Intraneural stimulation for auditory prosthesis: Modiolar trunk and intracranial stimulation sites

Hearing Research 242 (2008) 52–63

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Intraneural stimulation for auditory prosthesis: Modiolar trunk and intracranial stimulation sites John C. Middlebrooks a,*, Russell L. Snyder b,c a

Kresge Hearing Research Institute, Department of Otolaryngology and Biomedical Engineering, University of Michigan, 1301 East Ann Street, Ann Arbor, MI 48109-5506, USA Epstein Laboratory, Department of Otolaryngology, Head and Neck Surgery, University of California, San Francisco, CA 94143-0526, USA c Department of Psychology, Utah State University, Logan, UT 84322-2810, USA b

a r t i c l e

i n f o

Article history: Received 29 January 2008 Received in revised form 11 March 2008 Accepted 2 April 2008 Available online 7 April 2008 Keywords: Auditory nerve Cat Cochlear implant Cochlear nerve Intracranial Inferior colliculus

a b s t r a c t We have demonstrated recently in an animal model that stimulation with a penetrating auditory nerve electrode array is a feasible means of activating the ascending auditory pathway for auditory prosthesis. Compared to a conventional intrascalar cochlear implant, intraneural stimulation provides access to fibers serving a broader frequency range, activation of more tonotopically restricted fiber populations, lower thresholds, and reduced interference between simultaneously stimulated channels. The spread of excitation by a single intraneural electrode is broader than that by an acoustic tone but narrower than that by a cochlear-implant electrode. In the present study, we compare in an animal model two sites of intraneural stimulation: the modiolar trunk of the nerve accessed using a transcochlear approach and the intracranial portion of the nerve accessed using a posterior fossa approach. The two stimulation sites offer very similar thresholds, spread of activation, and dynamic ranges. The intracranial site differed in that there was greater between-animal variation in tonotopic patterns. We discuss the implications of these results for possible improvements in hearing prosthesis for human subjects. Ó 2008 Elsevier B.V. All rights reserved.

1. Introduction Among the first efforts at auditory prosthesis were attempts to stimulate the auditory pathway with electrodes implanted directly into the auditory nerve. In pioneering experiments by Simmons and colleagues, bundles of 4 or 6 75-lm-diameter wires were inserted into the auditory nerves of human volunteers using a transcochlear approach (Simmons, 1966; Simmons et al., 1965, 1979). Those subjects could distinguish among electrodes and could discriminate current levels and rates of pulsatile stimulation. Simultaneous stimulation with pairs of electrodes produced little or no change in threshold, suggesting a high level of channel independence. Nevertheless, thresholds for eliciting auditory sensation were inexplicably high, and there was essentially no speech recognition using auditory cues alone. Contemporaneous with those

Abbreviations: BP, bipolar configuration of cochlear-implant electrodes; CF, characteristic frequency; EABR, electrically-evoked auditory brainstem response; FSDR, frequency-specific dynamic range; ICC, central nucleus of the inferior colliculus; INIntCr, intraneural stimulation in the intracranial portion of the nerve; INMod, intraneural stimulation in the modiolar trunk of the nerve; MP, monopolar configuration of cochlear-implant electrodes; nC, nanoCoulombs; UEA, Utah electrode array * Corresponding author. Tel.: +1 734 763 7965; fax: +1 734 764 0014. E-mail addresses: [email protected] (J.C. Middlebrooks), [email protected] (R.L. Snyder). 0378-5955/$ - see front matter Ó 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.heares.2008.04.001

studies of intraneural stimulation, Simmons and other research groups began to achieve promising results with electrodes implanted in the scala tympani (reviewed by Wilson, 2008). For a number of reasons, intrascalar cochlear implants caught the attention of the prosthesis-research and clinical communities, and intrascalar cochlear implants were favored for further development. At the present time, more than 100,000 intrascalar cochlear implants have been implanted world-wide. Present-day cochlear implants consist of as many as 22 electrodes arrayed longitudinally along the scala tympani. These implants can support excellent speech recognition in quiet conditions. Speech reception with cochlear implants suffers in the presence of ambient noise, however, and pitch recognition is poor. In part, these limitations might be due to the remote position of stimulating electrodes relative to excitable neural elements (i.e., auditory nerve fibers, cell bodies, and/or peripheral processes). Scala tympani electrodes are separated from excitable neural elements by a wall of porous bone and lie within a volume of electrically conductive perilymph. The bone tends to attenuate the current from electrodes to the nerve, thereby elevating thresholds for excitation and blunting access to frequency-specific nerve populations. The perilymph permits longitudinal current flow and further diffuses the signal from an electrode to target neural elements. The perilymph also provides a low-impedance path among electrodes, frustrating efforts to focus electrical fields using

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2. Methods All experiments were conducted acutely in barbiturate-anesthetized cats according to a protocol approved by the University Committee on Use and Care of Animals at the University of Michigan. The modiolar trunk of the auditory nerve was stimulated in nine animals. Data from those animals have been presented previously (Middlebrooks and Snyder, 2007); those data are reviewed and additional data are presented here. Stimulation of the intracranial portion of the nerve using a posterior fossa approach was tested in seven additional animals. In all animals, tonotopic activation of the ascending auditory pathway was monitored by recording at multiple sites along the tonotopic axis of the central nucleus of the inferior colliculus (ICC). The basic methods for recording from the ICC and for stimulation of the auditory nerve using a transcochlear approach have been presented previously (Middlebrooks and Snyder, 2007) and will be summarized here. The meth-

ods for stimulation with the posterior fossa approach will be presented here in more detail. Stimulus presentation and data acquisition were controlled by a Windows-based personal computer running custom MATLAB scripts (The Mathworks; Natick, MA) and interfaced with System 3 equipment from Tucker-Davis Technologies (TDT; Alachua, FL). Acoustic stimuli were 40-ms tone pips (with 5-ms rise/fall times) presented through a tube sealed in the left ear canal; stimulus levels were calibrated in situ using a probe-tube microphone. Electrical stimuli were single biphasic pulses, initially cathodic, 40 ls per phase. Stimulating pulses were generated by a custom 16-channel optically isolated current source that was controlled by a 16-bit digital-to-analog converter (TDT RX8); the current source had maximum compliance voltage of ±30 V and output impedance of 4.3 MOhm at 1 kHz. In each animal, the right inferior colliculus was visualized by aspiration of overlying cerebral cortex. Extracellular recording from the ICC employed silicon-substrate probes from NeuroNexus Technologies (Ann Arbor, MI, USA); (see Anderson, 2008). Each recording probe had 32 recording sites, 400 lm2 in area, arrayed at 100-lm intervals along a single 15-lm-thick shank. The probe was inserted in the coronal plane, oriented from dorsolateral to ventromedial, 45° from the mid-sagittal plane. The probe trajectory was approximately parallel to the tonotopic gradient of characteristic frequency (CF) in the ICC. The position of the probe was adjusted to yield single- or multi-unit responses with CFs ranging from about 1 to 32 kHz. A fairly consistent low-to-high-CF progression was observed in all animals. Those CF progressions are illustrated in Fig. 1. Most of the CF-versus-depth lines are parallel. The range of vertical offset of the lines reflects between-experiment variability in the depth of the recording probe. After satisfactory placement of a recording probe, the intracranial volume over the ICC was filled with warmed 2% agarose in Ringer’s solution, and then the recording probe was sealed in place with acrylic cement and dental sticky wax. The animal’s head was positioned for access to the auditory nerve via either the transcranial or posterior fossa approach, and a final set of auditory responses to tones

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configurations of multiple electrodes. Finally, most cochlear implants are inserted at the cochlear base and reach no further than the middle turn of the 2-1/2-turn cochlea. For that reason, frequency-specific stimulation of fibers from the cochlear apex that subserve low-frequency hearing is particularly challenging. These obstacles to efficient frequency-specific stimulation of restricted auditory nerve-fiber populations contribute to poor frequency resolution, limited channel independence, and for the need for relatively high operating currents. We recently have re-visited intraneural stimulation as a mode of auditory prosthesis (Middlebrooks and Snyder, 2007). In principle, a penetrating intraneural stimulating array would provide intimate contact between electrodes and auditory nerve fibers, offering a direct current path to restricted populations of nerve fibers. We conducted experiments in an animal model, stimulating auditory nerve fibers using an intraneural array of 16 iridium-plated electrodes distributed at 100-lm intervals along a single silicon-substrate shank. We monitored activation of the central auditory pathway by recording simultaneously from up to 32 sites along the tonotopic axis of the inferior colliculus. Single arrays were inserted into the auditory nerve from a lateral transcochlear approach, passing transversely through the modiolar trunk of the auditory nerve closely basal to the basal cochlear turn. Compared to stimulation with banded intrascalar electrodes in the same experimental animals, intraneural stimulation showed more restricted excitation of frequency-restricted neural populations, specific access to a broader range of frequencies, reduced thresholds for excitation, and reduced between-channel interference. Our results using intraneural stimulation in an animal model offer hope for improved performance of human auditory prosthethetic devices. Among the basic issues that must be addressed before intraneural stimulation can be translated into human auditory prosthesis is the identification of an optimal approach to the auditory nerve. Identification of the optimal approach must begin by deciding whether it is better to stimulate a peripheral portion of the nerve, accessed through the ear, or the central portion of the nerve, accessed from within the skull. We address that issue in the present report. We review some of our previous results and those of others obtained using a transcochlear approach to the modiolar trunk of the nerve, and compare those results with new data obtained using a posterior fossa approach to the intracranial portion of the nerve. Thresholds, spread of excitation, and dynamic ranges were generally similar using the two approaches, but considerable differences were observed in regard to tonotopic organization and the variability in tonotopic organization among animals. Those differences, as well as other factors including surgical access and safety of the nerve, are considered in Section 4.

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IC Recording Depth (μm) Fig. 1. Tonotopic organization in the ICC. Each line represents data from one of the 16 animals that were studied. Characteristic frequencies (CFs) were measured at 100-lm increments of depth at 32 sites in the ICC. Depths are indicated relative to the most superficial recording site on the recording probe.

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was collected. In animals studied with the transcochlear approach to the auditory nerve, the cochlea was deafened by intrascalar application of 10% neomycin sulfate, which results in loss of all auditory responses within about 10 minutes (Middlebrooks and Snyder, 2007; Nuttall et al., 1977). Waveforms recorded from the ICC were digitized and recorded on computer disk for off-line spike sorting, as described previously (Middlebrooks and Snyder, 2007). Approximately 10% of recording sites yielded well isolated single units. All other recordings that were used for quantitative analysis consisted of spikes from unresolved clusters of 2 or more units. The sensitivity of neural spike counts to changes in stimulus level was quantified by a procedure derived from signal detection theory (Green and Swets, 1966; Macmillan and Creelman, 2005) as described previously (Middlebrooks and Snyder, 2007). The signal detection procedure was based on trial-by-trial spike counts and yielded a discrimination index, d0 . For example, d’ = 1 indicates that one could achieve 76% correct in discriminating an increase in current level. The tonotopic spread of excitation in response to acoustic or electrical stimulation was represented by spatial tuning curves, which plot d0 cumulated across increasing stimulus levels at various depths along the ICC tonotopic axis. Examples of spatial tuning curves for 1, 4, and 16 kHz tones are shown in Fig. 2. The contour lines are drawn at intervals of 1 d0 unit. The outer extent of the colored area shows the tonotopic spread of excitation at a criterion of d’ = 1. At 10 dB above threshold, spatial tuning curves typically extended approximately 500 lm in the tonotopic dimension for middle and high frequencies and typically were somewhat broader for lower frequencies. Intraneural stimulating arrays, also from NeuroNexus, were similar to the recording probes. Each stimulating array had 16 iridium-plated sites, each site 703 lm2 in area, spaced at 100-lm intervals along a single shank. For the transcochlear approach to the modiolar trunk of the auditory nerve, the bulla was opened to expose the round window, and the round window margin was enlarged with a diamond burr. A small hole was made in the osseous spiral lamina and the stimulating array was advanced with a micropositioner; the probe was oriented from ventrolateral to dorsomedial, 45° from the horizontal plane. Fig. 3 shows the distal 1.5 mm of the stimulating array (inset) and shows the array passing through the osseous spiral lamina into the modiolar trunk

Fig. 3. Intra-operative view of an inserted intraneural electrode using the transcochlear approach to the modiolar trunk of the auditory nerve. The dashed line indicates the original margin of the round window prior to surgical enlargement. The stimulating array is shown inserted through a surgical hole in the osseous spiral lamina. The inset shows the stimulating array with its 16 stimulating sites. From Middlebrooks and Snyder (2007).

of the nerve. The stimulating array traversed the modiolar trunk of the nerve at the level of the basal hook region, roughly perpendicular to the long axis of nerve fibers. In the posterior fossa approach, the intracranial portion of the auditory nerve was exposed on the floor of the fossa by first removing the alate portion of the temporal bone posterior to the tentorium and aspirating the lateral cerebellum. The auditory nerve was visualized by gentle retraction of the brainstem. Then small diamond burrs were used to thin the roof of the medial portion of the internal auditory canal from the internal meatus extending 2 mm lateral. Care was taken not to damage the nerve by heating

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Sound Level (dB SPL) Fig. 2. Spatial tuning curves in response to pure-tone stimulation. Spatial tuning curves represent the distribution of spike activity along the tonotopic axis (depth) of the ICC in response to particular stimuli. Each panel indicates the response to pure tones at the indicated frequency. The vertical axis represents depth along the recording probe, which was oriented from dorsolateral to ventromedial, approximately parallel to the tonotopic axis. The contours and colors represent cumulative d0 for discrimination of sound levels based on trial-by-trial spike counts at each recording depths. Contours are drawn in steps of 1 d0 unit. The spread of activation along the ICC tonotopic axis broadens somewhat with increasing sound pressure level, represented on the horizontal axis. Cat 0509.

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to P32 kHz (Fig. 4A and B); the range of the tonotopic excitation pattern that could be measured was limited by the 3.1-mm length of the 32-channel recording probe and by the 6.3-oct calibrated range of the acoustic stimulus-delivery system. Stimulation of other sites activated intermediate frequency regions (e.g., 3 kHz, Fig. 4F) or produced two-lobed patterns (Fig. 4C). The tonotopic progression of activity evoked at sites along the intraneural array seen in Fig. 4 is typical of nearly all animals studied using the transcochlear approach to the nerve. The most superficial intraneural sites in the stimulating array (Fig. 4A and B) produced isolated activity in ICC regions representing high frequencies corresponding to the cochlear base. Stimulation at a deeper intraneural site (Fig. 4C) produced a two-lobed pattern involving the low- and high-frequency extremes on the map, corresponding to excitation of both apical and basal fibers. The deepest three intraneural sites in this example showed a progression from very low-frequency activation (Fig. 4D) gradually shifting to middle frequencies (Fig. 4F). The tonotopic progression that was seen with the transcochlear approach to the nerve is consistent with the spiral anatomical organization of the nerve that was described by Arnesen and Osen (1978). For that reason, we refer to this as the ‘‘spiral” tonotopic pattern. Arensen and Osen showed that fibers from the cochlear apex lie in the center of the nerve and that fibers from the middle and basal turns of the cochlea tend to lie successively more superficial. The fibers from the most basal ‘‘hook” region of the cochlea lie adjacent to the apical fibers such that electrical current might spread to both apical and basal fibers without activating middle-turn fibers, thus explaining the twolobed pattern in the ICC that we often observed. The complete spiral tonotopic pattern was observed in seven of the nine animals that were studied with the transcochlear approach to the modiolar trunk of the nerve. In the 2 remaining

the bone. The thin remaining dorsal bone was removed with jeweler’s forceps. The intraneural stimulating arrays used for the posterior fossa approach to the nerve were identical to those used for the transcochlear approach. The arrays traversed the nerve in the sagittal plane from dorsocaudal to ventrorostral, 10° from the coronal plane. Two or more placements of stimulating arrays were made in each of nearly all of the animals. Summary data and illustrated examples are based on the one array placement in each animal that was judged the ‘‘best” in the sense that it showed the most restricted activation of frequency-specific neural populations and the broadest overall range of activated frequency regions. 3. Results Stimulation with electrical pulses through intraneural electrodes typically resulted in low-threshold excitation of restricted populations of nearby auditory nerve fibers. The tonotopic locations of fiber populations excited by various electrodes were distributed throughout the entire frequency range of cochlear fibers. The limited tonotopic spread of excitation from each stimulation site was evident in the restricted spread of activation along the tonotopic axis of the ICC. Fig. 4 shows examples from one animal that was studied using the transcochlear approach to the modiolar trunk of the auditory nerve. Each panel represents the response to stimulation at one intraneural site; in this example, sites were stimulated at 300 lm intervals along the electrode array. The left-side vertical axes plot the depth along the recording array in the ICC, and the right-side axes plot the corresponding CFs, which were determined prior to deafening the animal. In this example, stimulation at various sites produced frequency-specific activation extending across the ICC representations of 62 kHz (Fig. 4D and E)

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Current (dB re 1 μA) Fig. 4. Spatial tuning curves in response to intraneural stimulation in the modiolar trunk of the auditory nerve using the transcochlear approach. Each panel shows the response to stimulation with single electrical pulses at one depth in the nerve; the depth indicated in each panel is relative to the most superficial stimulation site. Characteristic frequency, shown on the right axis, is based on measurements made prior to deafening the cochlea and inserting the intraneural array. Cat 0503.

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animals, we were unable to locate the middle-turn representation, even though we advanced the electrode array until it reached an obstruction (i.e., presumably bone). That is, we observed highfrequency activation from superficial sites, the characteristic bimodal high/low pattern followed by a jump to low frequency activation, and low-frequency activation from deep sites, but no progression to middle frequencies at the deepest sites. Responses to intraneural stimulation of the intracranial portion of the auditory nerve shared many features with that of stimulation of the modiolar trunk, including low thresholds and restricted spread of excitation, both of which are quantified in a later section. Nevertheless, stimulation of the intracranial portion resulted in a greater variety of tonotopic patterns. The tonotopic organization of the intracranial portion of the nerve was explored in 7 animals. Three of those animals showed a spiral tonotopy that was very similar to that seen with stimulation of the modiolar trunk of the nerve: high-, high-/low-, low-, and middle-frequency activation resulting from stimulation of a sequence of superficial to deep intraneural sites. In three of the remaining four animals, at least one array placement showed incomplete spiral tonotopy that lacked isolated activation of the high-frequency ICC region. An example of such an ‘‘incomplete” spiral pattern is shown in Fig. 5. A sequence of superficial to deep stimulation sites produced a progression of low-frequency (1.6 kHz) to middle-frequency (7 kHz) activation, like the deeper half of the typical spiral pattern. The superficial sites (Fig. 5A–D) showed some high-frequency activation, but the thresholds for high frequencies (presumably basal fibers) remained higher than thresholds for low frequencies. That is, the tonotopic pattern in this array placement covered a CF range of only 2.1 oct and lacked the isolated basal-turn stimulation was typical of superficial neural stimulation sites in the complete spiral pattern. Isolated high-frequency stimulation was not achieved in this example even when the stimulating array

was withdrawn to a point at which the most superficial stimulation site began to exit the nerve. The seventh animal was tested with only one array placement, which failed to show the typical spiral pattern. Overall, in all six of the animals that were explored with multiple stimulating array placements, the tonotopic organization showed at least a vestige of the spiral pattern for one or more placements. Five of the animals studied with stimulation of the intracranial portion of the nerve exhibited one or more array placements in which there was a different tonotopic pattern, a predominantly monotonic progression of activation from low to high frequencies resulting from stimulation at superficial to deep sites. An example is shown in Fig. 6. In this example, the most superficial site (Fig. 6A) activated a restricted low-frequency region of the ICC (1 kHz) and stimulation of successively deeper intraneural sites resulted in a systematic shift toward higher-frequency activation, terminating in activation of the 16-kHz CF region of the ICC (Fig. 6H). The most superficial stimulating electrode produced some activation of the highest frequencies at a relatively high threshold but, again, partial withdrawal of the stimulating array did not result in any increase in high-frequency stimulation. In all of the array placements in which there was a monotonic lowto-high-frequency progression, the deepest site activated CF regions at or above 8 kHz. In contrast, in all placements showing the spiral tonotopy, the deepest site activated frequencies at or below 8 kHz, and activation of higher frequencies was found at more superficial sites. The tonotopy of stimulation of modiolar trunk and intracranial portions of the auditory nerve is summarized in Fig. 7. Each data point represents the estimated locus along the tonotopic axis of the ICC site showing the lowest activation threshold as a function of depth of the stimulation site in the nerve. One stimulating array placement is represented for each animal. The thick green line in

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Intraneural Depth (μm from most superficial site) Fig. 7. Summary of tonotopic patterns of intraneural stimulation. Each line represents data from one stimulating-array placement in one animal. The frequency corresponding to each intraneural stimulation site is represented by the CF measured at the ICC depth showing the lowest threshold for that stimulation site. Locations of intraneural stimulation sites are given by the depth relative to the most superficial site on the stimulating array. Thick lines represent the examples shown in Figs. 4–6. (A) Modiolar trunk stimulation sites. (B) Intracranial stimulation sites.

Fig. 7A and thick cyan and dark blue lines in Fig. 7B correspond to the spatial tuning curves shown in Figs. 4–6, respectively. Note that CF increases from the bottom to top along the vertical axis in this figure, whereas the vertical axes of spatial tuning curves show from top to bottom the natural superficial-to-deep progression of increasing CF. For the modiolar trunk (Fig. 7A), every tonotopic sequence began with activation of high-frequency ICC region from superficial intraneural sites, jumped abruptly to low-frequency ICC regions, then drifted back toward middle frequencies (1–8 kHz) resulting from stimulation at the deepest intraneural sites. The intracranial portion of the nerve (Fig. 7B) showed two discrete patterns. The spiral pattern (shown for three cases) began at the highest frequencies for superficial stimulation, jumped to the lowest frequencies, and progressed back toward middle frequencies. In contrast, the monotonic pattern began at the lowest frequencies and progressed monotonically to middle-to-high frequencies. The examples of ‘‘partial spiral” (Fig. 5, shown in Fig. 7 in cyan) and ‘‘monotonic” (Fig. 6, shown in Fig. 7 in dark blue) look similar in Fig. 7, but note that the partial spiral example covers only a 2.1-oct range of CFs, whereas the monotonic example covers a 4-oct range. Fig. 8 shows three schematic cross sections of the cat’s auditory nerve, which are based on the work of Arnesen and Osen (Arnesen and Osen, 1978). Various fill patterns indicate the estimated locations of nerve fibers from the apical (cross hatching), middle (clear), and basal (stippled) turns. Fig. 8A shows the more distal (i.e., further from the brain) of the two sections that they drew. The line labeled ‘‘Modiolar Spiral” indicates a plausible trajectory of our stimulating-array placements in the modiolar trunk of the nerve using the transcochlear approach. Fig. 8B shows the more proximal section as drawn by Arnesen and Osen. We can account for the tonotopy of nerve excitation that we observed with intracranial penetrations only by rotating the proximal section as

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shown in Fig. 8C. In that figure, the line labeled ‘‘Intracranial Spiral” represents the array placements that yielded the spiral pattern of tonotopy and the line labeled ‘‘Intracranial Monotonic” represents array placements that yielded the monotonic pattern. The differences in tonotopy observed among the various intracranial array placements can be accounted for largely by whether or not the array passed through a superficial fascicle of fibers from the cochlear base prior to entering a fascicle of apical fibers. Intraneural stimulation typically provided frequency-specific activation of wide-spread ranges of the tonotopic axis of the ICC. For each of the stimulating-array placements represented in Fig. 7, the CF regions activated in the modiolar trunk spanned 3.7–5.9 oct (median 5 oct) and those activated in the intracranial portion spanned 2.3–5.5 oct (median 4.7 oct). The spread of activation by stimulation through single intraneural electrodes was substantially more restricted than has been observed in previous physiological studies using intrascalar electrodes. In a previous study (Middlebrooks and Snyder, 2007), we compared the spread of excitation in response to single acoustical tones, electrical stimulation with conventional intrascalar cochlear-implant electrodes in monopolar (MP) and narrow bipolar (BP) configurations, and intraneural stimulation using the transcochlear approach to the modiolar trunk (labeled INMod). We represented spread of excitation by the percentage of the 32 ICC recording sites that were active according to a criterion of d0 = 1. Fig. 9 shows those data along with the new data from stimulation of the intracranial portion of the nerve using the posterior fossa approach (labeled INIntCr). Data are shown for stimulus levels 3, 6, and 10 dB above threshold. At these stimulus levels, intraneural stimulation of either the modiolar trunk or the intracranial portion of the nerve produced significantly broader spread of activation than did pure tone stimulation (p < 0.0001; analysis of variance with Bonferroni correction), and intraneural stimulation of either portion of the nerve produced narrower spread than did either intrascalar cochlear-implant configuration (p < 0.0001). There was no significant difference between the spread of excitation resulting from stimulation of the modiolar trunk or intracranial portion of the nerve (p > 0.05). Thresholds for stimulation with intraneural electrodes consistently were lower than those for stimulation with a conventional intrascalar electrode. In each animal, we selected the intraneural stimulation site that gave the most isolated activation of frequency regions corresponding to fibers from apical, middle, or basal turns. Fig. 10 plots thresholds for those selected sites in the intracranial portion of the nerve as well as data from Middlebrooks and Snyder (2007) showing thresholds for the stimulation in the modiolar trunk and for conventional cochlear-implant stimulation with MP and BP configurations. All of the intraneural thresholds were lower than either MP or BP (p < 0.0001, analysis of variance with Bonferroni correction); also, thresholds for MP were significantly lower than for BP (p < 0.005). In contrast, there were no significant differ-

Percent of ICC Recording Sites Active

Fig. 8. Schematic cross sections of the auditory nerve showing distribution of fibers from apical, medial, and basal cochlea. Panels (A) and (B) are re-drawn from Arnesen and Osen (1978) and represent levels that are distal (A) and proximal (B) relative to the brain. The line in A labeled ‘‘Modiolar Spiral” represents the approximate trajectory of stimulating-array placements using the transcochlear approach. Panel (C) shows the more proximal section rotated 90° to accord with the tonotopy of the present stimulation data. Lines labeled ‘‘Intracranial Spiral” and ‘‘Intracranial Monotonic” show approximate trajectories of arrays yielding those tonotopic patterns.

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Fig. 9. Distributions of spread of excitation for various stimulation modes. These box-and-whisker plots show the distribution among animals and stimulating electrodes (or tone frequencies) of spread of ICC activation. Spread of activation was given by the percent of ICC recording sites that were active according to a criterion of d0 = 1. In cases in which the activation pattern consisted of multiple lobes, all active sites in all lobes were counted. The boxes have horizontal lines at the lower quartile, median, and upper quartile. The whiskers indicate the extent of data lying within 1.5 times the inter-quartile distance from the upper and lower quartiles. Plus signs indicate outliers. The number written over each box indicates the number of stimulating electrodes or tone frequencies contained in each distribution. In the abscissa, Tone, INMod, INIntCr, BP, and MP indicate, respectively, tonal acoustical stimulation, intraneural stimulation in the modiolar trunk of the nerve, intraneural stimulation of the intracranial portion of the nerve, intrascalar stimulation with a bipolar configuration, and intrascalar stimulation with a monopolar configuration. Data for the Tone, INMod, BP, and MP conditions are from Middlebrooks and Snyder (2007).

ences among the distributions of any of the intraneural thresholds (p > 0.05). Mean thresholds for the lateral intraneural, medial intraneural, BP, and MP conditions were 26.7, 22.8, 60.3, 50.6 dB re 1 lA, respectively. A threshold of 26.7 dB re 1 lA is 21.6 lA, which corresponds to 0.87 nanoCoulombs (nC) of charge, assuming perfect charge transfer during the 40-ms/phase current pulses. In our previous study (Middlebrooks and Snyder, 2007), we defined the frequency-specific dynamic range (FSDR) as the range of stimulus currents over which activation was restricted to a single contiguous tonotopic region. Stimulus levels beyond the FSDR typically resulted in activation of remote frequency regions (i.e., additional lobes of activity) or in wide-spread non-specific activation. Fig. 11 shows the distributions of FSDRs obtained in the previous study as well as new data obtained using the posterior fossa approach to the intracranial portion of the nerve. Intraneural stimulation of apical-, middle-, and basal-turn fibers in the modiolar trunk showed a significantly greater FSDR than did monopolar intrascalar stimulation (p < 0.001, analysis of variance with Bonferoni correction), and stimulation of modiolar trunk apical- and

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difference between intracranial intraneural stimulation with either of the intrascalar configurations. Pair-wise comparisons, however, showed that FSDRs for intracranial stimulation of apical- and middle-turn fibers were significantly greater than FSDRs for intrascalar monopolar stimulation (p < 0.05). Pair-wise comparisons of stimulation of the modiolar trunk versus the intracranial portion of the nerve showed significantly greater FSDR for stimulation of apicaland middle-turn fibers in the modiolar trunk (p < 0.05) but no significant different for the basal fibers (p = 0.058). Inspection of Fig. 11 suggests that more significant differences between modiolar trunk versus intracranial portions of the nerve and between intracranial versus intrascalar stimulation might appear if tested with a larger sample size.

4. Discussion 0.1

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Fig. 10. Distributions of thresholds for various stimulation modes. In each animal, one stimulation site was selected to represent intraneural excitation of apical, middle, or basal fibers or intrascalar stimulation with bipolar or monopolar configuration. The number written over each box and whiskers indicates the number of animals represented in each distribution. The left vertical axis gives thresholds in a measure of current, and the right vertical axis gives threshold in charge, assuming perfect transfer of charge during the 40-ls phase duration of the electrical pulse. Other abbreviations and details are shown in Fig. 9.

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The present results obtained with intraneural stimulation of the intracranial portion of the auditory nerve in many respects reinforce those described previously for stimulation of the modiolar trunk of the nerve (Middlebrooks and Snyder, 2007). Specifically, compared to electrical stimulation with a conventional intrascalar cochlear-implant, thresholds were lower, spread of excitation was more restricted, and the accessible frequency range was broader. The major difference between modiolar trunk and intracranial stimulation was in the variability in the tonotopic organization that was observed in the intracranial portion. In this Discussion, we begin by reviewing previous studies of intraneural stimulation in humans and animals. We then consider the differences in tonotopic organization observed in the present study between modiolar trunk and intracranial stimulation sites. We review some of the benefits that might be expected if intraneural stimulation were adapted for human auditory prosthesis. We address the relative merits of various sites of stimulation of the human auditory nerve. Finally, we consider some of the challenges that lie in the path of translation of this mode of auditory prosthesis from acute animal studies to a practical clinical device.

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Fig. 11. Distribution of frequency-specific dynamic ranges (FSDRs) for various stimulation modes. The FSDR for each stimulation site was given by the difference in current from the threshold at the most sensitivity ICC site to the current at which ICC activation either jumped to a distant tonotopic locus or spread non-specifically along the tonotopic axis. The number written over each box and whiskers indicates the number of animals represented in each distribution. Other abbreviations and details are shown in Fig. 9.

middle-turn fibers showed greater FSDR than did bipolar intrascalar stimulation (p < 0.05). After Bonferoni correction, the analysis of variance across all the illustrated conditions showed no significant

The first detailed studies of intraneural stimulation of the auditory nerve were conducted in a small number of human volunteers by Simmons and colleagues (Simmons, 1966, 1983; Simmons et al., 1979). The stimulating arrays were 4–6 75-lm-diameter wires inserted into the modiolar trunk of the nerve using a transcochlear approach through the basal turn of the cochlea. The subjects reported distinct sensations in response to stimulation of various electrodes, they could assign loudness values to stimuli that varied in current level, and they assigned pitch sensations that increased monotonically with stimulus rates increasing to 300 pulses per second (Simmons et al., 1979). Stimulation of one electrode at a near-threshold level produced essentially no change in the threshold of a simultaneously stimulated second electrode, although simultaneous supra-threshold stimulation of pairs of electrodes produced conspicuous additive loudness effects (Simmons, 1983). The temporal bone of one human patient was studied post-mortem after 5 years of intraneural stimulation (Simmons et al., 1986). Two of the four wires lay in the intended positions within the modiolus, whereas the other two had been deflected into the vestibule. Histological examination revealed little or no local tissue reaction to the chronic stimulation of the modiolar electrodes. Simmons (Simmons, 1979) also tested the effects of chronic intraneural stimulation with wire electrodes in a cat model. Stimulation over 6–16 months showed no evidence of damage due to electrical stimulation. A group at the University of Michigan conducted preliminary studies of intraneural implantation and stimulation with

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silicon-substrate thin-film electrodes that were early versions of those used in the present study; that work has been reviewed by Arts and colleagues (2003). Most of the early work at Michigan focused on histo-compatibility of the auditory nerve and brain tissue with the silicon-substrate array. Chronic implantation and stimulation of the arrays in the cochlear nuclei of guinea pigs showed adverse tissue reaction only at stimulation levels far higher than the levels needed to elicit scalp middle-latency responses (Niparko et al., 1989a,b). Chronic (5-week) implantation of silicon arrays into the guinea-pig modiolus showed essentially no adverse tissue response aside from some loss of spiral ganglion cells along the path of the implant (Zappia et al., 1990); note that the stimulating array apparently was oriented further into the core of the modiolus in the study by Zappia and colleagues than in the present study. Middlelatency response thresholds in those guinea pigs with intraneural stimulation were around 2 nC, about double the mean threshold for eliciting ICC unit activity in the present study. Normann and colleagues at the University of Utah have worked with a silicon-substrate electrode array that is quite different from the Michigan device. The Utah electrode array (UEA) consists of multiple silicon spikes, each 1 or 1.5 mm in length, 80 lm in diameter at the base, tapering to a sharp tip which contains a single platinum recording or stimulating site. The spikes are arrayed on a square grid with 400-lm spacing between the spikes. The Utah group has reported a series of incremental steps toward intraneural stimulation with the UEA. Badi et al. (2002) evaluated approaches to the auditory nerve in human, pig, and cat cadavers, and determined that the cat would be a suitable animal model for further study. Dummy 4  5 (i.e., 20-spike) UEAs were implanted in the modiolar trunk of the auditory nerve in anesthetized cats. Measurements of electrically-evoked auditory brainstem responses (EABRs) elicited with a tungsten intraneural electrode demonstrated that the nerve remained viable throughout exposure of the nerve and implantation of the UEA. Badi and colleagues (Badi et al., 2003) implanted functional UEAs chronically in cat auditory nerves and recorded EABRs as long as 52 h after implantation. Histological examination of those animals revealed no significant damage to the nerve resulting from stimulation. Hillman et al. (2003) implanted functional UEAs acutely in cats and recorded EABRs with median thresholds of 1.13 nC. Badi et al. (2006) recorded EABRs in response to single biphasic pulses presented sequentially on pairs of UEA electrodes at 300-ls intervals. A subtraction method was used to test the overlap of neural populations activated by the two electrodes. At least at near-thresholds stimulus levels, many electrode pairs showed activation of substantially independent neural populations. Interaction between electrode pairs was most evident when current levels on the two probes were approximately equal, which likely reflects the subtraction technique that was used to detect interactions. In our recent work, the pulses presented simultaneously on two intraneural electrodes at levels at P10 dB above threshold demonstrated superposition in the sense that the pattern of ICC activation evoked by two simultaneous pulses closely resembled the linear sum of the ICC responses to each pulse alone (Middlebrooks and Snyder, 2007). That is, stimulation of one electrode had negligible effect on the response to a second electrode. Kim and colleagues (Kim et al., 2007) estimated the spread of excitation elicited by intraneural stimulation with a 3  4 (12-electrode) UAE by recording from the cat’s cortical area A1 with a 10  10 (100-electrode) UEA. Stimulation at individual intraneural sites activated discrete regions in A1, consistent with the restricted tonotopic activation observed in the present study. Based on their independent measures in different cats, Kim and colleagues estimated the tonotopic gradient in A1 as 0.53 octaves of CF per millimeter of distance along the cortical tonotopic axis. Using that value and the spacing of centroids of electrically evoked activity in

A1, those authors estimated that the frequency regions spanned by their intraneural stimuli spanned no more than 1.17 oct of CF in any single animal. That range is considerably smaller than the ranges of 5 oct observed in the present study. One possible explanation for the limited frequency range of excitation measured in the Utah study is that the 10  10-element recording array in the cortex probably did not sample the low-frequency representation in A1, which is located on the bank of the posterior ectosylvian sulcus (Merzenich et al., 1975), and thus failed to detect intraneural excitation of fibers from the cochlear apex. Another possible explanation is that the 1-mm spikes of the UEA reached only far enough into the auditory nerve to access the fibers from the cochlear base, which are located superficial in the nerve. We generally find that in the modiolar trunk (Fig. 7A) stimulation sites yielding low-threshold excitation of apical fibers typically are located at least 600 lm deep to the most superficial low-threshold basal sites, which themselves are a few 100 lm deep to the surface of the nerve. The UEA with 1-mm spikes likely would not have reached the apical-turn fibers and almost certainly would have missed the middle-turn fibers, which we typically find near the tips of our 1.5-mm electrode arrays. 4.2. Tonotopic organization of intraneural stimulation Arnesen and Osen (1978) examined the geometry of fibers in the cat auditory nerve using microdissection. They demonstrated that fibers tended to form a ‘‘roll”, with successively more basal fibers lying superficial to those arising more apically. They illustrated two cross sections of the nerve, one more distal relative to the brain than the other. At the distal level, the basal fibers covered essentially the entire nerve trunk except for a ‘‘small triangle” at which apical and middle fibers extend to the nerve surface. Consistent with that organization, as re-drawn in the present Fig. 8A, all of our stimulating-array placements in the modiolar trunk passed through basal-turn fibers before entering fascicles from the apical and middle turns. The exposed segment of apical and middle fibers occupies a somewhat larger angle at a more proximal level, as shown in the nerve cross section in Fig. 8B. That section is shown rotated about 90° in Fig. 8C to accord with the present stimulation results. Given that orientation of the nerve and the orientation of our penetrations, approximately 45° from the mid-sagittal plane, a particular array placement would yield either a ‘‘spiral” or ‘‘monotonic” tonotopic progression depending on whether or not it passed through the superficial fascicle of basal-turn fibers. Indeed, in many of the array placements yielding monotonic tonotopy, high-level stimulation of the most superficial sites showed excitation of high-frequency regions, consistent with non-specific spread of excitation to the basal-turn fibers. 4.3. Intraneural stimulation for auditory prosthesis Many users of conventional cochlear implants enjoy good speech reception, at least in quiet surroundings. Nevertheless, most users are challenged by the presence of ambient noise and exhibit poor pitch perception and poor spatial hearing, even with bilateral implants in quiet. By every measure that we tested in our animal model, results of intraneural stimulation differed from those of intrascalar cochlear-implant stimulation in a way that would predict superior performance of an auditory prosthetic device. In this section, we list particular features of intraneural stimulation and consider how those features might influence performance if intraneural stimulation were to be adopted for a practical auditory prosthesis. 4.3.1. Useable in cases of non-patent scala tympani Implantation of a conventional intrascalar electrode array is hindered or is not feasible in cases in which the scala tympani is

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occluded by bone as a sequela of meningitis or severe otosclerosis. Bone growth might complicate implantation of an intraneural array, but if access to the nerve could be gained, one might expect successful stimulation results. Of course, intraneural stimulation, like intrascalar stimulation, requires a more-or-less intact auditory nerve. It would not be indicated for cases in which the auditory nerve was severed, as in many cases of tumor removal. 4.3.2. Reduced stimulation thresholds Mean thresholds for the most sensitive stimulating sites in each animal were 23.9 and 33.8 dB lower for intraneural stimulation at the modiolar trunk site than for intrascalar stimulation in the same animals using monopolar and bipolar configurations, respectively. Those differences correspond to 16- and 48-fold reductions in the current needed to activate the ascending auditory pathway. Those sizeable reductions in stimulating currents in a human auditory prosthesis would, at least, result in appreciable improvements in battery life. At best, the reduced current requirements might eliminate the need for an external battery pack, leading to development of a totally implantable device. 4.3.3. Stimulation of frequency-specific neural populations Intraneural stimulation resulted in significantly more restricted patterns of activity along the tonotopic axis of the ICC than did intrascalar stimulation using either monopolar or bipolar configurations. In a human auditory prosthesis, more tonotopically restricted activation presumably would offer more precise transmission of spectral information about speech and other sounds, thereby improving speech recognition and enhancing segregation of signals from background noise. More restricted activation patterns also would reduce interference among channels, as discussed below. 4.3.4. Access to the entire cochlear frequency range, including lowfrequency fibers from the cochlear apex Using the transcochlear approach to the modiolar trunk of the cat’s auditory nerve, we consistently stimulated fibers representing both upper and lower limits of the range of frequencies represented by CFs in the ICC; our access to the highest and lowest frequencies was somewhat less consistent for the intracranial portion of the nerve, probably because of our lack of understanding of the nerve’s topography geometry at this cross-sectional level. In contrast, intrascalar stimulation in our animal model never provided specific stimulation of the low-frequency fibers from the cochlear apex. Intrascalar electrode arrays used in humans are inserted in the (high-frequency) basal turn of the cochlea and typically extend only to loci in the middle turn representing frequencies no lower than 600 Hz (Skinner et al., 2002; Wardrop et al., 2005). Recent reports have reported electrode placements yielding place-pitch sensations as low as 300 Hz (Baumann and Nobbe, 2006; Boex et al., 2006), but discrimination among those apical electrodes is poor. That is, subjects reported the same pitch sensations for electrodes located 2 mm apart, which should correspond to a difference of an octave in the cochlear frequency map (Baumann and Nobbe, 2006). Lack of place-pitch cues to frequencies below 600 Hz impairs pitch perception in the range of 100 to 600 Hz, which corresponds to the range of most musical melodies and encompasses the fundamental pitches of most human speaking voices. In principle, intraneural stimulation in humans should offer frequency-specific stimulation of the entire audible frequency range, including those low frequencies. Another possible benefit of access to low-frequency fibers from the cochlear apex is that specific stimulation of those fibers would selectively engage low-frequency brainstem pathways that, in normal-hearing listeners, are adapted to transmit acoustic fine structure. At frequencies below 1.5 kHz, normal-hearing listeners

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exhibit sensitivity to interaural phase differences, indicating that their cochleas, auditory nerves, and brainstem pathways preserve information about the cycle-by-cycle time structure of sounds (Licklider et al., 1950). Moreover, at least in experimental animals, frequency representation is biased toward low frequencies in structures that process fine-structure information (Goldberg and Brown, 1969; Guinan et al., 1972; Osen, 1969). One might speculate that brainstem pathways that process higher-frequency sounds might never receive fine structure information from the auditory nerve and, therefore, might not be adapted to preserve fine timing. Intrascalar cochlear implants provide only limited frequency-specific stimulation below 1.5 kHz. One would expect intraneural stimulation to offer a greater range of frequency-specific stimulation in the range of frequencies in which humans hear temporal fine structure. Enhanced coding of temporal fine structure might improve pitch recognition based on temporal cues and might enhance sound localization based on interaural phase cues. 4.3.5. Dynamic range In our animal model, the range of electrical stimulus levels over which intraneural stimulation produced tonotopically restricted spread of excitation (the FSDR) was significantly greater than that shown by intrascalar stimulation. In a human auditory prosthesis, increased FSDR would contribute to a decrease in interference among channels, thereby increasing the number of functionally independent channels available for transmission of spectral information. Also, an overall increase in the dynamic range available for stimulation of the prosthesis would reduce the amount of amplitude compression needed to match the wide dynamic range of sound to the limited dynamic range of electrical hearing. A decrease in compression would reduce the distortion of speech signals and might improve speech recognition; that speculation conflicts with a published study using cochlear implants and the SPEAK processor (Zeng and Galvin, 1999) although it remains to be tested with other processors and with the much larger dynamic range offered by intraneural stimulation. 4.3.6. Reduced interference among channels In our previous study that compared intraneural stimulation of the modiolar trunk of the auditory nerve with intrascalar stimulation (Middlebrooks and Snyder, 2007), we quantified the amount by which presentation of a pulse through one electrode influenced the threshold for a pulse presented simultaneously on a nearby channel. Intrascalar electrodes showed appreciable interference between channels in that the response to a pulse on one electrode could vary from no response to full saturation depending on the stimulus level on a nearby channel. In contrast, interference among intraneural electrodes was in most cases negligible. Reduction in between-channel interference with intraneural stimulation likely was a result of at least three factors: reduced spread of excitation on individual channels, increased FSDR, and higher-impedance current paths among electrodes resulting from the fascicular organization of the nerve. In a typical intrascalar cochlear implant, simultaneous stimulation of nearby channels results in appreciable interference among channels. For instance, a stimulus through one electrode can produce a 10 dB decrease in the threshold on a nearby channel stimulated simultaneously (Boëx et al., 2003; de Balthasar et al., 2003; Eddington et al., 1978; Favre and Pelizzone, 1993; Shannon, 1983). Such interference is largely mitigated in cochlear implant by use of pulsatile interleaved stimulation strategies (Wilson et al., 1991). One disadvantage of pulsatile stimulation is that the temporal fine structure contained in the acoustic input is eliminated and replaced by the timing of the constant-rate electrical pulse train. Loss of fine-structure information degrades temporal cues to pitch and,

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in cases of bilateral implants, eliminates interaural differences in the timing of fine structure as cues for spatial hearing. A second disadvantage of pulsatile stimulation is that, at least for pulse ranges lower than 2000 pulses per second, it produces hypersynchrony of auditory nerve fibers, which has been argued to lead to decreased dynamic ranges (Rubinstein and Hong, 2003; Rubinstein et al., 1999). The dramatically reduced between-channel interference observed with intraneural stimulation might eliminate the need for pulsatile stimulation and raises the possibility of use of stimulation strategies employing continuous waveforms. Continuous waveforms would preserve the natural fine structure of acoustic waveforms, thereby preserving temporal pitch cues and interaural-phase-difference cues for spatial hearing. Also, at least on low-frequency channels, non-pulsatile stimulating waveforms might result in more stochastic excitation of nerve fibers, because a slowly varying electrical waveform would result in greater between-fiber dispersion of threshold crossing compared to the abrupt threshold crossing by a rectangular pulse. 4.3.7. Tonotopy of stimulation A minor disadvantage of intraneural stimulation compared to intrascalar stimulation is that there often is a non-monotonic relationship between position on the intraneural stimulating array and stimulated frequency, as in the ‘‘spiral” tonotopic pattern found in all modiolar trunk array placements in cats and in many of the intracranial placements. In contrast, an intrascalar electrode array shows a fairly reliable high to low progression of frequency associated with stimulation of basal to apical sites, although one does not necessarily know the particular frequency excited by each intrascalar electrode. For a post-lingually-deaf user of an intraneural prosthesis, it should be possible to re-map intraneural electrode numbers to produce a monotonic sequence of perceived frequencies. That procedure might involve something like asking the user to pitch order multiple pairs of stimulated electrodes. A different procedure would be needed for an uncooperative user, such as an infant or a pre-lingually deaf user who did not have a clear sense of high or low pitch. Such a procedure might involve a physiological measure, such as a scalp potential. One assumes that intraneural stimulating sites yielding multilobed excitation patterns would produce ambiguous frequency percepts. Most likely, such sites would need to be disabled. 4.4. Steps toward a practical clinical device Our experiments in an acute animal model have demonstrated the feasibility of intraneural stimulation and suggest several possible benefits that could be expected from an intraneural electrode array as a mode of stimulation for human auditory prosthesis. We consider here some of the challenges that must be overcome prior to human trials. These include tests of effects of long-term implantation and intraneural stimulation, development of the optimal surgical approach, development of a chronically implantable electrode array and associated electronics, and optimization of speech processing strategies. Animal studies of intraneural stimulation have evaluated only short-term implantation; in our studies, for example, intraneural arrays were in place and stimulated for no more than 12 h. Chronic studies in animals are needed to test the long-term safety and bio-compatibility of intraneural stimulation. Of particular concern are physical trauma to the auditory nerve due to insertion and motion of the nerve relative to a rigid stimulating array, foreign body reactions, and adverse reactions to long-term direct electrical stimulation. The danger of physical trauma to the nerve likely will vary with the site of implantation. The transcochlear approach to the modiolar trunk, at least in the acute cat preparation, leaves lit-

tle room for the nerve to move and appears to result in minimal insertion trauma (Middlebrooks and Snyder, 2007). The posterior fossa approach would be of greater concern in that regard, since the human auditory canal is larger and the nerve has more room to move in response to movements of the brain and pulsation of the meatal artery. The available results regarding foreign-body reactions are encouraging: studies of chronic implantation of silicon-substrate devices in brain tissue (Niparko et al., 1989a,b) and in the auditory nerve (Zappia et al., 1990) have shown minimal tissue reaction, at least up to 5 weeks post-implantation. Regarding effects of long-term stimulation, Badi et al. (2003) recorded EABR’s up to 52 h after the onset of continuous intraneural stimulation but, of course, it will be necessary to confirm safety of chronic stimulation over much longer periods in animals before intraneural arrays could be tested in humans. Another concern relevant to the longevity of intraneural stimulation is the effect of auditory nerve-fiber loss on the efficacy of stimulation. A human candidate for auditory prosthesis typically will have suffered some attrition of auditory nerve fibers. It will be important to test in animals whether lack of a full complement of nerve fibers results in any decrement in prosthesis performance, e.g., any increase in threshold or decrease in specificity of stimulation. Development of surgical approaches would necessarily begin with a choice of which portion of the auditory nerve to stimulate. Stimulation of the intracranial portion using a posterior fossa approach would offer the advantage of full visibility of a longer section of the nerve, offering ready access to all frequency ranges and allowing easier insertion of multiple electrode arrays. Another advantage of the posterior fossa approach would be that there would be less danger of compromising residual acoustic hearing. Although we have successfully preserved hearing in some animals during array implantation using the transcochlear approach, hearing preservation is more reliable using the posterior fossa approach. There would be numerous disadvantages to the posterior fossa approach. One is that access to the intracranial portion of the nerve would require a craniotomy, with its increased danger of meningitis and of cerebrospinal fluid leakage. Other concerns would be the danger of trauma to the nerve resulting from motion of the pulsating nerve relative to a rigid electrode array or ischemia of the cochlea due to spasm of the meatal artery. Finally, the present results suggest that, at least in cats, the tonotopic organization within the intracranial portion of the nerve appears to be more variable than in the modiolar trunk; moreover, in human, fibers of the vestibular nerve tend to lie dorsal to fibers of the auditory nerve, adding to the risk of damage to vestibular fibers. A group of surgeons at the University of Michigan have explored in temporal-bone studies an ‘‘infra-labyrinthine” approach that provide access to a peripheral portion of the nerve in the internal auditory canal while remaining outside the otic capsule (Kazkayasi, Wiet, and Arts, personal communication). Advantages of that approach are that the dura remains intact until the actual insertion of the stimulating array and that the eighth nerve is accessed at a point at which the auditory and vestibular branches are anatomically separate. One disadvantage is that at that point of access, the nerve lies within a space in the internal auditory canal that is relatively large in cross section. For that reason, it is free to move with pulsations and is subject to damage from a rigid stimulating array. A second disadvantage is that, in about 1/3 of temporal bones, Kazkayasi and colleagues found that the access was blocked by the jugular bulb. Badi et al. (2002) have described briefly a transcochlear approach using a modification of the extended facial recess approach that is used for conventional cochlear implantation. Further studies of transcochlear approaches are ongoing at the University of Michigan (Wiet and Arts, personal communication). Biomedical engineering work is needed to develop a device suitable for chronic implantation. Tests of single-shank thin-film

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silicon-substrate devices have yielded promising results, but the devices that we have worked with lack the flexible cable and connector needed for chronic implantation. Also, the stimulation arrays that we have used make only a single transit across the cat’s auditory nerve. In the larger human auditory nerve, it would be desirable to implant two or more parallel shafts to provide more continuous access to the tonotopic frequency range. Finally, there is a need for sound-processing software and hardware that would fully exploit the potential benefits of intraneural stimulation. Existing cochlear-implant speech processor would serve as a starting point but, at the least, one would need to adjust for higher stimulating electrode impedance, lower thresholds, broader dynamic ranges, and larger numbers of functionally independent channels. As indicated above, the greatly reduced between-channel interference that is evident with intraneural stimulation might foster the use of continuous-waveform stimulation strategies that might result in even broader dynamic ranges and better transmission of temporal fine structure. 4.5. Concluding remarks We have demonstrated the feasibility of intraneural stimulation for auditory prosthesis. Comparison of modiolar trunk and intracranial sites of stimulation in acute animal studies show little systematic difference aside from greater variation of the tonotopy of stimulation in the intracranial portion of the nerve. By every measure that we tested in our acute animal model, intracranial stimulation offers advantages over stimulation with a conventional intrascalar cochlear implant. Nevertheless, more work needs to be done before human trials of practical auditory prosthetic devices employing intraneural stimulation can be attempted. Acknowlegements We thank Jim Wiler for his expert technical support and Zekiye Onsan for help with the figures. Dr. Bryan Pfingst and Alana Kirby provided useful comments on the manuscript. Supported by NIDCD NO1-DC-5-0005 and P30-DC05188. References Anderson, D.J., 2008. Penetrating multichannel electrodes in auditory science, prosthesis research and implant design. Hear. Res. 242 (1–2), 31–41. Arnesen, A.R., Osen, K.K., 1978. The cochlear nerve in the cat: topography, cochleotopy, and fiber spectrum. J. Comp. Neurol. 178, 661–678. Arts, H.A., Jones, D.A., Anderson, D.J., 2003. Prosthetic stimulation of the auditory system with intraneural electrodes. Ann. Otol. Rhinol. Laryngol. 112 (Suppl. 191), 20–25. Badi, A.N., Hillman, T., Shelton, C., Normann, R.A., 2002. A technique for implantation of a 3-dimensional penetrating electrode array in the modiolar nerve of cats and humans. Arch. Otolaryngol. Head Neck Surg. 128, 1019–1025. Badi, A.N., Owa, A.O., Shelton, C., Normann, R.A., 2006. Electrode independence in intraneural cochlear nerve stimulation. Otol. Neurotol. 28, 16–24. Badi, A.N., Kertesz, M.D., Gurgel, R.K., Shelton, C., Normann, R.A., 2003. Development of a novel eighth-nerve intraneural auditory neuroprosthesis. Laryngoscope 113, 833–842. Baumann, U., Nobbe, A., 2006. The cochlear implant electrode-pitch function. Hear. Res. 213, 34–42. Boex, C., Baud, L., Cosendai, G., Sigrist, A., Kos, M.-I., Pelizzone, M., 2006. Acoustic to electric pitch comparisons in cochlear implant subjects with residual hearing. J. Assoc. Res. Otol. 7, 110–124. Boëx, C., de Balthasar, C., Kos, M.I., Pelizzone, M., 2003. Electrical field interactions in different cochlear implant systems. J. Acoust. Soc. Am. 114, 2049–2057. de Balthasar, C., Boex, C., Cosendai, G.G., Valentini, G., Sigrist, A., Pelizzone, M., 2003. Channel interactions with high-rate biphasic electrical stimulation in cochlear implant subjects. Hear. Res. 182, 77–87.

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