TY - JOUR A1 - Bieniussa, Linda A1 - Kahraman, Baran A1 - Skornicka, Johannes A1 - Schulte, Annemarie A1 - Voelker, Johannes A1 - Jablonka, Sibylle A1 - Hagen, Rudolf A1 - Rak, Kristen T1 - Pegylated insulin-like growth factor 1 attenuates hair cell loss and promotes presynaptic maintenance of medial olivocochlear cholinergic fibers in the cochlea of the progressive motor neuropathy mouse JF - Frontiers in Neurology N2 - The progressive motor neuropathy (PMN) mouse is a model of an inherited motor neuropathy disease with progressive neurodegeneration. Axon degeneration associates with homozygous mutations of the TBCE gene encoding the tubulin chaperone E protein. TBCE is responsible for the correct dimerization of alpha and beta-tubulin. Strikingly, the PMN mouse also develops a progressive hearing loss after normal hearing onset, characterized by degeneration of the auditory nerve and outer hair cell (OHC) loss. However, the development of this neuronal and cochlear pathology is not fully understood yet. Previous studies with pegylated insulin-like growth factor 1 (peg-IGF-1) treatment in this mouse model have been shown to expand lifespan, weight, muscle strength, and motor coordination. Accordingly, peg-IGF-1 was evaluated for an otoprotective effect. We investigated the effect of peg-IGF-1 on the auditory system by treatment starting at postnatal day 15 (p15). Histological analysis revealed positive effects on OHC synapses of medial olivocochlear (MOC) neuronal fibers and a short-term attenuation of OHC loss. Peg-IGF-1 was able to conditionally restore the disorganization of OHC synapses and maintain the provision of cholinergic acetyltransferase in presynapses. To assess auditory function, frequency-specific auditory brainstem responses and distortion product otoacoustic emissions were recorded in animals on p21 and p28. However, despite the positive effect on MOC fibers and OHC, no restoration of hearing could be achieved. The present work demonstrates that the synaptic pathology of efferent MOC fibers in PMN mice represents a particular form of “efferent auditory neuropathy.” Peg-IGF-1 showed an otoprotective effect by preventing the degeneration of OHCs and efferent synapses. However, enhanced efforts are needed to optimize the treatment to obtain detectable improvements in hearing performances. KW - cochlea KW - microtubules KW - MOC fibers KW - hearing loss KW - pegylated insulin-like growth factor 1 KW - outer hair cell (OHC) KW - motor neuropathy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-276669 SN - 1664-2295 VL - 13 ER - TY - JOUR A1 - Engert, Jonas A1 - Doll, Julia A1 - Vona, Barbara A1 - Ehret Kasemo, Totta A1 - Spahn, Bjoern A1 - Hagen, Rudolf A1 - Rak, Kristen A1 - Voelker, Johannes T1 - mRNA abundance of neurogenic factors correlates with hearing capacity in auditory brainstem nuclei of the rat JF - Life N2 - Neural stem cells (NSCs) have previously been described up to the adult stage in the rat cochlear nucleus (CN). A decreasing neurogenic potential was observed with critical changes around hearing onset. A better understanding of molecular factors affecting NSCs and neurogenesis is of interest as they represent potential targets to treat the cause of neurologically based hearing disorders. The role of genes affecting NSC development and neurogenesis in CN over time on hearing capacity has remained unclear. This study investigated the mRNA abundance of genes influencing NSCs and neurogenesis in rats’ CN over time. The CN of rats on postnatal days 6, 12, and 24 were examined. Real-time quantitative polymerase chain reaction arrays were used to compare mRNA levels of 84 genes relevant to NSCs and neurogenesis. Age- and hearing-specific patterns of changes in mRNA abundance of neurogenically relevant genes were detected in the rat CN. Additionally, crucial neurogenic factors with significant and relevant influence on neurogenesis were identified. The results of this work should contribute to a better understanding of the molecular mechanisms underlying the neurogenesis of the auditory pathway. KW - real-time PCR KW - auditory pathway KW - neurogenesis KW - cochlear nucleus Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357392 SN - 2075-1729 VL - 13 IS - 9 ER - TY - JOUR A1 - Engert, Jonas A1 - Rak, Kristen A1 - Bieniussa, Linsa A1 - Scholl, Miriam A1 - Hagen, Rudolf A1 - Völker, Johannes T1 - Evaluation of the Neurogenic Potential in the Rat Inferior Colliculus from Early Postnatal Days Until Adulthood JF - Molecular Neurobiology N2 - Neural stem cells (NSCs) have been recently identified in the inferior colliculus (IC). These cells are of particular interest, as no casual therapeutic options for impaired neural structures exist. This research project aims to evaluate the neurogenic potential in the rat IC from early postnatal days until adulthood. The IC of rats from postnatal day 6 up to 48 was examined by neurosphere assays and histological sections. In free-floating IC cell cultures, neurospheres formed from animals from early postnatal to adulthood. The amount of generated neurospheres decreased in older ages and increased with the number of cell line passages. Cells in the neurospheres and the histological sections stained positively with NSC markers (Doublecortin, Sox-2, Musashi-1, Nestin, and Atoh1). Dissociated single cells from the neurospheres differentiated and were stained positively for the neural lineage markers β-III-tubulin, glial fibrillary acidic protein, and myelin basic protein. In addition, NSC markers (Doublecortin, Sox-2, CDK5R1, and Ascl-1) were investigated by qRT-PCR. In conclusion, a neurogenic potential in the rat IC was detected and evaluated from early postnatal days until adulthood. The identification of NSCs in the rat IC and their age-specific characteristics contribute to a better understanding of the development and the plasticity of the auditory pathway and might be activated for therapeutic use. KW - central auditory pathway KW - inferior colliculus KW - neural progenitor cells KW - neural stem cells KW - neurosphere Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-235811 SN - 0893-7648 VL - 58 ER - TY - JOUR A1 - Engert, Jonas A1 - Spahn, Bjoern A1 - Bieniussa, Linda A1 - Hagen, Rudolf A1 - Rak, Kristen A1 - Voelker, Johannes T1 - Neurogenic stem cell niche in the auditory Thalamus: in vitro evidence of neural stem cells in the rat medial geniculate body JF - Life N2 - The medial geniculate body (MGB) is a nucleus of the diencephalon representing a relevant segment of the auditory pathway and is part of the metathalamus. It receives afferent information via the inferior brachium of the inferior colliculus and transmits efferent fibers via acoustic radiations to the auditory cortex. Neural stem cells (NSCs) have been detected in certain areas along the auditory pathway. They are of great importance as the induction of an adult stem cell niche might open a regenerative approach to a causal treatment of hearing disorders. Up to now, the existence of NSCs in the MGB has not been determined. Therefore, this study investigated whether the MGB has a neural stem cell potential. For this purpose, cells were extracted from the MGB of PND 8 Sprague-Dawley rats and cultured in a free-floating cell culture assay, which showed mitotic activity and positive staining for stem cell and progenitor markers. In differentiation assays, the markers β-III-tubulin, GFAP, and MBP demonstrated the capacity of single cells to differentiate into neuronal and glial cells. In conclusion, cells from the MGB exhibited the cardinal features of NSCs: self-renewal, the formation of progenitor cells, and differentiation into all neuronal lineage cells. These findings may contribute to a better understanding of the development of the auditory pathway. KW - neurosphere KW - auditory pathway KW - neural stem cell potential Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-319387 SN - 2075-1729 VL - 13 IS - 5 ER - TY - JOUR A1 - Herrmann, David P. A1 - Müller-Graff, Franz-Tassilo A1 - Kaulitz, Stefan A1 - Cebulla, Mario A1 - Kurz, Anja A1 - Hagen, Rudolf A1 - Neun, Tilmann A1 - Rak, Kristen T1 - Application of intentional facial nerve stimulation during cochlear implantation as an electrophysiological tool to estimate the intracochlear electrode position JF - Scientific Reports N2 - This proof of concept describes the use of evoked electromyographic (EMG) activation of the facial nerve for intraoperative monitoring of the electrode insertion during cochlear implantation (CI). Intraoperative EMG measurements from the facial nerve were conducted in nine patients undergoing CI implantation. Electric current pulses were emitted from contacts on the CI array during and immediately after electrode insertion. For control, the results of EMG measurements were compared to postoperative flat panel volume computed tomography scans with secondary reconstruction (fpVCT\(_{SECO}\)). During insertion, the EMG response evoked by the electrical stimulation from the CI was growing with the stimulating contact approaching the facial nerve and declined with increasing distance. After full insertion, contacts on the apical half of the CI array stimulated higher EMG responses compared with those on the basal half. Comparison with postoperative imaging demonstrated that electrode contacts stimulating high EMG responses had the shortest distances to the facial nerve. It could be demonstrated that electrically evoked EMG activation of the facial nerve can be used to monitor the progress during CI electrode insertion and to control the intracochlear electrode position after full insertion. KW - facial nerve KW - electromyographic KW - cochlear implantation Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300197 VL - 12 IS - 1 ER - TY - JOUR A1 - Juergens, Lukas A1 - Bieniussa, Linda A1 - Voelker, Johannes A1 - Hagen, Rudolf A1 - Rak, Kristen T1 - Spatio-temporal distribution of tubulin-binding cofactors and posttranslational modifications of tubulin in the cochlea of mice JF - Histochemistry and Cell Biology N2 - The five tubulin-binding cofactors (TBC) are involved in tubulin synthesis and the formation of microtubules. Their importance is highlighted by various diseases and syndromes caused by dysfunction or mutation of these proteins. Posttranslational modifications (PTMs) of tubulin promote different characteristics, including stability-creating subpopulations of tubulin. Cell- and time-specific distribution of PTMs has only been investigated in the organ of Corti in gerbils. The aim of the presented study was to investigate the cell type-specific and time-specific expression patterns of TBC proteins and PTMs for the first time in murine cochleae over several developmental stages. For this, murine cochleae were investigated at the postnatal (P) age P1, P7 and P14 by immunofluorescence analysis. The investigations revealed several profound interspecies differences in the distribution of PTMs between gerbil and mouse. Furthermore, this is the first study to describe the spatio-temporal distribution of TBCs in any tissue ever showing a volatile pattern of expression. The expression analysis of TBC proteins and PTMs of tubulin reveals that these proteins play a role in the physiological development of the cochlea and might be essential for hearing. KW - tubulin-binding cofactors KW - tubulin KW - development KW - cochlea KW - posttranslational modifications KW - hearing Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234852 SN - 0948-6143 VL - 154 ER - TY - JOUR A1 - Köping, Maria A1 - Shehata-Dieler, Wafaa A1 - Cebulla, Mario A1 - Rak, Kristen A1 - Oder, Daniel A1 - Müntze, Jonas A1 - Nordbeck, Peter A1 - Wanner, Christoph A1 - Hagen, Rudolf A1 - Schraven, Sebastian T1 - Cardiac and renal dysfunction is associated with progressive hearing loss in patients with Fabry disease JF - PLoS ONE N2 - Background Fabry disease (FD) is an X-linked recessive hereditary lysosomal storage disorder which results in the accumulation of globotriaosylceramid (Gb3) in tissues of kidney and heart as well as central and peripheral nervous system. Besides prominent renal and cardiac organ involvement, cochlear symptoms like high-frequency hearing loss and tinnitus are frequently found with yet no comprehensive data available in the literature. Objective To examine hearing loss in patients with FD depending on cardiac and renal function. Material and methods Single-center study with 68 FD patients enrolled between 2012 and 2016 at the Department of Oto-Rhino-Laryngology, Plastic, Aesthetic and Reconstructive Head and Neck Surgery of the University of Würzburg. Every subject underwent an oto-rhino-laryngological examination as well as behavioral, electrophysiological and electroacoustical audiological testing. High-frequency thresholds were evaluated by using a modified PTA\(_{6}\) (0.5, 1, 2, 4, 6, 8) and HF-PTA (6, 8 kHz). Renal function was measured by eGFR, cardiac impairment was graduated by NYHA class. Results Sensorineural hearing loss was detected in 58.8% of the cohort, which occurred typically in sudden episodes and affected especially high frequencies. Hearing loss is asymmetric, beginning unilaterally and affecting the contralateral ear later. Tinnitus was reported by 41.2%. Renal and cardiac impairment influenced the severity of hearing loss (p < 0.05). Conclusions High frequency hearing loss is a common problem in patients with FD. Although not life-threatening, it can seriously reduce quality of life and should be taken into account in diagnosis and therapy. Optimized extensive hearing assessment including higher frequency thresholds should be used. KW - cardiac dysfunction KW - renal dysfunction KW - Fabry disease KW - hearing loss Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-169961 VL - 12 IS - 11 ER - TY - JOUR A1 - Müller-Graff, Franz-Tassilo A1 - Ilgen, Lukas A1 - Schendzielorz, Philipp A1 - Voelker, Johannes A1 - Taeger, Johannes A1 - Kurz, Anja A1 - Hagen, Rudolf A1 - Neun, Tilmann A1 - Rak, Kristen T1 - Implementation of secondary reconstructions of flat-panel volume computed tomography (fpVCT) and otological planning software for anatomically based cochlear implantation JF - European Archives of Oto-Rhino-Laryngology N2 - Purpose For further improvements in cochlear implantation, the measurement of the cochlear duct length (CDL) and the determination of the electrode contact position (ECP) are increasingly in the focus of clinical research. Usually, these items were investigated by multislice computed tomography (MSCT). The determination of ECP was only possible by research programs so far. Flat-panel volume computed tomography (fpVCT) and its secondary reconstructions (fpVCT\(_{SECO}\)) allow for high spatial resolution for the visualization of the temporal bone structures. Using a newly developed surgical planning software that enables the evaluation of CDL and the determination of postoperative ECP, this study aimed to investigate the combination of fpVCT and otological planning software to improve the implementation of an anatomically based cochlear implantation. Methods Cochlear measurements were performed utilizing surgical planning software in imaging data (MSCT, fpVCT and fpVCT\(_{SECO}\)) of patients with and without implanted electrodes. Results Measurement of the CDL by the use of an otological planning software was highly reliable using fpVCT\(_{SECO}\) with a lower variance between the respective measurements compared to MSCT. The determination of the inter-electrode-distance (IED) between the ECP was improved in fpVCT\(_{SECO}\) compared to MSCT. Conclusion The combination of fpVCT\(_{SECO}\) and otological planning software permits a simplified and more reliable analysis of the cochlea in the pre- and postoperative setting. The combination of both systems will enable further progress in the development of an anatomically based cochlear implantation. KW - interelectrode-distance KW - Cochlear duct length KW - Cochlear planning software KW - fpVCT KW - secondary reconstruction KW - MSCT Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266798 SN - 1434-4726 VL - 279 IS - 5 ER - TY - JOUR A1 - Noyalet, Laurent A1 - Ilgen, Lukas A1 - Bürklein, Miriam A1 - Shehata-Dieler, Wafaa A1 - Taeger, Johannes A1 - Hagen, Rudolf A1 - Neun, Tilmann A1 - Zabler, Simon A1 - Althoff, Daniel A1 - Rak, Kristen T1 - Vestibular aqueduct morphology and Meniere’s disease - development of the vestibular aqueduct score by 3D analysis JF - Frontiers in Surgery N2 - Improved radiological examinations with newly developed 3D models may increase understanding of Meniere's disease (MD). The morphology and course of the vestibular aqueduct (VA) in the temporal bone might be related to the severity of MD. The presented study explored, if the VA of MD and non-MD patients can be grouped relative to its angle to the semicircular canals (SCC) and length using a 3D model. Scans of temporal bone specimens (TBS) were performed using micro-CT and micro flat panel volume computed tomography (mfpVCT). Furthermore, scans were carried out in patients and TBS by computed tomography (CT). The angle between the VA and the three SCC, as well as the length of the VA were measured. From these data, a 3D model was constructed to develop the vestibular aqueduct score (VAS). Using different imaging modalities it was demonstrated that angle measurements of the VA are reliable and can be effectively used for detailed diagnostic investigation. To test the clinical relevance, the VAS was applied on MD and on non-MD patients. Length and angle values from MD patients differed from non-MD patients. In MD patients, significantly higher numbers of VAs could be assigned to a distinct group of the VAS. In addition, it was tested, whether the outcome of a treatment option for MD can be correlated to the VAS. KW - vestibular aqueduct (VA) KW - 3D analysis KW - temporal bone KW - saccotomy KW - computed tomography KW - Meniere’s disease Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-312893 SN - 2296-875X VL - 9 ER - TY - JOUR A1 - Sprinzl, Georg Mathias A1 - Magele, Astrid A1 - Schoerg, Philipp A1 - Hagen, Rudolf A1 - Rak, Kristen A1 - Kurz, Anja A1 - Van de Heyning, Paul A1 - Calvino, Miryam A1 - Lassaletta, Luis A1 - Gavilán, Javier T1 - A novel representation of audiological and subjective findings for acoustical, bone conduction and direct drive hearing solutions JF - Journal of Personalized Medicine N2 - Background: The benefit of hearing rehabilitation is often measured using audiological tests or subjective questionnaires/interviews. It is important to consider both aspects in order to evaluate the overall benefits. Currently, there is no standardized method for reporting combined audiological and patient reported subjective outcome measures in clinical practice. Therefore, this study focuses on showing the patient’s audiological, as well as subjective outcomes in one graph using data from an existing study. Method: The present paper illustrated a graph presenting data on four quadrants with audiological and subjective findings. These quadrants represented speech comprehension in quiet (unaided vs. aided) as WRS% at 65 dB SPL, speech recognition in noise (unaided vs. aided) as SRT dB SNR, sound field threshold (unaided vs. aided) as PTA\(_4\) in dB HL, wearing time and patient satisfaction questionnaire results. Results: As an example, the HEARRING graph in this paper represented audiological and subjective datasets on a single patient level or a cohort of patients for an active bone conduction hearing implant solution. The graph offered the option to follow the user’s performance in time. Conclusion: The HEARRING graph allowed representation of a combination of audiological measures with patient reported outcomes in one single graph, indicating the overall benefit of the intervention. In addition, the correlation and consistency between some results (e.g., aided threshold and aided WRS) can be better visualized. Those users who lacked performance benefits on one or more parameters and called for further insight could be visually identified. KW - bone conduction implant KW - hearing aids Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-311210 SN - 2075-4426 VL - 13 IS - 3 ER -