Dataset Information

Neurotrophin Gene Therapy in Deafened Ears with Cochlear Implants: Long-term Effects on Nerve Survival and Functional Measures.

ABSTRACT: 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.

SUBMITTER: Pfingst BE

PROVIDER: S-EPMC5688043 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Neurotrophin Gene Therapy in Deafened Ears with Cochlear Implants: Long-term Effects on Nerve Survival and Functional Measures.

Pfingst Bryan E BE Colesa Deborah J DJ Swiderski Donald L DL Hughes Aaron P AP Strahl Stefan B SB Sinan Moaz M Raphael Yehoash Y

Journal of the Association for Research in Otolaryngology : JARO 20170803 6

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 ...[more]

PMID: 28776202

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Project description:ObjectivesIn this study, we aimed to (1) review the long-term outcomes of cochlear implantation in children with cochlear nerve aplasia and (2) compare the development of their auditory and speech abilities to children with normal-sized cochlear nerves.DesignThis is a retrospective case-control study. Patients who underwent unilateral cochlear implant (CI) surgery in a tertiary referral center from September 2012 to December 2018 were reviewed. The study group included 55 children with cochlear nerve aplasia diagnosed using preoperative images. The control group included 35 children with normal-sized cochlear nerves. The control group did not differ from the study group in terms of age at implantation, pre-implantation auditory and speech abilities, or the electrode array type. Cochlear implantation outcomes were assessed using a test battery, including the Categories of Auditory Performance (CAP) score, the Speech Intelligibility Rating (SIR) score, behavioral audiometry, and closed- or open-set speech recognition tests. The development of auditory and speech abilities was compared between the two groups using Generalized Linear Mixed-effect Models.ResultsThe mean duration of CI usage was 4.5 years (SD = 1.5, range = 2.0 to 9.5) in the study group. The CAP scores, SIR scores, and aided hearing thresholds improved significantly post-implantation in the study group, but were significantly poorer than those in the control group. Generalized Linear Mixed-effect Models showed that the development of CAP and SIR scores was significantly slower in the study group than in the control group. Overall, 27 (49%) children with cochlear nerve aplasia had some degree of open-set speech perception skills, but the monosyllabic and bisyllabic word recognition rates were significantly lower than those in the control group.ConclusionFor children with cochlear nerve aplasia, auditory perception and speech intelligibility continued to improve in the long-term follow-up, but this progress was significantly slower than in children with normal-sized cochlear nerves. Most children with cochlear nerve aplasia could obtain the ability of common phrase perception and understanding simple spoken language with consistent CI usage and auditory rehabilitation.

Project description:INTRODUCTION:Substantial resources are required to provide lifelong postoperative care to people with cochlear implants. Most patients visit the clinic annually. We introduced a person-centred remote follow-up pathway, giving patients telemedicine tools to use at home so they would only visit the centre when intervention was required. OBJECTIVES:To assess the feasibility of comparing a remote care pathway with the standard pathway in adults using cochlear implants. DESIGN:Two-arm randomised controlled trial. Randomisation used a minimisation approach, controlling for potential confounding factors. Participant blinding was not possible, but baseline measures occurred before allocation. SETTING:University of Southampton Auditory Implant Service: provider of National Health Service care. PARTICIPANTS:60 adults who had used cochlear implants for at least 6 months. INTERVENTIONS:Control group (n=30) followed usual care pathway.Remote care group (n=30) received care remotely for 6 months incorporating: home hearing in noise test, online support tool and self-adjustment of device (only 10 had compatible equipment). MAIN OUTCOME MEASURES:Primary: change in patient activation; measured using the Patient Activation Measure.Secondary: change in hearing and quality of life; qualitative feedback from patients and clinicians. RESULTS:One participant in the remote care group dropped out. The remote care group showed a greater increase in patient activation than the control group. Changes in hearing differed between the groups. The remote care group improved on the Triple Digit Test hearing test; the control group perceived their hearing was worse on the Speech, Spatial and Qualities of Hearing Scale questionnaire. Quality of life remained unchanged in both groups. Patients and clinicians were generally positive about remote care tools and wanted to continue. CONCLUSIONS:Adults with cochlear implants were willing to be randomised and complied with the protocol. Personalised remote care for long-term follow-up is feasible and acceptable, leading to more empowered patients. TRIAL REGISTRATION NUMBER:ISRCTN14644286.

Project description:Cochlear implants provide individuals who are deaf with access to speech. Although substantial advancements have been made by novel technologies, there still is high variability in language development during childhood, depending on adaptation and neural plasticity. These factors have often been investigated in the auditory domain, with the mismatch negativity as an index for sensory and phonological processing. Several studies have demonstrated that the MMN is an electrophysiological correlate for hearing improvement with cochlear implants. In this study, two groups of cochlear implant users, both with very good basic hearing abilities but with non-overlapping speech performance (very good or very poor speech performance), were matched according to device experience and age at implantation. We tested the perception of phonemes in the context of specific other phonemes from which they were very hard to discriminate (e.g., the vowels in /bu/ vs. /bo/). The most difficult pair was individually determined for each participant. Using behavioral measures, both cochlear implants groups performed worse than matched controls, and the good performers performed better than the poor performers. Cochlear implant groups and controls did not differ during time intervals typically used for the mismatch negativity, but earlier: source analyses revealed increased activity in the region of the right supramarginal gyrus (220-260 ms) in good performers. Poor performers showed increased activity in the left occipital cortex (220-290 ms), which may be an index for cross-modal perception. The time course and the neural generators differ from data from our earlier studies, in which the same phonemes were assessed in an easy-to-discriminate context. The results demonstrate that the groups used different language processing strategies, depending on the success of language development and the particular language context. Overall, our data emphasize the role of neural plasticity and use of adaptive strategies for successful language development with cochlear implants.

Project description:ObjectiveThis paper reports a noninvasive method for quantifying neural synchrony in the cochlear nerve (i.e., peripheral neural synchrony) in cochlear implant (CI) users, which allows for evaluating this physiological phenomenon in human CI users for the first time in the literature. In addition, this study assessed how peripheral neural synchrony was correlated with temporal resolution acuity and speech perception outcomes measured in quiet and in noise in post-lingually deafened adult CI users. It tested the hypothesis that peripheral neural synchrony was an important factor for temporal resolution acuity and speech perception outcomes in noise in post-lingually deafened adult CI users.DesignStudy participants included 24 post-lingually deafened adult CI users with a Cochlear™ Nucleus® device. Three study participants were implanted bilaterally, and each ear was tested separately. For each of the 27 implanted ears tested in this study, 400 sweeps of the electrically evoked compound action potential (eCAP) were measured at four electrode locations across the electrode array. Peripheral neural synchrony was quantified at each electrode location using the phase locking value (PLV), which is a measure of trial-by-trial phase coherence among eCAP sweeps/trials. Temporal resolution acuity was evaluated by measuring the within-channel gap detection threshold (GDT) using a three-alternative, forced-choice procedure in a subgroup of 20 participants (23 implanted ears). For each ear tested in these participants, GDTs were measured at two electrode locations with a large difference in PLVs. For 26 implanted ears tested in 23 participants, speech perception performance was evaluated using Consonant-Nucleus-Consonant (CNC) word lists presented in quiet and in noise at signal-to-noise ratios (SNRs) of +10 and +5 dB. Linear Mixed effect Models were used to evaluate the effect of electrode location on the PLV and the effect of the PLV on GDT after controlling for the stimulation level effects. Pearson product-moment correlation tests were used to assess the correlations between PLVs, CNC word scores measured in different conditions, and the degree of noise effect on CNC word scores.ResultsThere was a significant effect of electrode location on the PLV after controlling for the effect of stimulation level. There was a significant effect of the PLV on GDT after controlling for the effects of stimulation level, where higher PLVs (greater synchrony) led to lower GDTs (better temporal resolution acuity). PLVs were not significantly correlated with CNC word scores measured in any listening condition or the effect of competing background noise presented at a SNR of +10 dB on CNC word scores. In contrast, there was a significant negative correlation between the PLV and the degree of noise effect on CNC word scores for a competing background noise presented at a SNR of +5 dB, where higher PLVs (greater synchrony) correlated with smaller noise effects on CNC word scores.ConclusionsThis newly developed method can be used to assess peripheral neural synchrony in CI users, a physiological phenomenon that has not been systematically evaluated in electrical hearing. Poorer peripheral neural synchrony leads to lower temporal resolution acuity and is correlated with a larger detrimental effect of competing background noise presented at a SNR of 5 dB on speech perception performance in post-lingually deafened adult CI users.

Dataset Information

Neurotrophin Gene Therapy in Deafened Ears with Cochlear Implants: Long-term Effects on Nerve Survival and Functional Measures.

Publications

Neurotrophin Gene Therapy in Deafened Ears with Cochlear Implants: Long-term Effects on Nerve Survival and Functional Measures.

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