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Though the exact causes of systemic lupus erythematosus (SLE) remain unknown, exposure to ultraviolet (UV) light is one of the few well-known triggers of cutaneous inflammation in SLE. However, the precise cell types which contribute to the early cutaneous inflammatory response in lupus, and the ways that UV dosing and interferons modulate these findings, have not been thoroughly dissected. Here, we explore these questions using the NZM2328 spontaneous murine model of lupus. In addition, we use iNZM mice, which share the NZM2328 background but harbor a whole-body knockout of the type I interferon (IFN) receptor, and wild-type BALB/c mice. 10-13-week-old female mice of each strain were treated with acute (300 mJ/cm 2 x1), chronic (100 mJ/cm 2 daily x5 days), or no UVB, and skin was harvested and processed for bulk RNA sequencing and flow cytometry. We identify that inflammatory pathways and gene signatures related to myeloid cells - namely neutrophils and monocyte-derived dendritic cells - are a shared feature of the acute and chronic UVB response in NZM skin greater than iNZM and wild-type skin. We also verify recruitment and activation of these cells by flow cytometry in both acutely and chronically irradiated NZM and WT mice and demonstrate that these processes are dependent on type I IFN signaling. Taken together, these data indicate a skewed IFN-driven inflammatory response to both acute and chronic UVB exposure in lupus-prone skin dominated by myeloid cells, suggesting both the importance of type I IFNs and myeloid cells as therapeutic targets for photosensitive patients and highlighting the risks of even moderate UV exposure in this patient population., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The cochlear implant (CI) is widely considered to be one of the most innovative and successful neuroprosthetic treatments developed to date. Although outcomes vary, CIs are able to effectively improve hearing in nearly all recipients and can substantially improve speech understanding and quality of life for patients with significant hearing loss. A wealth of research has focused on underlying factors that contribute to success with a CI, and recent evidence suggests that the overall health of the cochlea could potentially play a larger role than previously recognized. This article defines and reviews attributes of cochlear health and describes procedures to evaluate cochlear health in humans and animal models in order to examine the effects of cochlear health on performance with a CI. Lastly, we describe how future biologic approaches can be used to preserve and/or enhance cochlear health in order to maximize performance for individual CI recipients., (© 2022. The Author(s) under exclusive licence to Association for Research in Otolaryngology.)

Outcomes of cochlear implantation are likely influenced by the biological state of the cochlea. Fibrosis is a pathological change frequently seen in implanted ears. The goal of this work was to investigate the relationship between fibrosis and impedance. To that end, we employed an animal model of extensive fibrosis and tested whether aspects of impedance differed from controls. Specifically, an adenovirus with a TGF-β1 gene insert (Ad.TGF-β1) was injected into guinea pig scala tympani to elicit rapid onset fibrosis and investigate the relation between fibrosis and impedance. We found a significant correlation between treatment and rate of impedance increase. A physical circuit model of impedance was used to separate the effect of fibrosis from other confounding factors. Supported by preliminary, yet nonconclusive, electron microscopy data, this modeling suggested that deposits on the electrode surface are an important contributor to impedance change over time., (Copyright © 2022. Published by Elsevier B.V.)

It is generally believed that the efficacy of cochlear implants is partly dependent on the condition of the stimulated neural population. Cochlear pathology is likely to affect the manner in which neurons respond to electrical stimulation, potentially resulting in differences in perception of electrical stimuli across cochlear implant recipients and across the electrode array in individual cochlear implant users. Several psychophysical and electrophysiological measures have been shown to predict cochlear health in animals and were used to assess conditions near individual stimulation sites in humans. In this study, we examined the relationship between psychophysical strength-duration functions and spiral ganglion neuron density in two groups of guinea pigs with cochlear implants who had minimally-overlapping cochlear health profiles. One group was implanted in a hearing ear (N = 10) and the other group was deafened by cochlear perfusion of neomycin, inoculated with an adeno-associated viral vector with an Ntf3-gene insert (AAV.Ntf3) and implanted (N = 14). Psychophysically measured strength-duration functions for both monopolar and tripolar electrode configurations were then compared for the two treatment groups. Results were also compared to their histological outcomes. Overall, there were considerable differences between the two treatment groups in terms of their psychophysical performance as well as the relation between their functional performance and histological data. Animals in the neomycin-deafened, neurotrophin-treated, and implanted group (NNI) exhibited steeper strength-duration function slopes; slopes were positively correlated with SGN density (steeper slopes in animals that had higher SGN densities). In comparison, the implanted hearing (IH) group had shallower slopes and there was no relation between slopes and spiral ganglion density. Across all animals, slopes were negatively correlated with ensemble spontaneous activity levels (shallower slopes with higher ensemble spontaneous activity levels). We hypothesize that differences in strength-duration function slopes between the two treatment groups were related to the condition of the inner hair cells, which generate spontaneous activity that could affect the across-fiber synchrony and/or the size of the population of neural elements responding to electrical stimulation. In addition, it is likely that spiral ganglion neuron peripheral processes were present in the IH group, which could affect membrane properties of the stimulated neurons. Results suggest that the two treatment groups exhibited distinct patterns of variation in conditions near the stimulating electrodes that altered detection thresholds. Overall, the results of this study suggest a complex relationship between psychophysical detection thresholds for cochlear implant stimulation and nerve survival in the implanted cochlea. This relationship seems to depend on the characteristics of the electrical stimulus, the electrode configuration, and other biological features of the implanted cochlea such as the condition of the inner hair cells and the peripheral processes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Amplitudes of electrically evoked compound action potentials (eCAPs) as a function of the stimulation level constitute the eCAP amplitude growth function (AGF). The slope of the eCAP AGF (i.e., rate of growth of eCAP amplitude as a function of stimulation level), recorded from subjects with cochlear implants (CIs), has been widely used as an indicator of survival of cochlear nerve fibers. However, substantial variation in the approach used to calculate the slope of the eCAP AGF makes it difficult to compare results across studies. In this study, we developed an improved slope-fitting method by addressing the limitations of previously used approaches and ensuring its application for the estimation of the maximum slopes of the eCAP AGFs recorded in both animal models and human listeners with various etiologies., Design: The new eCAP AGF fitting method was designed based on sliding window linear regression. Slopes of the eCAP AGF estimated using this new fitting method were calculated and compared with those estimated using four other fitting methods reported in the literature. These four methods were nonlinear regression with a sigmoid function, linear regression, gradient calculation, and boxcar smoothing. The comparison was based on the fitting results of 72 eCAP AGFs recorded from 18 acutely implanted guinea pigs, 46 eCAP AGFs recorded from 23 chronically implanted guinea pigs, and 2094 eCAP AGFs recorded from 200 human CI users from 4 patient populations. The effect of the choice of input units of the eCAP AGF (linear versus logarithmic) on fitting results was also evaluated., Results: The slope of the eCAP AGF was significantly influenced by the slope-fitting method and by the choice of input units. Overall, slopes estimated using all five fitting methods reflected known patterns of neural survival in human patient populations and were significantly correlated with speech perception scores. However, slopes estimated using the newly developed method showed the highest correlation with spiral ganglion neuron density among all five fitting methods for animal models. In addition, this new method could reliably and accurately estimate the slope for 4 human patient populations, while the performance of the other methods was highly influenced by the morphology of the eCAP AGF., Conclusions: The novel slope-fitting method presented in this study addressed the limitations of the other methods reported in the literature and successfully characterized the slope of the eCAP AGF for various animal models and CI patient populations. This method may be useful for researchers in conducting scientific studies and for clinicians in providing clinical care for CI users., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Mice with chronic cochlear implants can significantly contribute to our understanding of the relationship between cochlear health and implant function because of the availability of molecular tools for controlling conditions in the cochlea and transgenic lines modeling human disease. To date, research in implanted mice has mainly consisted of short-term studies, but since there are large changes in implant function following implant insertion trauma, and subsequent recovery in many cases, longer-term studies are needed to evaluate function and perception under stable conditions. Because frequent anesthetic administration can be especially problematic in mice, a chronic model that can be tested in the awake condition is desirable. Electrically-evoked compound action potentials (ECAPs) recorded with multichannel cochlear implants are useful functional measures because they can be obtained daily without anesthesia. In this study, we assessed changes and stability of ECAPs, electrically-evoked auditory brainstem responses (EABRs), ensemble spontaneous activity (ESA), and impedance data over time after implanting mice with multichannel implants. We then compared these data to histological findings in these implanted cochleae, and compared results from this chronic mouse model to data previously obtained in a well-established chronically-implanted guinea pig model. We determined that mice can be chronically implanted with cochlear implants, and ECAP recordings can be obtained frequently in an awake state for up to at least 42 days after implantation. These recordings can effectively monitor changes or stability in cochlear function over time. ECAP and EABR amplitude-growth functions (AGFs), AGF slopes, ESA levels and impedances in mice with multichannel implants appear similar to those found in guinea pigs with long-term multichannel implants. Animals with better survival of spiral ganglion neurons (SGNs) and inner hair cells (IHCs) have steeper AGF slopes, and larger ESA responses. The time course of post-surgical ear recovery may be quicker in mice and can show different patterns of recovery which seem to be dependent on the degree of insertion trauma and subsequent histological conditions. Histology showed varying degrees of cochlear damage with fibrosis present in all implanted mouse ears and small amounts of new bone in a few ears. Impedance changes over time varied within and across animals and may represent changes over time in multiple variables in the cochlear environment post-implantation. Due to the small size of the mouse, susceptibility to stress, and the higher potential for implant failure, chronic implantation in mice can be challenging, but overall is feasible and useful for cochlear implant research., Competing Interests: Declaration of Competing Interest The authors declare no COI., (Copyright © 2021. Published by Elsevier B.V.)

This study examined how multiple measures based on the electrically evoked compound action potential (ECAP) amplitude-growth functions (AGFs) were related to estimates of neural [spiral ganglion neuron (SGN) density and cell size] and electrode impedance measures in 34 specific pathogen free pigmented guinea pigs that were chronically implanted (4.9-15.4 months) with a cochlear implant electrode array. Two interphase gaps (IPGs) were used for the biphasic pulses and the effect of the IPG on each ECAP measure was measured ("IPG effect"). When using a stimulus with a constant IPG, SGN density was related to the across-subject variance in ECAP AGF linear slope, peak amplitude, and N1 latency. The SGN density values also help to explain a significant proportion of variance in the IPG effect for AGF linear slope and peak amplitude measures. Regression modeling revealed that SGN density was the primary dependent variable contributing to across-subject variance for ECAP measures; SGN cell size did not significantly improve the fitting of the model. Results showed that simple impedance measures were weakly related to most ECAP measures but did not typically improve the fit of the regression model.

Fibrous tissue and/or new bone are often found surrounding a cochlear implant in the cochlear scalae. This new intrascalar tissue could potentially limit cochlear implant function by increasing impedance and altering signaling pathways between the implant and the auditory nerve. In this study, we investigated the relationship between intrascalar tissue and 5 measures of implant function in guinea pigs. Variation in both spiral ganglion neuron (SGN) survival and intrascalar tissue was produced by implanting hearing ears, ears deafened with neomycin, and neomycin-deafened ears treated with a neurotrophin. We found significant effects of SGN density on 4 functional measures but adding intrascalar tissue level to the analysis did not explain more variation in any measure than was explained by SGN density alone. These results suggest that effects of intrascalar tissue on electrical hearing are relatively unimportant in comparison to degeneration of the auditory nerve, although additional studies in human implant recipients are still needed to assess the effects of this tissue on complex hearing tasks like speech perception. The results also suggest that efforts to minimize the trauma that aggravates both tissue development and SGN loss could be beneficial.

The electrically-evoked compound action potential (ECAP) is correlated with spiral ganglion neuron (SGN) density in cochlear implanted animals. In a previous study, we showed that ECAP amplitude growth function (AGF) linear slopes for stimuli with a constant interphase gap (IPG) changed significantly over time following implantation. Related studies have also shown that 1) IPG sensitivity for ECAP measures ("IPG Effect") is related to SGN density in animals and 2) the ECAP IPG Effect is related to speech recognition performance in humans with cochlear implants. The current study examined how the ECAP IPG Effect changed following cochlear implantation in four non-deafened guinea pigs with residual inner hair cells (IHCs) and 5 deafened, neurotrophin-treated guinea pigs. Simple impedances were measured on the same days as the ECAP measures. Generally, non-deafened implanted animals with higher SGN survival demonstrated higher ECAP AGF linear slope and peak amplitude values than the deafened, implanted guinea pigs. The ECAP IPG Effect for the AGF slopes and peak amplitudes was also larger in the hearing animals. The N1 latencies for a constant IPG were not different between groups, but the N1 latency IPG Effect was smaller in the non-deafened, implanted animals. Similar to previously reported results, ECAP measures using a fixed or changing IPG required as many as three months after implantation before a stable point could be calculated, but this was dependent on the animal and condition. For all ECAP measures most animals showed greater variance in the first 30 days post-implantation. Post-implantation changes in ECAPs and impedances were not correlated with one another. Results from this study are helpful for estimating the mechanisms underlying ECAP characteristics and have implications for clinical application of the ECAP measures in long-term human cochlear implant recipients. Specifically, these measures could help to monitor neural health over a period of time, or during a time of stability these measures could be used to help select electrode sites for activation in clinical programming., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The ability to measure the voltage readout from a sensor implanted inside the living cochlea enables continuous monitoring of intracochlear acoustic pressure locally, which could improve cochlear implants. We developed a piezoelectric intracochlear acoustic transducer (PIAT) designed to sense the acoustic pressure while fully implanted inside a living guinea pig cochlea. The PIAT, fabricated using micro-electro-mechanical systems (MEMS) techniques, consisted of an array of four piezoelectric cantilevers with varying lengths to enhance sensitivity across a wide frequency bandwidth. Prior to implantation, benchtop tests were conducted to characterize the device performance in air and in water. When implanted in the cochlea of an anesthetized guinea pig, the in vivo voltage response from the PIAT was measured in response to 80-95 dB sound pressure level 1-14 kHz sinusoidal acoustic excitation at the entrance of the guinea pig's ear canal. All sensed signals were above the noise floor and unaffected by crosstalk from the cochlear microphonic or external electrical interference. These results demonstrate that external acoustic stimulus can be sensed via the piezoelectric voltage response of the implanted MEMS transducer inside the living cochlea, providing key steps towards developing intracochlear acoustic sensors to replace external or subcutaneous microphones for auditory prosthetics.

Because cochlear implants function by stimulating the auditory nerve, it is assumed that the condition of the nerve plays an important role in the efficacy of the prosthesis. Thus, considerable research has been devoted to methods of preserving the nerve following deafness. Neurotrophins have been identified as a potential contributor to neural health, but most of the research to date has been done in young animals and for short periods (less than 3 to 6 months) after the onset of treatment. The first objective of the current experiment was to examine the effects of a neurotrophin gene therapy delivery method on spiral ganglion neuron (SGN) preservation and function in the long term (5 to 14 months) in mature guinea pigs with cochlear implants. The second objective was to examine several potential non-invasive monitors of auditory nerve health following the neurotrophin gene therapy procedure. Eighteen mature adult male guinea pigs were deafened by cochlear perfusion of neomycin and then one ear was inoculated with an adeno-associated viral vector with an Nft3-gene insert (AAV.Ntf3) and implanted with a cochlear implant electrode array. Five control animals were deafened and inoculated with an empty AAV and implanted. Data from 43 other guinea pig ears from this and previous experiments were used for comparison: 24 animals implanted in a hearing ear, nine animals deafened and implanted with no inoculation, and ten normal-hearing non-implanted ears. After 4 to 21 months of psychophysical and electrophysiological testing, the animals were prepared for histological examination of SGN densities and inner hair cell (IHC) survival. Seventy-eight percent of the ears deafened and inoculated with AAV.Ntf3 showed better SGN survival than the 14 deafened-control ears. The degree of SGN preservation following the gene therapy procedure was variable across animals and across cochlear turns. Slopes of psychophysical multipulse integration (MPI) functions were predictive of SGN density, but only in animals with preserved IHCs. MPI was not affected by the AAV.Ntf3 treatment, but there was a minor improvement in temporal integration (TI). AAV.Ntf3 treatment had significant effects on ECAP and EABR amplitude growth func-tion (AGF) slopes; the reduction in slope in deafened ears was ameliorated by the AAV.Ntf3 treatment. Slopes of the ECAP and EABR AGFs were predictive of SGN density in a broad area near and just apical to the implant. The highest ensemble spontaneous activity (ESA) values were seen in animals with surviving IHCs, but AAV.Ntf3 treatment in deafened ears resulted in slightly higher ESA values compared to deafened untreated ears. Overall, a combination of the psychophysical and electrophysiological measures can be useful for monitoring the health of the implanted cochlea in guinea pigs. These measures should be applicable for assessing cochlear health in human subjects.

Partial loss and subsequent recovery of cochlear implant function in the first few weeks following cochlear implant surgery has been observed in previous studies using psychophysical detection thresholds. In the current study, we explored this putative manifestation of insertion trauma using objective functional measures: electrically-evoked compound action potential (ECAP) amplitude-growth functions (ECAP amplitude as a function of stimulus level). In guinea pigs implanted in a hearing ear with good post-implant hearing and good spiral ganglion neuron (SGN) survival, consistent patterns of ECAP functions were observed. The slopes of ECAP growth functions were moderately steep on the day of implant insertion, decreased to low levels over the first few days after implantation and then increased slowly over several weeks to reach a relatively stable level. In parallel, ECAP thresholds increased over time after implantation and then recovered, although more quickly, to a relatively stable low level as did thresholds for eliciting a facial twitch. Similar results were obtained in animals deafened but treated with an adenovirus with a neurotrophin gene insert that resulted in good SGN preservation. In contrast, in animals implanted in deaf ears that had relatively poor SGN survival, ECAP slopes reached low levels within a few days after implantation and remained low. These results are consistent with the idea that steep ECAP growth functions require a healthy population of auditory nerve fibers and that cochlear implant insertion trauma can temporarily impair the function of a healthy SGN population., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Temporal integration (TI; threshold versus stimulus duration) functions and multipulse integration (MPI; threshold versus pulse rate) functions were measured behaviorally in guinea pigs and humans with cochlear implants. Thresholds decreased with stimulus duration at a fixed pulse rate and with pulse rate at a fixed stimulus duration. The rates of threshold decrease (slopes) of the TI and MPI functions were not statistically different between the guinea pig and human subject groups. A characteristic of the integration functions that the two groups shared was that the slopes of the TI functions were similar in magnitude to slopes of the MPI function only at low pulse rates (< approximately 300 pulses per second). This is consistent with the notion that the TI functions and the MPI functions at the low rates are mediated by a mechanism of long-term integration described in the statistical "multiple looks" model. Histological analysis of the guinea pig cochleae suggested that the slopes of both the MPI and the TI functions were dependent on sensory and neural health near the stimulated regions. The strongest predictor for spiral ganglion cell densities measured near the stimulation sites was the slope of the MPI functions below 1,000 pps. Several mechanisms may be considered to account for the association of shallow integration functions with poor sensory and neural status. These mechanisms are related to abnormal across-fiber synchronization, increased refractoriness and adaptation with impaired neural function, and steep growth of neural excitation with current level associated with neural pathology. The slope of the integration functions can potentially be used as a non-invasive measure for identifying stimulation sites with poor neural health and selecting those sites for removal or rehabilitation, but these applications remain to be tested.

Amazing progress has been made in providing useful hearing to hearing-impaired individuals using cochlear implants, but challenges remain. One such challenge is understanding the effects of partial degeneration of the auditory nerve, the target of cochlear implant stimulation. Here we review studies from our human and animal laboratories aimed at characterizing the health of the implanted cochlea and the auditory nerve. We use the data on cochlear and neural health to guide rehabilitation strategies. The data also motivate the development of tissue-engineering procedures to preserve or build a healthy cochlea and improve performance obtained by cochlear implant recipients or eventually replace the need for a cochlear implant. This article is part of a Special Issue entitled ., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Perception of electrical stimuli varies widely across users of cochlear implants and across stimulation sites in individual users. It is commonly assumed that the ability of subjects to detect and discriminate electrical signals is dependent, in part, on conditions in the implanted cochlea, but evidence supporting that hypothesis is sparse. The objective of this study was to define specific relationships between the survival of tissues near the implanted electrodes and the functional responses to electrical stimulation of those electrodes. Psychophysical and neurophysiological procedures were used to assess stimulus detection as a function of pulse rate under the various degrees of cochlear pathology. Cochlear morphology, assessed post-mortem, ranged from near-normal numbers of hair cells, peripheral processes and spiral ganglion cells, to complete absence of hair cells and peripheral processes and small numbers of surviving spiral ganglion cells. The psychophysical and neurophysiological studies indicated that slopes and levels of the threshold versus pulse rate functions reflected multipulse integration throughout the 200 ms pulse train with an additional contribution of interactions between adjacent pulses at high pulse rates. The amount of multipulse integration was correlated with the health of the implanted cochlea with implications for perception of more complex prosthetic stimuli., (© 2011 Acoustical Society of America)

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., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Previous studies have shown that residual acoustic hearing supplements cochlear implant function to improve speech recognition in noise as well as perception of music. The current study had two primary objectives. First, we sought to determine how cochlear implantation and electrical stimulation over a time period of 14 to 21 months influence cochlear structures such as hair cells and spiral ganglion neurons. Second, we sought to investigate whether the structures that provide acoustic hearing also affect the perception of electrical stimulation. We compared psychophysical responses to cochlear implant stimulation in two groups of adult guinea pigs. Group I (11 animals) received a cochlear implant in a previously untreated ear, while group II (ten animals) received a cochlear implant in an ear that had been previously infused with neomycin to destroy hearing. Psychophysical thresholds were measured in response to pulse-train and sinusoidal stimuli. Histological analysis of all group I animals and a subset of group II animals was performed. Nine of the 11 group I animals showed survival of the organ of Corti and spiral ganglion neurons adjacent to the electrode array. All group I animals showed survival of these elements in regions apical to the electrode array. Group II animals that were examined histologically showed complete loss of the organ of Corti in regions adjacent and apical to the electrode array and severe spiral ganglion neuron loss, consistent with previous reports for neomycin-treated ears. Behaviorally, group II animals had significantly lower thresholds than group I animals in response to 100 Hz sinusoidal stimuli. However, group I animals had significantly lower thresholds than group II animals in response to pulse-train stimuli (0.02 ms/phase; 156 to 5,000 pps). Additionally, the two groups showed distinct threshold versus pulse rate functions. We hypothesize that the differences in detection thresholds between groups are caused by the electrical activation of the hair cells in group I animals and/or differences between groups in the condition of the spiral ganglion neurons.

The survival of the auditory nerve in cases of sensorineural hearing loss is believed to be a major factor in effective cochlear implant function. The current study assesses two measures of cochlear implant thresholds following a post-deafening treatment intended to halt auditory nerve degeneration. We used an adenoviral construct containing a gene insert for brain-derived neurotrophic factor (BDNF), a construct that has previously been shown to promote neuronal survival in a number of biological systems. We implanted ototoxically deafened guinea pigs with a multichannel cochlear implant and delivered a single inoculation of an adenovirus suspension coding for BDNF (Ad.BDNF) into the scala tympani at the time of implantation. Thresholds to electrical stimulation were assessed both psychophysically and electrophysiologically over a period of 80 days. Spiral ganglion cell survival was analyzed at the 80 days time point. Compared to the control group, the Ad.BDNF treated group had lower psychophysical and electrophysiological thresholds as well as higher survival of spiral ganglion cells. Electrophysiological, but not psychophysical, thresholds correlated well with the density of spiral ganglion cells. These results indicate that the changes in the anatomy of the auditory nerve induced by the combination of Ad.BDNF inoculation and the electrical stimulation used for testing improved functional measures of CI performance.

Previous studies have shown large decreases in cochlear implant psychophysical detection thresholds during the weeks following the onset of electrical testing. The current study sought to determine the variables underlying these threshold decreases by examining the effects of four deafening and implantation procedures on detection thresholds and implant impedances. Thirty-two guinea pigs were divided into four matched groups. Group I was deafened and implanted Day 0 and began electrical testing Day 1. Group II was deafened and implanted Day 0 and began electrical testing Day 45. Group III was deafened Day 0, implanted Day 45 and began electrical testing Day 46. Group IV was not predeafened but was implanted Day 0 and began electrical testing Day 1. All groups showed threshold decreases over time but the magnitude of change, time course and final stable threshold levels depended on the type and time course of treatment. Impedances increased over the first two weeks following the onset of electrical testing except in Group II. Results suggest that multiple mechanisms underlie the observed threshold shifts including (1) recovery of the cochlea from a temporary pathology caused by the deafening and/or implantation procedures, (2) effects of electrical stimulation on the auditory pathway, and (3) tissue growth in the implanted cochlea. They also suggest that surviving hair cells influence electrical threshold levels.