-adjusted maps (Zhou and Pfingst, 2014b). Interest-ingly, increasing the stimulation levels at all sites by the sameamount did not improve speech reception thresholds. Modulationsensitivity at the adjusted levels at the sub-optimal sites wasimproved relative to that prior to level adjustment, suggesting thatthe improvement in speech reception thresholds following site-specific level adjustments was a result of increased acuity fordetecting envelope modulation.

4.3. Future directions

The effects of these optimization strategies have only beentested acutely. The results were promising since long term trainingmight further enhance these benefits. Preliminary results with alimited number of subjects have shown that although speechrecognition performance fluctuates over time, the relative differ-ences between the optimized map and the subject's everyday mapremains. Studies designed for systematic long term training arewarranted to examine whether these benefits could be furtherincreased. Subjective reports from patients reveal that these



optimized processor maps provide a perceptual clarity and arehelpful in their daily communications.

Many of the site selection and site-rehabilitation strategiestested to date are too time consuming for everyday use in the clinic.A goal for future studies is to identify simpler and more efficientmeasures for identifying the better and weaker sites in the cochlearimplant electrode array so that the clinician can quickly determinewhich sites to choose for the processor map and/or for parameteradjustment.

5. Improving cochlear health

The ultimate goal for tissue engineering approaches addressingcochlear pathology is to bring the cochlea to a normal healthy state,at which point the cochlear implant will be obsolete. Whileachieving that goal seems distant, many partial successes in pre-serving and/or regenerating the biology of the cochlea can beapplied today and in the near future to enhance the function of thecochlear implant. From the studies reviewed in Sections 2 and 3, itis evident that conditions near individual electrodes in the cochlearimplant are important for various features of implant function,including speech recognition in background noise. While the spe-cifics of which conditions are important for implant function arenot known, strong candidates include the number of survivingspiral ganglion cell bodies and central processes, the presence orabsence of auditory nerve peripheral processes, and the health ofthe surviving neurons, which is likely influenced by the presence ofinner hair cells and supporting cells. Surgical and tissue engineer-ing techniques are being developed that can support the survival,and in some cases regeneration or replacement, of these basic el-ements. These will be reviewed in Subsections 5.2 and 5.3 below.

5.1. Hearing preservation

Cochlear implant functionality has improved dramatically sincethe original single-channel implants. As the quality of speechrecognition achieved with cochlear implants increases, the im-plants are becoming the therapy of choice for people who havesome residual hearing but are achieving inadequate benefit fromacoustic hearing aids. Thus, many patients are being implanted inears that still have some acoustic hearing. A number of studies inhumans and animals have shown that at least some residualacoustic hearing can be preserved by using less traumatic implantdesigns, careful surgical technique (often referred to as “soft sur-gery”) and pharmacological agents such as steroids (e.g., Turneret al., 2008; Kang et al., 2010; Pfingst et al., 2011; von Ilberg et al.,2011). Such residual hearing in implanted ears can supplementelectrical hearing by providing temporal fine structure and low-frequency hearing that is usually not adequately provided by theimplant. Importantly however, these procedures also serve topreserve the health of the implanted cochlea and auditory nerve,providing functional benefits for electrical hearing per se asdetailed in Section 3 above.

5.2. Neural preservation

One of the benefits of preservation of IHCs, as noted above, isthat they support the preservation and health of the auditory nerve.Supporting cells in the organ of Corti can serve a similar function(Sugawara et al., 2005). In cochleae where IHCs and supportingcells are absent or nonfunctional, auditory-neuron preservation canbe enhanced by delivering one or more therapeutic reagents. Themost common molecules used in laboratory animal experiments tomaintain the neural substrate in deaf ears are neurotrophins(Budenz et al., 2012; Ramekers et al., 2012). Neurotrophins are


soluble molecules that are secreted by cells and act by binding tocell surface receptors (von Bartheld and Fritzsch, 2006). Oncebinding occurs, the receptors undergo dimerization and auto-phosphorylation. This leads to activation of downstream signalingpathways, resulting in a diverse range of cellular responsesincluding survival, growth, proliferation and more, depending onthe stage of development and type of cell. NT-3 and BDNF havebeen the most commonly used neurotrophins for preservingauditory neurons. Nerve preservation with neurotrophins has beendemonstrated in several animal models for human disease,including ototoxicity (Shibata et al., 2011; Wise et al., 2005) andhereditary-based deafness (Fukui et al., 2012; Takada et al., 2014;Yu et al., 2014).

To be clinically applicable, the delivery of neurotrophins willneed to be accomplished by a delivery method that can maintainlong term presence of neurotrophins in the cochlear fluids.Although there is currently no perfect delivery vehicle, severalmethods are showing progress and promise. Delivery via viralvectors, especially adeno-associated viral vectors (AAVs), may leadto long term gene expression with little or no side effects (Lalwaniet al., 1998; Sapieha et al., 2006). Long-term survival of the meso-thelial cells that are transfectedwhen the AAVs are injected into thescala tympani is prerequisite for sustained neurotrophin secretion.The extent of turnover in this tissue needs to be better character-ized. Cochlear implants with drug-eluting capability offer anothermethod for secretion of neurotrophins (or other reagents) into thecochlea (Jolly et al., 2010). The advantage of the latter method is thelack of any risks associated with viral vectors and the ability tocontrol the concentration and rate of delivery. Other methods suchas mini-osmotic pumps or electroporation of naked DNA may beused for short term delivery of neurotrophins (the former) or thegenes encoding them (the latter) (Hendricks et al., 2008; Pinyonet al., 2014).

5.3. Preserving fluid spaces

The presence of fibrous tissue in the scala tympani is a commonfinding in animal and human ears that receive cochlear implants.Because the fibrous tissue is in close proximity to the implantelectrodes, it can lead to increased impedance and might have anegative impact on hearing with the prosthesis. Models to addressthe effects of fibrous tissue on current spread (Hanekom, 2005)may be helpful for further elucidating the interaction between theelectrode and the cochlear fluid space. Adverse effects, includinguncontrolled ossification of the cochlea leading to resorption of allneural substrate, suggest the need to better understand the causesfor connective tissue growth and means to prevent or reverse it.

One commonly discussed cause for connective tissue growth isan inflammatory response. An attempt to reduce inflammatorytissue response with intraoperative intracochlear steroid deposi-tion has shown lower postoperative impedances (e.g., Paascheet al., 2009). Advances in elucidating the signals that mediate theimmune response in the cochlea were recently accomplished bychallenging the ear with an immunogenic reagent lipopolysac-charide (LPS) and then assessing levels of micro-RNAs. The studyhas identified three different micro-RNAs that were elevated(Rudnicki et al., 2014). These molecules can serve as targets thatmay be blocked for preventing inflammatory reaction therebyreducing the connective tissue growth.

5.4. Regeneration

5.4.1. Auditory nerve peripheral processesIn the deaf cochlea, peripheral processes of the auditory nerve

which once innervated the inner hair cells tend to die back, leaving



the cell body and central axon intact and available for activation byelectrical stimulation. It is generally believed, but not yet proven,that if the peripheral processes can be induced to grow toward theimplanted electrode array, cochlear implant function will beimproved. Hypothesized benefits of regrowing the peripheralprocesses include reduced thresholds and improved spatial reso-lution (reduced channel interaction).

Experiments using BDNF or NT-3 have shown that elevatedlevels of the neurotrophins in the cochlear fluids attract sproutingof auditory nerve fibers toward the source of the neurotrophins(Glueckert et al., 2008; Shibata et al., 2010; Wise et al., 2010). Wehave used adeno-associated viral vectors (AAVs) with neurotrophingene inserts to upregulate production of neurotrophins in the deafears. When introduced into the scala tympani of ears with no haircells or supporting cells, these vectors can transfect cells in themesothelial layer lining the scala tympani and secrete the neuro-trophin which can then attract neurites to grow toward the sourceof the neurotrophin in the area where the cochlear implant elec-trodes would reside (Fig. 7).

5.4.2. Inner hair cellsAn additional way to enhance the cochlear substrate is by

generating new inner hair cells. These may help sustain the neu-rons and may also contribute to the acoustic hearing in treatedears. Early demonstration of hair cell regeneration in explants ofmature mammalian ears has been accomplished using over-expression of developmental genes (Shou et al., 2003). This wasfollowed by demonstration of new ectopic hair cells in matureguinea pig ears (Kawamoto et al., 2003). Once a substantialnumber of new IHCs can be reliably grown in deaf ears, theircontribution would be to significantly enhance the outcome of theprosthesis and possibly to replace it. It is therefore imperative thatimplanted ears retain as much as possible of the original auditoryepithelium, which can serve as a substrate for hair-cellregeneration.

Fig. 7. Example of neurite growth toward the basilar membrane area in a deaf, neu-rotrophin treated ear. A whole-mount of the basal turn of the guinea pig cochleastained for neurofilaments (red) and actin (green) and viewed with epi-fluorescence isshown. The ear was deafened with neomycin, injected with AAV.NTF-3 a week laterand obtained for histology 3 months after that. The auditory epithelium does notcontain differentiated hair cells or supporting cells. Instead, it is composed of flat orcuboidal simple epithelium. Nerve fibers are seen entering the epithelium andtraversing the epithelial cells. This experiment was similar to that reported by Shibataet al. (2010) except that AAV was used in this case instead of Ad as the vector for genetherapy. (For interpretation of the references to colour in this figure legend, the readeris referred to the web version of this article.)


5.4.3. Spiral ganglion cellsIn addition to replacement of hair cells, placing new neurons in

the cochlea is being experimentally pursued for treating ears with asevere or complete loss of auditory neurons. The use of stem cells isthe most feasible approach for introducing new neurons into thecochlea. Several groups have been able to accomplish this goal (Baset al., 2014; Shi and Edge, 2013) and improvement in auditorybrainstem response (ABR) thresholds in an animal model of audi-tory neuropathy has been demonstrated (Chen et al., 2012).

6. Conclusions

Several lines of evidence strongly suggest that conditions in thecochlea and the auditory nerve in localized areas near the cochlear-implant electrode array play an important role in implant function.Psychophysical and electrophysiological studies in human subjectsdemonstrating subject-specific patterns of implant function thatvary considerably from one stimulation site to the next are mosteasily explained in terms of variation in conditions near the indi-vidual electrodes in the scala tympani. These conditions couldinclude proximity of neurons to the electrodes, the health of thoseneurons and the presence of bone or fibrous tissue in the currentpaths from the electrodes to the neurons. The functional measureshave been used successfully to guide processor fitting, resulting inimproved speech recognition in human cochlear implant users.Psychophysical and electrophysiological studies in animals showacross-ear differences that are correlated with anatomical mea-sures of cochlear conditions and neural health. However, theanatomical measures examined to date generally account for onlyabout 50% of variance in the psychophysical or electrophysiologicalmeasures of implant function (e.g., Pfingst et al., 2011, 2014).Additional research is needed to understand the relationship be-tween cochlear structure and implant function. For clinical appli-cation it is critical to understand the relationship betweenpsychophysical and electrophysiological measures of implantfunction, cochlear health, and speech recognition. The literaturedocuments a wide range of successes and failures from attempts topredict speech recognition based on psychophysical and electro-physiological measures and to apply these measures in clinicalpractice (e.g., Fu, 2002; Miller et al., 2008; Hughes and Stille, 2008;McKay et al., 2013a), so much work remains to be done. Overall, thestudies described in this paper demonstrate the importance ofcochlear health for cochlear implant function and support ongoingtissue engineering experiments in animals that are designed toimprove the conditions in the cochlea and improve the function ofthe cochlear implant, or in the long run possibly enable normalhearing.

Acknowledgments

The research was supported by NIH-NIDCD R01 DC010786, R01DC 007634, R01 DC010412, T32 DC00011, T32 DC005356 and P30DC05188, the U. of M. Center for Organogenesis and a contract fromMED-EL. We thank our dedicated subjects with cochlear implantsfor participation in these studies. We thank Caroline Arnedt, Jen-nifer Benson, Lisa Beyer, Raisa Gao, Elizabeth Hyde, Lisa Kabara,Moaz Sinan, Gina Su and Donald Swiderski, for their assistancewithdata collection and analysis.

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