Patricia A. Leake

Cochlear pathology of long term neomycin induced deafness in cats

The long term sequelae of hair cell destruction consequent from administration of the ototoxic aminoglycoside antibiotic, neomycin sulfate, were evaluated in histological and ultrastructural studies of cochlear morphology in cats. Complete hearing loss, as defined by an absence of brainstem evoked responses to click stimulation at 120 dB peak SPL, was induced by intramuscular injections of neomycin at 50 mg/kg body weight/day, and cochlear pathology was studied at 6 months and 1, 3 and 4 years following onset of profound deafness. In these long term ototoxicity cases the organ of Corti was collapsed and resorbed over the basal one-quarter to three-quarters of the cochlear spiral, depending on duration of deafness. Significant progressive reduction in the spiral ganglion cell population and sequential degenerative alterations in the remaining neurons were observed with increasing time elapsed after induced hearing loss. The sequence of pathological alterations in spiral ganglion neurons appeared to be: a) swelling, demyelination and degeneration of the peripheral dendrites; b) demyelination and shrinkage of the cell soma with preservation of the central axon; and c) demyelination of the central axon and degeneration of the cell perikaryon. In apical cochlear regions, severe degeneration of the spiral ganglion preceded the collapse of the tunnel of Corti and regional loss of pillar cells. Residual populations of spiral ganglion neurons were as low as 1-2% of the normal values in the most severely degenerated cochleae in the series. Light microscopic and ultrastructural studies revealed a selective survival advantage for the unmyelinated type II neurons over the myelinated type I neurons with these long survival periods. The prolonged time course and atrophic nature of these pathological alterations suggests that degeneration of spiral ganglion neurons progresses continuously following drug-induced insult to the cochlea. Some possible factors contributing to this long term progressive degeneration will be discussed.

Chronic electrical stimulation by a cochlear implant promotes survival of spiral ganglion neurons after neonatal deafness

This investigation examined the consequences of neonatal deafness and chronic intracochlear electrical stimulation delivered by a cochlear implant during maturation. Kittens were bilaterally deafened by an ototoxic drug administered daily for 2 weeks immediately after birth. Unilateral electrical stimulation was initiated at 7–10 weeks of age and continued over periods of 22–47 weeks (4 hours/day; 5 days/week). Bipolar intracochlear electrodes delivered one of several different electrical signals designed to be temporally challenging to the central auditory system. Morphometric evaluation of spiral ganglion (SG) cell somata within Rosenthals canal demonstrated a mean of ≈50% of normal cell density maintained in the chronically stimulated ears, compared with ≈30% on the control deafened side. This 20% difference in density was highly significant and was greater than differences reported in earlier studies using 30 pps stimulation delivered by either intracochlear bipolar or round window monopolar electrodes. However, the duration of stimulation was also longer in the present study, so it is unclear to what extent the nature of the temporally challenging stimulation vs. its duration contributed to the marked increase in survival. Measurements of the SG cell somata revealed a pronounced decrease in cell diameter in neonatally deafened cats studied about 1 year after deafening, and an additional decrease after long‐term deafness (2.5–6.5 years). Furthermore, in the cochlear regions with the greatest stimulation‐induced differences in SG cell density, direct measurements of cross‐sectional soma area of the largest cells revealed that cells were significantly larger in the stimulated ears. Thus, in addition to the marked increase in the number of surviving SG cells, larger soma area contributed modestly to the pronounced increase in neural density following chronic electrical stimulation. J. Comp. Neurol. 412:543–562, 1999.

Chronic intracochlear electrical stimulation induces selective survival of spiral ganglion neurons in neonatally deafened cats.

Ten newborn kittens were deafened by systemic administration of neomycin sulfate. Profound hearing losses were documented by ABR and FFR (500 Hz) testing. At 9-17 weeks of age, the young deafened cats were unilaterally implanted with a multichannel scala tympani electrode. Six of the animals were chronically stimulated at 6 dB above electrically evoked ABR thresholds for 1 h/day for periods of 1 month or 3 months. Stimuli were charge-balanced biphasic pulses (200 microseconds/phase, 30 pps.) The remaining 4 cats underwent identical deafening and implantation schedules but were not stimulated. Results indicate that administration of neomycin in neonatal cats induced degeneration of hair cells and spiral ganglion cell loss that was bilaterally symmetrical between the two cochleas of each individual animal, although there was variation between animals in the severity of the ototoxic drug effect. In animals receiving passive (unstimulated) implants, morphometric analysis of spiral ganglion cell density showed no significant difference in ganglion cell survival between the implanted cochleas and the contralateral control ears. In contrast, animals that were chronically stimulated for 3 months showed significantly better neuronal survival in implanted and stimulated cochleas as compared to contralateral deafened control ears. The induced conservation of spiral ganglion neurons was observed consistently within the basal cochlear region near the stimulating electrodes. In more apical regions there was no significant difference between the stimulated and control cochleas. The mechanisms underlying this selective conservation of spiral ganglion neurons induced by chronic intracochlear electrical stimulation are uncertain. Since no comparable chronic stimulation studies have been conducted in adults, it is not known whether similar conservation effects could be induced in mature animals.

Chronic intracochlear electrical stimulation in the neonatally deafened cat. I: Expansion of central representation

Intracochlear electrical stimulation via cochlear prostheses has been employed as a means of providing some hearing to deaf children. Since chronically restricted stimuli are known to have profound effects on central nervous system development, it is important to examine the effects of chronic intracochlear electrical stimulation in a neonatally deafened animal model. In this study neonatally deafened cats were implanted with a scala tympani electrode consisting of two pairs of electrodes. Chronic electrical stimulation was delivered using one electrode pair and consisted of charge-balanced biphasic pulses (200 microseconds/phase, 30 pps) at 2 dB above the electrically evoked auditory brain stem response (EABR) threshold for 4 h/day or at 6 dB 1 h/day, 5 days/week, for up to 3 months. The second electrode pair was unstimulated and served as an internal control. Following chronic stimulation, acute mapping experiments were performed in the central nucleus of the inferior colliculus (ICC) using single unit and multi-unit recording techniques and activating each electrode pair separately. In addition to these chronically stimulated animals, 2 other groups of experimental animals were studied: A normal group consisting of prior normal adult cats that were acutely implanted; and an unstimulated control group consisting of neonatally deafened adult cats that were either acutely implanted or implanted at 8-10 weeks of age but not chronically stimulated. Among the major findings of this study are: Electrical stimulation of the intracochlear bipolar electrode consistently produces activation of a reproducibly limited sector of the ICC. The location of this activated sector was found to be consistent with the known cochleotopic organization of the ICC and the intracochlear location of the stimulating electrodes. No major differences in the spatial representation of activated electrodes were found between prior normal cats and neonatally deafened unstimulated cats. The locations, shapes and widths of these spatial representations were virtually indistinguishable indicating that ICC cochleotopic organizations were equivalent in these two experimental groups. In contrast, the ICC representation of chronically stimulated electrode pairs were found to be significantly different. The average area activated by chronically stimulated electrode pairs at 6 dB above minimum threshold was approximately twice that of unstimulated deafened animals and prior normal animals; and it was larger, but not significantly so, than the average of the unstimulated electrode pair in the same experimental group.(ABSTRACT TRUNCATED AT 400 WORDS)

A temporal bone study of insertion trauma and intracochlear position of cochlear implant electrodes. I: Comparison of Nucleus banded and Nucleus Contour electrodes.

In recent years, new designs of cochlear implant electrodes have been introduced in an attempt to improve efficiency and performance by locating stimulation sites closer to spiral ganglion neurons and deeper into the scala tympani. The goal of this study was to document insertion depth, intracochlear position and insertion trauma with the Nucleus Contour electrode and to compare results to those observed with the earlier generation Nucleus banded electrode. For this comparison eight Nuclears banded electrodes and 18 Contour electrodes were implanted in cadaver temporal bones using a realistic surgical exposure. Two experienced cochlear implant surgeons and two otology fellows with specialized training in cochlear implant surgery were selected for the study to represent a range of surgical experience similar to that of surgeons currently performing the procedure throughout the world. Following insertion of the electrodes, specimens were imaged using plain film X-ray, embedded in acrylic resin, cut in radial sections with the electrodes in place, and each cut surface was polished. Insertion depth was measured in digitized X-ray images, and trauma was assessed in each cross-section. The Contour electrode inserted more deeply (mean depth=17.9 mm or 417 degrees ) than the banded electrode (mean depth=15.3 mm or 285 degrees ). The incidence and severity of trauma varied substantially among the temporal bones studied. However, the nature and frequency of injuries observed with the two devices were very similar. The Contour electrode was clearly positioned closer to the modiolus than the banded model, and also appeared easier to use. Based on this difference in position and data from previous studies we conclude that the Contour electrode may provide lower thresholds and improved channel selectivity, but the incidence of trauma remains a problem with the newer design. The relative influences of electrode positioning and neural degeneration that may result from trauma are as yet unclear.

Chronic intracochlear electrical stimulation in neonatally deafened cats: Effects of intensity and stimulating electrode location

An earlier study conducted in this laboratory suggested that chronic intracochelear electrical stimulation at moderate current levels can at least partially delay or prevent the retrograde degeneration of primary auditory (spiral ganglion) neurons that otherwise is progressive after neonatal deafness induced by ototoxic drug administration. Increased survival of spiral ganglion neurons was observed within the basal cochlear region near the stimulating biopolar electrode pairs, while in more apical regions there was no significant difference between the stimulated and control cochleas. The mechanisms underlying this maintenance of spiral ganglion neurons induced by chronic electrical stimulation are uncertain, especially since increased neuronal survival was observed over broader sectors of the ganglion than would be expected to be directly activated by the bipolar electrodes and moderate stimulation intensity (6 dB above electrically evoked auditory brainstem response threshold) used. In this report, data are presented from a second series of neonatally deafened and chronically stimulated cats. The parameters for chronic electrical stimulation were manipulated in two simple ways. First, the intensity of the electrical stimulus was reduced from the earlier study, while the duration of chronic stimualtion periods was increased; and secondly, two different intracochlear positions of stimulating electrodes were employed in different experimental groups. Results indicate that elecrical stimulation of the cochlea at an extremely low intensity (2 dB above electrically evoked auditory brainstem response threshold) is sufficient to at least partially prevent or delay ganglion cell degeneration in the deafened cochlea. In addition, data suggest a differential distribution of the maintained or conserved ganglion cells, such that when the stimulating electrode pair was positioned near the base of the cochlea increased ganglion survival in a more basal cochlear sector, while stimulation at a more apical site resulted in increased neuronal survival extending to more apical regions.

Changes in the cat cochlear nucleus following neonatal deafening and chronic intracochlear electrical stimulation

The effects of chronic intracochlear electrical stimulation on the cochlear nucleus (CN) were studied in eight cats that were neonatally deafened by daily intramuscular injections of neomycin. Profound hearing loss was confirmed in each animal by auditory brainstem response (ABR) and frequency following response (500 Hz) testing. Five of the kittens were implanted unilaterally with a scala tympani electrode array at ages 8-16 weeks. These kittens were stimulated daily for four hours at 2 dB above the evoked ABR threshold, over a period of three months, and subsequently euthanized for histological analysis at 26-32 weeks of age. The three remaining deaf kittens were maintained without stimulation over prolonged periods in order to study the long-term consequences of neonatal deafening, and were euthanized at 66-133 weeks of age. This study compares the CN of these deafened experimental animals and the CN of normal adult cats. Three experimental parameters were examined: CN volume, cross-sectional area of spherical cells in the rostral anteroventral cochlear nucleus (AVCN), and spherical cell density in this same region. The CN in animals that received electrical stimulation showed significant bilateral degenerative changes in all three measured parameters. Total nuclear volume was reduced by 35-36%, spherical cell size was reduced by 20-26%, and spherical cell density decreased by 36-42%, as compared to the normal cat CN. Comparisons were also made in the stimulated animals between CN ipsilateral to the stimulated cochlea and the contralateral, unstimulated CN.(ABSTRACT TRUNCATED AT 250 WORDS)

Considerations for Design of Future Cochlear Implant Electrode Arrays: Electrode Array Stiffness, Size, and Depth of Insertion

The level of hearing rehabilitation enjoyed by cochlear implant (CI) recipients has increased dramatically since the introduction of these devices. This improvement is the result of continual development of these systems and the inclusion of subjects with less severe auditory pathology. Developments include advanced signal processing, higher stimulation rates, greater numbers of channels, and more efficient electrode arrays that are less likely to produce insertion damage. New directions in the application of CIs, particularly in combined acoustic and electrical stimulation, and increasing performance expectations will place greater demands on future electrode arrays. Specifically, the next generation of arrays must be reliably inserted without damage, must maintain residual acoustic function, and may need to be inserted more deeply. In this study, we measured the mechanical properties of eight clinical and prototype human CI electrode arrays and evaluated insertion trauma and insertion depth in 79 implanted cadaver temporal bones. We found that the size and shape of the array directly affect the incidence of observed trauma. Further, arrays with greater stiffness in the plane perpendicular to the plane of the cochlear spiral are less likely to cause severe trauma than arrays with similar vertical and horizontal stiffness.

A temporal bone study of insertion trauma and intracochlear position of cochlear implant electrodes. II: Comparison of Spiral Clarion™ and HiFocus II™ electrodes

In recent years, several new designs of cochlear implant electrodes have been introduced clinically with the goal of optimizing perimodiolar placement of stimulation sites. Previous studies suggest that perimodiolar electrodes may increase both the efficiency and performance of a cochlear implant. This is the second of two studies designed to examine the positioning of electrodes and the occurrence of insertion-related injury with these newer designs and to directly compare two perimodiolar electrodes to their predecessors. In our previous report we compared the Nucleus banded electrode with the Nucleus Contour perimodiolar electrode. In the present study, using the same protocol, we examine the Spiral Clarion electrode and its successor, the HiFocus II electrode with attached positioner. Eight Spiral Clarion arrays and 20 HiFocus II electrodes with positioners were inserted into human cadaver temporal bones. Following insertion, the specimens were embedded in acrylic resin, cut in quarters with a diamond saw and polished. Insertion depth, proximity to the modiolus and trauma were evaluated in X-ray images and light microscopy. The newer electrode was consistently positioned closer to the modiolus than the previous device whereas the angular depth of insertion measured for the two electrodes was similar. The incidence of trauma was minimal when either electrode was inserted to a depth of less than 400 degrees . However, severe trauma was observed in every case in which the HiFocus II with positioner was inserted beyond 400 degrees and in some cases in which the Spiral Clarion was inserted beyond 400 degrees . To evaluate the possible role of electrode size in the trauma observed we modeled both devices relative to the dimensions of the scala tympani. We found that the fully inserted HiFocus II electrode with positioner was larger than the scala tympani in approximately 70% of temporal bones measured. The results suggest that both the Clarion spiral and HiFocus II with positioner can be inserted with minimal trauma, but in many cases not to the maximum depth allowed by the design.

Chronic intracochlear electrical stimulation in the neonatally deafened cat. II. Temporal properties of neurons in the inferior colliculus.

The major focus of this study was to define the effects of chronic intracochlear electrical stimulation (ICES) on single unit responses in the inferior colliculus from three experimental groups: 1) normal adults 2) neonatally-deafened/unstimulated adults; and 3) neonatally-deafened/chronically stimulated adults. The major findings include: 1) IC neurons in normal adults showed a diversity of perstimulus responses to ICES which were qualitatively similar to those evoked by acoustic stimuli. They responded with: an onset burst, a sustained discharge, a decrease in their spontaneous activity, or a strong post-stimulus response. The excitatory responses showed either a monotonic or a nonmonotonic increase in activity with increasing stimulus intensity. Response latencies ranged from 5 to over 40 ms. 2) Responses to ICES in normal and deafened/unstimulated animals were virtually indistinguishable from one another. 3) In contrast, responses to ICES in neonatally deafened stimulated animals were different from normal and from deafened, unstimulated animals. Their perstimulus response latencies were significantly shorter, their late response latencies were significantly longer, and the frequency of occurrence of inhibitory and late responses were significantly higher. From these results we conclude that the responses to intracochlear electrical stimulation are directly comparable to those observed following normal acoustic stimulation; that development of cochleotopic organization of the inferior colliculus is not affected by the almost complete lack of normal acoustic input experienced by neonatally deafened animals; and that the basic response properties of IC units are likewise unaffected by neonatal deafening. Moreover, the results suggest that, although the limited regime of electrical stimulation employed in these studies produced no major qualitative distortions in the perstimulus response patterns of IC neurons, it did result in some quantitative changes in those responses.