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: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:ObjectivesThis study aimed to create an objective predictive model for assessing the functional status of the cochlear nerve (CN) in individual cochlear implant (CI) users.DesignStudy participants included 23 children with cochlear nerve deficiency (CND), 29 children with normal-sized CNs (NSCNs), and 20 adults with various etiologies of hearing loss. Eight participants were bilateral CI users and were tested in both ears. As a result, a total of 80 ears were tested in this study. All participants used Cochlear Nucleus CIs in their test ears. For each participant, the CN refractory recovery function and input/output (I/O) function were measured using electrophysiological measures of the electrically evoked compound action potential (eCAP) at three electrode sites across the electrode array. Refractory recovery time constants were estimated using statistical modeling with an exponential decay function. Slopes of I/O functions were estimated using linear regression. The eCAP parameters used as input variables in the predictive model were absolute refractory recovery time estimated based on the refractory recovery function, eCAP threshold, slope of the eCAP I/O function, and negative-peak (i.e., N1) latency. The output variable of the predictive model was CN index, an indicator for the functional status of the CN. Predictive models were created by performing linear regression, support vector machine regression, and logistic regression with eCAP parameters from children with CND and the children with NSCNs. One-way analysis of variance with post hoc analysis with Tukey's honest significant difference criterion was used to compare study variables among study groups.ResultsAll three machine learning algorithms created two distinct distributions of CN indices for children with CND and children with NSCNs. Variations in CN index when calculated using different machine learning techniques were observed for adult CI users. Regardless of these variations, CN indices calculated using all three techniques in adult CI users were significantly correlated with Consonant-Nucleus-Consonant word and AzBio sentence scores measured in quiet. The five oldest CI users had smaller CN indices than the five youngest CI users in this study.ConclusionsThe functional status of the CN for individual CI users was estimated by our newly developed analytical models. Model predictions of CN function for individual adult CI users were positively and significantly correlated with speech perception performance. The models presented in this study may be useful for understanding and/or predicting CI outcomes for individual patients.

Project description:ImportanceTo date, no randomized clinical trial on the comparison between simultaneous and sequential bilateral cochlear implants (BiCIs) has been performed.ObjectiveTo investigate the hearing capabilities and the self-reported benefits of simultaneous BiCIs compared with those of sequential BiCIs.Design, setting, and participantsA multicenter randomized clinical trial was conducted between January 12, 2010, and September 2, 2012, at 5 tertiary referral centers among 40 participants eligible for BiCIs. Main inclusion criteria were postlingual severe to profound hearing loss, age 18 to 70 years, and a maximum duration of 10 years without hearing aid use in both ears. Data analysis was conducted from May 24 to June 12, 2016.InterventionsThe simultaneous BiCI group received 2 cochlear implants during 1 surgical procedure. The sequential BiCI group received 2 cochlear implants with an interval of 2 years between implants.Main outcomes and measuresFirst, the results 1 year after receiving simultaneous BiCIs were compared with the results 1 year after receiving sequential BiCIs. Second, the results of 3 years of follow-up for both groups were compared separately. The primary outcome measure was speech intelligibility in noise from straight ahead. Secondary outcome measures were speech intelligibility in noise from spatially separated sources, speech intelligibility in silence, localization capabilities, and self-reported benefits assessed with various hearing and quality of life questionnaires.ResultsNineteen participants were randomized to receive simultaneous BiCIs (11 women and 8 men; median age, 52 years [interquartile range, 36-63 years]), and another 19 participants were randomized to undergo sequential BiCIs (8 women and 11 men; median age, 54 years [interquartile range, 43-64 years]). Three patients did not receive a second cochlear implant and were unavailable for follow-up. Comparable results were found 1 year after simultaneous or sequential BiCIs for speech intelligibility in noise from straight ahead (difference, 0.9 dB [95% CI, -3.1 to 4.4 dB]) and all secondary outcome measures except for localization with a 30° angle between loudspeakers (difference, -10% [95% CI, -20.1% to 0.0%]). In the sequential BiCI group, all participants performed significantly better after the BiCIs on speech intelligibility in noise from spatially separated sources and on all localization tests, which was consistent with most of the participants' self-reported hearing capabilities. Speech intelligibility-in-noise results improved in the simultaneous BiCI group up to 3 years following the BiCIs.Conclusions and relevanceThis study shows comparable objective and subjective hearing results 1 year after receiving simultaneous BiCIs and sequential BiCIs with an interval of 2 years between implants. It also shows a significant benefit of sequential BiCIs over a unilateral cochlear implant. Until 3 years after receiving simultaneous BiCIs, speech intelligibility in noise significantly improved compared with previous years.Trial registrationtrialregister.nl Identifier: NTR1722.

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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