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Electrophysiological validation of a human prototype auditory midbrain implant in a guinea pig model.

ABSTRACT: The auditory midbrain implant (AMI) is a new treatment for hearing restoration in patients with neural deafness or surgically inaccessible cochleae who cannot benefit from cochlear implants (CI). This includes neurofibromatosis type II (NF2) patients who, due to development and/or removal of vestibular schwannomas, usually experience complete damage of their auditory nerves. Although the auditory brainstem implant (ABI) provides sound awareness and aids lip-reading capabilities for these NF2 patients, it generally only achieves hearing performance levels comparable with a single-channel CI. In collaboration with Cochlear Ltd. (Lane Cove, Australia), we developed a human prototype AMI, which is designed for electrical stimulation along the well-defined tonotopic gradient of the inferior colliculus central nucleus (ICC). Considering that better speech perception and hearing performance has been correlated with a greater number of discriminable frequency channels of information available, the ability of the AMI to effectively activate discrete frequency regions within the ICC may enable better hearing performance than achieved by the ABI. Therefore, the goal of this study was to investigate if our AMI array could achieve low-threshold, frequency-specific activation within the ICC, and whether the levels for ICC activation via AMI stimulation were within safe limits for human application. We electrically stimulated different frequency regions within the ICC via the AMI array and recorded the corresponding neural activity in the primary auditory cortex (A1) using a multisite silicon probe in ketamine-anesthetized guinea pigs. Based on our results, AMI stimulation achieves lower thresholds and more localized, frequency-specific activation than CI stimulation. Furthermore, AMI stimulation achieves cortical activation with current levels that are within safe limits for central nervous system stimulation. This study confirms that our AMI design is sufficient for ensuring safe and effective activation of the ICC, and warrants further studies to translate the AMI into clinical application.

SUBMITTER: Lenarz M

PROVIDER: S-EPMC2504634 | biostudies-other | 2006 Dec

REPOSITORIES: biostudies-other

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Project description:BackgroundToxoplasma gondii is an obligate intracellular parasite with a worldwide distribution. Congenital infection in humans and animals may lead to severe symptoms in the offspring, especially in the brain. A suitable animal model for human congenital toxoplasmosis is currently lacking. The aim of this study is to establish and validate the guinea pig as a model for human congenital toxoplasmosis by investigating the impact of the T. gondii infection dose, the duration of infection and the gestational stage at infection on the seroconversion, survival rate of dams, fate of the offspring, T. gondii DNA loads in various offspring tissues and organs and the integrity of the offspring brain.MethodsPregnant guinea pigs were infected with three different doses (10, 100, 500 oocysts) of T. gondii strain ME49 at three different time points during gestation (15, 30, 48 days post-conception). Serum of dams was tested for the presence of T. gondii antibodies using immunoblotting. T. gondii DNA levels in the dam and offspring were determined by qPCR. Offspring brains were examined histologically.ResultsWe found the survival rate of dams and fate of the offspring to be highly dependent on the T. gondii infection dose with an inoculation of 500 oocysts ending lethally for all respective offspring. Moreover, both parameters differ depending on the gestational stage at infection with infection in the first and third trimester of gestation resulting in a high offspring mortality rate. The duration of infection was found to substantially impact the seroconversion rate of dams with the probability of seroconversion exceeding 50% after day 20 post-infection. Furthermore, the infection duration of dams influenced the T. gondii DNA loads in the offspring and the integrity of offspring brain. Highest DNA levels were found in the offspring brain of dams infected for ≥ 34 days.ConclusionThis study contributes to establishing the guinea pig as a suitable model for human congenital toxoplasmosis and thus lays the foundation for using the guinea pig as a suitable animal model to study scientific questions of high topicality and clinical significance, which address the pathogenesis, diagnosis, therapy and prognosis of congenital toxoplasmosis.

Project description:Background: The success of a cochlear implant (CI), which is the standard therapy for patients suffering from severe to profound sensorineural hearing loss, depends on the number and excitability of spiral ganglion neurons (SGNs). Brain-derived neurotrophic factor (BDNF) has a protective effect on SGNs but should be applied chronically to guarantee their lifelong survival. Long-term administration of BDNF could be achieved using genetically modified mesenchymal stem cells (MSCs), but these cells should be protected - by ultra-high viscous (UHV-) alginate ('alginate-MSCs') - from the recipient immune system and from uncontrolled migration. Methods: Brain-derived neurotrophic factor-producing MSCs were encapsulated in UHV-alginate. Four experimental groups were investigated using guinea pigs as an animal model. Three of them were systemically deafened and (unilaterally) received one of the following: (I) a CI; (II) an alginate-MSC-coated CI; (III) an injection of alginate-embedded MSCs into the scala tympani followed by CI insertion and alginate polymerization. Group IV was normal hearing, with CI insertion in both ears and a unilateral injection of alginate-MSCs. Using acoustically evoked auditory brainstem response measurements, hearing thresholds were determined before implantation and before sacrificing the animals. Electrode impedance was measured weekly. Four weeks after implantation, the animals were sacrificed and the SGN density and degree of fibrosis were evaluated. Results: The MSCs survived being implanted for 4 weeks in vivo. Neither the alginate-MSC injection nor the coating affected electrode impedance or fibrosis. CI insertion with and without previous alginate injection in normal-hearing animals resulted in increased hearing thresholds within the high-frequency range. Low-frequency hearing loss was additionally observed in the alginate-injected and implanted cochleae, but not in those treated only with a CI. In deafened animals, the alginate-MSC coating of the CI significantly prevented SGN from degeneration, but the injection of alginate-MSCs did not. Conclusion: Brain-derived neurotrophic factor-producing MSCs encapsulated in UHV-alginate prevent SGNs from degeneration in the form of coating on the CI surface, but not in the form of an injection. No increase in fibrosis or impedance was detected. Further research and development aimed at verifying long-term mechanical and biological properties of coated electrodes in vitro and in vivo, in combination with chronic electrical stimulation, is needed before the current concept can be tested in clinical trials.

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Electrophysiological validation of a human prototype auditory midbrain implant in a guinea pig model.

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