Cochlear infrastructure for electrical hearing

Abstract

Although the cochlear implant is already the world's most successful neural prosthesis, opportunities for further improvement abound. Promising areas of current research include work on improving the biological infrastructure in the implanted cochlea to optimize reception of cochlear implant stimulation and on designing the pattern of electrical stimulation to take maximal advantage of conditions in the implanted cochlea. In this review we summarize what is currently known about conditions in the cochlea of deaf, implanted humans and then review recent work from our animal laboratory investigating the effects of preserving or reinnervating tissues on psychophysical and electrophysiological measures of implant function. Additionally we review work from our human laboratory on optimizing the pattern of electrical stimulation to better utilize strengths in the cochlear infrastructure. Histological studies of human temporal bones from implant users and from people who would have been candidates for implants show a range of pathologic conditions including spiral ganglion cell counts ranging from approximately 2% to 92% of normal and partial hair cell survival in some cases. To duplicate these conditions in a guinea pig model, we use a variety of deafening and implantation procedures as well as post-deafening therapies designed to protect neurons and/or regenerate neurites. Across populations of human patients, relationships between nerve survival and functional measures such as speech have been difficult to demonstrate, possibly due to the numerous subject variables that can affect implant function and the elapsed time between functional measures and postmortem histology. However, psychophysical studies across stimulation sites within individual human subjects suggest that biological conditions near the implanted electrodes contribute significantly to implant function, and this is supported by studies in animal models comparing histological findings to psychophysical and electrophysiological data. Results of these studies support the efforts to improve the biological infrastructure in the implanted ear and guide strategies which optimize stimulation patterns to match patient-specific conditions in the cochlea.

Fig. 1

Example of patchy nerve survival in an ototoxically deafened human cochlea as seen in a surface preparation by Johnsson and colleagues (1981). The inset shows the upper half of middle and apical turns of the cochlea. Degeneration is more severe in the basal turns (main figure). Nerve fibers in the osseous spiral lamina are stained with osmium tetroxide. OC = supporting cells in the Organ of Corti. No hair cells were found. Reproduced, with permission, from Acta Oto-Laryngologica, 1981, Supplement 383, page 12, Figure 9.

Fig. 2

Across-site patterns of various psychophysical measures for three human subjects with Nucleus CI24R(CS) or Freedom implants (one subject per column). All three subjects had bilateral implants. Functions for the right ear are shown in red and those for the left ear are shown in blue. Across site patterns for 7 psychophysical measures are shown. Monopolar stimulation with 500 ms trains of 50 μs/phase pulses at 900 pulses/s (pps) was used in all cases except gap detection where the pulse rate was 1000 pps. Top row: Triangles = maximum comfortable loudness levels (C levels); Circles = detection threshold levels (T levels). Second row: Dynamic ranges (C levels minus T levels). Third row: Modulation detection thresholds (MDTs) measured at 50% of the dynamic range (50% DR). Sinusoidal modulation of phase duration at 10 Hz around a mean of 50 μs/phase was used. Units for MDTs are modulation depth in dB re 100% modulation. Fourth row: MDTs measured in the presence of an unmodulated pulse train (masker) presented at 50% DR on an adjacent channel and interleaved with the modulated pulse train. The masker site was the next apical site to the site where the MDTs were measured in all cases except when the MDTs were measured for site 22 and the masker was on the adjacent basal site. Fifth row: Amount of masking = masked MDTs (data from row 4) minus nonmasked MDTs (data from row 3). Sixth row: Gap detection thresholds (GDTs) measured at 50% DR. Details o f the psychophysical procedures are similar to those reported in Pfingst et al., 2008 and Garadat and Pfingst, 2011.

Fig. 3

Histological results for three representative animals differing in the treatment and implantation procedures. All three animals received an eight-electrode Nucleus animal cochlear implant (Cochlear Corp., Lane Cove, Australia) in their left ear. The implants were inserted through a cochleostomy made approximately 0.7 mm apical to the round window. The electrodes were spaced at approximately 0.75 mm intervals and were labeled A through H with A being the most apical. The “Hearing” animal received the cochlear implant in an ear that had normal hearing prior to implantation. After implantation while pulse rate data in Fig. 6 were collected, thresholds for 16 kHz pure tones were elevated by 8.1 dB relative to the pre-implant thresholds. The “Deaf + AAV.NTF-3” animal was deafened prior to implantation by systemic administration of kanamycin (400 mg/kg) and ethacrynic acid (35 mg/kg). Seven days later, the left ear was inoculated with AAV.NTF-3 (5 μL) injected into the scala tympani through the cochleostomy and then, 20 minutes after the inoculation, the cochlear implant was inserted. The “Deaf” animal was deafened in the left ear by local injection of neomycin sulfate (60 μl, 10% w/v) through the round window prior to implantation. Histological data were obtained from peri-midmodiolar sections that were centered at the location of the primary electrode used for psychophysical and electrophysiological data collection (Electrode B, which was located in the first half of the basal turn approximately 3.8 mm on average from the round window). Five 2.5 μm sections were analyzed and spaced at intervals of 25 μm. Means of results for these five sections are shown. Inner hair cells (IHC) were counted only if a nucleus was present. Percent normal (left ordinate) is shown where normal equals one hair cell per section. The outer hair cells (OHC) were counted if any part of the cell was visible and normal equals 3 hair cells per section. Individual peripheral processes could not be counted in the peri-midmodiolar sections so density of peripheral processes was estimated on a scale of 0 to 3, with 3 being normal. Spiral ganglion cell packing density (right ordinate) was estimated by counting the number of cells with a nucleus in the cross section of Rosenthal's canal and dividing by the area of that cross section. Histological results for the hearing animal and those for the deaf animal are similar to those reported by Kang and colleagues (2010).

Fig. 4

Spectra for ensemble spontaneous activity recorded from Electrode B for the three animals for which histology is shown in Fig. 3. A peak in the spectrum near 900 Hz (-29.7 dB re 1 V) is typical of animals with residual acoustic hearing and presumed spontaneous activity in the auditory nerve (See Kang et al., 2010: mean = -33.4 dB, s.d. = 1.84, n = 11). The lack of a distinct peak and the low potentials (max -42.9 dB) near 900 Hz in the deaf animal is also similar to data reported previously (Kang et al., 2010: mean = -44.4 dB, s.d. = 2.5, n = 4). The intermediate voltage (-40.6 dB) recorded for the Deaf + AAV.NTF-3 treated animal is similar to that found in four other animals that were treated with neomycin followed by AAV.NTF-3 (unpublished results: mean = -41.1 dB, s.d. = 2.2 , n = 4).

Fig. 5

Electrically-evoked compound action potential (ECAP) input/output functions for the three animals for which histology is given in Fig. 3. Potentials were evoked by monopolar stimulation of Electrode B and recordings were made from Electrode A. Stimuli were 25 μs/phase biphasic pulses of alternating initial-phase polarity presented at 50 pps, delivered using a MED-EL Pulsar ci100 receiver/stimulator connected to the implant through a percutaneous connector. ECAP amplitudes were calculated as the peak to peak voltages: P2 (latency ~0.3 ms) minus N2 (latency ~0.8 ms) from waveforms averaged over 20 pulses. The differences in slopes of the ECAP input/output functions across the three conditions shown here have been duplicated in preliminary data from experiments currently in progress involving three hearing animals, four deafened AAV.NTF-3 inoculated animals and two deafened AAV.empty inoculated animals.

Fig. 6

Psychophysical detection thresholds for monopolar pulsatile stimulation of Electrode B as a function of pulse rate for the three animals for which histology is shown in Fig. 3. Stimuli were 25 μs/phase biphasic pulses delivered by a controlled-current stimulator (built in house). Stimulus levels in μA were controlled in 1 dB steps. Detection thresholds (50% correct detections) are presented in dB relative to 1 mA peak. Pulse-train duration was 200 ms. Means and standard deviations for three repeated measures are shown. Other details of the psychophysical training and testing procedures are given in Kang et al., 2010. Best-fit linear regression lines were fit to the data points below 1000 pps and separate lines were fit to the data above 1000 pps. These slopes, in dB per doubling of pulse rate, are given in the inset table. Differences between the deaf and hearing animals in the slopes and levels of these functions are similar to those reported in Kang et al., 2010. Experiments are currently in progress for two other guinea pigs that were deafened and inoculated with AAV.NTF-3. Slopes for these animals for pulse rates below 1 kpps were similar to those for the deafened AAV.NTF-3 treated animal in this graph (-0.88 and -1.36 dB/doubling).