Background and Aim: „CI-Wizard“ is a new, three-dimensional software planning tool for cochlear implant surgery with manual and semi-automatic algorithms to visualize anatomical risk structures of the lateral skull base preoperatively. Primary endpoints of the study represented the evaluation of the CI Wizards usability, accuracy, subjectively perceived and objectively measured time in clinical practice. Materials and Methods: In a period from January 2014 to March 2015, n=36 participants were included in this study. These members were divided into three groups of equal number (n=12), but different level of experience. Senior doctors and consultants (group 1), residents (group 2) and medical students (group 3) segmented twelve different CT-scan data sets of the CI Wizard (four per participant). In total, n=144 data sets were collected. The usability of the CI Wizard was measured by the given questionnaire with an interval rating scale. The Jaccard coefficient (JT) was used to evaluate the accuracy of the anatomical structures segmented. The subjectively-perceived time was measured with an interval rating scale in the questionnaire and was compared with the objectively mean measured time (time interact). Results: Across all three groups, the usability of the CI Wizard has been assessed between 1 ('very good') and 2 ('with small defects'). Subjectively, the time was stated as 'appropriate' by questionnaire. Objective measurements of the required duration revealed averages of n=9.8 minutes for creating a target view. Concerning the accuracy, semi automatic anatomical structures such as the external acoustic canal (JT=0.90), the tympanic cavity (JT=0.87), the ossicles (JT=0.63), the cochlea (JT=0.66) and the semicircular canals (JT=0.61) reached high Jaccard values, which describes a great match of the segmented structures between the partcipants and the gold standard. Facial nerve (JT=0.39) and round window (JT=0.37) reached lower Jaccard values. Very little overlap tendency was found for the chorda tympani (JT=0.11). Conclusion: This software program represents a further important step in the development of pre-operative planning tools in cochlear implant surgery. The study revealed a high level of satisfaction in the usability. The subjectively required time was considered as „appropriate“ and the objectively mean measured time was n=9.8 minutes short enough, so that a clinical application seems realistic. Particularly for semi-automatically segmented structures, it represented a good accuracy. For purely manual segmented structures, further improvements are desirable. Finally, this program also provides a good learning tool for medical students and residents to become familiar with the anatomy of the lateral skull base.:1 Einführung 1 1.1 Cochlea Implantate (CI) 1 1.2 Bildverarbeitungsprogamme zur präoperativen Planung eines Cochlea Implantates 2 1.2.1 Segmentierung in der Medizin 2 1.2.2 CI-Wizard 4 1.3 Fragebogen 6 1.4 Zielsetzung 6 1.5 Zusammenfassung der Ergebnisse 7 2 Publikation 8 3 Zusammenfassung 19 4 Literaturverzeichnis 23 Anlagen 26 Beitrag der Promovendin bei geteilter Erstautorenschaft 34 Erklärung über die eigenständige Abfassung der Arbeit 35 Lebenslauf 36 Danksagung 37

Detailed knowledge of the role that particular genes and factors play during the development and in the normal function of the auditory system is necessary to develop successful regenerative inner ear therapies. Islet1 transcription factor and brain derived neurothrophic factor (BDNF) have great potential to play a role in regenerative inner ear therapy as both have been shown to be sufficient for self-repair regeneration in cochlea in animal studies. In this study we looked at the roles these two factors play in the development and function of the auditory system. In the transgenic mice used in the study, overexpression of Isl1 affected cell specification during embryonic development, leading to enlargement of the cochleovestibular ganglion and accelerated nerve fiber extension and branching in mutant embryos. The hearing of young transgenic mice was not affected. However, it started to decline in 1-month-old animals. This early onset of age-related hearing loss was found to be a consequence of the neurodegeneration of the olivocochlear system caused by Pax2-driven Isl1 misexpression in the hindbrain. Our data provide the first evidence that the alternation of the olivocochlear system efferent system accelerates the age-related functional decline of hearing without the loss of OHCs. The functional role of...

The tegmentum vasculosum of the duckling consists of a highly folded epithelium which extends over the dorsal and lateral walls of the cochlear duct, separating the scala media from the scala vestibuli. This epithelium consists of two distinct cell types, dark cells and light cells, and is well vascularized. The surface of the epithelium is formed by a mosaic of alternating dark and light cells. The goblet-shaped dark cells have an electron-dense, organelle-rich cytoplasm, and are expanded basally by extensive basolateral plasma membrane infoldings, within which are numerous mitochondria. Dark cells are isolated from each other and from the capillaries within the epithelium by intervening light cells. In contrast, columnar light cells exhibit an electron-lucent, organelle-poor cytoplasm and may extend from the underlying capillaries to the endolymphatic surface. Light cells contain abundant, coated endocytic vesicles on their apical surfaces and are bound, apically, to other light cells or to dark cells by tight junctions and desmosomes. Laterally, light cells are linked to each other either by complex, fluid-filled membrane interdigitations or by extensive gap junctions. Plasma membrane interdigitations and obvious, fluid-filled intercellular spaces characterize the lateral borders between light and dark cells. Vascular corrosion casting reveals the three-dimensional anatomy of the cochlear vasculature. A continuous arteriolar loop fed by anterior and posterior cochlear arterioles encircles the cochlear duct. The rich capillary beds of the tegmentum vasculosum are supplied by arching arterioles arising from this loop. These capillaries are the continuous type and are situated primarily within the core of the epithelium or along its border with the scala vestibuli. The structure and blood supply of the tegmentum vasculosum are characteristic of an epithelium involved in active transport.

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<p>Sensorineural hearing loss imparts two serious hearing deficits in hearing-impaired people: reduced dynamic range of hearing and reduced frequency selectivity. Psychophysically, these deficits render loss of speech audibility and speech intelligibility to a hearing-impaired person. Studies of an impaired cochlea in cats have shown that the hearing loss originates from damage to or complete loss of inner and outer hair cells. Neurophysiology of an impaired cochlea in cats shows that the tuning curves of the auditory nerve fibers become elevated and broadened. Amplification in hearing aids has been used to restore audibility in hearing-impaired people. Multiband compression has been commercially available in conventional hearing aids to compensate for the reduced dynamic range of hearing. However, little has been achieved to improve the intelligibility of speech in the hearing-impaired people. The aim of this thesis is to restore not only the speech audibility in a hearing-impaired person, but also to improve their speech intelligibility through some hearing-aid signal processing. The compensation technique used in this thesis for speech intelligibility is based on the hypothesis that a narrowband response of the auditory nerve fibers to speech signals ensure phonemic discriminability in the central nervous system.</p><p>Miller et al. [1999] have proposed contrast-enhancing frequency shaping ( CEFS) to compensate for the broadband responses of the fibers to first and second formants (Fl and F2) of a speech stimulus. Bruce [2004] has shown that the multiband compression can be combined with CEFS without counteracting each other. In Bruce's algorithm, a multiband compressor is serially combined with a time-domain CEFS filter. The MICEFS algorithm, herein presented, is a combination of multiband compression and an improved version of CEFS implemented in the frequency domain. The frequency domain implementation of MICEFS has improved the time delay response of the algorithm by 10 ms as compared to series implementation proposed by Bruce. The total time delay of the MICEFS algorithm is 16 ms, which is still longer than the standard time delay of 10 ms in hearing aids. The MICEFS algorithm was tested on a computational model of auditory periphery [Bruce et al., 2003] using a synthetic vowel and a synthetic sentence. The testing paradigm consisted of five conditions: 1) unmodified speech presented to a normal cochlea; 2) speech modified with halfgain rule presented to an impaired cochlea; 3) CEFS modified speech presented to the impaired cochlea; 4) speech modified with MICEFS presented to the impaired cochlea, and; 5) MICEFS-modified speech with some added noise in the formant estimation presented to an impaired cochlea. The spectral enhancement filter used in MICEFS has improved the synchrony capture of the fibers to the first three formants of a speech stimulus. MICEFS has also restored the correct tonotopic representation in the average discharge rate of the fibers at the first three formants of the speech.</p> / Thesis / Master of Applied Science (MASc)

Les neuropathies optiques héréditaires se caractérisent par une dégénérescence des cellules ganglionnaires de la rétine entraînant une perte visuelle modérée voire la cécité. L'atrophie optique dominante (AOD) ou maladie de Kjer et la neuropathie optique de Leber (NOHL), sont les deux formes les plus fréquentes. Il existe quatre loci d'AOD mais seulement deux gènes identifiés : OPA1 et OPA3 codant des protéines mitochondriales. La NOHL est due à des mutations de l'ADN mitochondrial (ADNmt). Aucun traitement n'existe pour soigner ces pathologies ou ralentir leur progression. Nous nous sommes intéressés au gène YWHAH, situé au locus OPA5, codant la protéine 14-3-3eta, un des gènes majoritairement exprimés dans les GCRs. Le criblage de YWHAH dans des banques d'ADNs de patients exempts de mutation dans OPA1, OPA3 et l'ADNmt a permis d'identifier deux mutations hétérozygotes chez des patients présentant une AOD et une surdité profonde.14-3-3eta joue un rôle de protection dans l'apoptose. En effet, les fibroblastes de patients et des cellules surexprimant une 14-3-3eta mutée s'avèrent moins résistants à un stress apoptotique. Pour évaluer l'effet des mutations de 14-3-3eta sur la fonction visuelle et auditive nous avons généré une souris reproduisant une mutation humaine. Les souris 14-3-3eta hétéro et homozygotes ont une atteinte auditive de 15 à 20 décibels dès 2 mois, et seules les souris homozygotes présentent une altération de la fonction visuelle à partir de 12 mois affectant les interneurones et les photorécepteurs de la rétine. La souris mutante présente un phénotype moins grave que chez l'homme, mais son étude permet d'impliquer 14-3-3eta dans des atteintes neurosensorielles / Inherited Optic Neuropathies (ION) are characterized by the degeneration of the Retinal Ganglion Cells (RGCs), leading to moderate visual loss or legal blindness. Dominant Optic Atrophy or Kjer disease (DOA) and Leber Hereditary Optic Neuropathy (LHON) are the most common forms of IONs. There are four loci for DOA, but only two genes have been identified: OPA1 and OPA3 encoding mitochondrial proteins. LHON is caused by mitochondrial DNA (mtDNA) mutations. There is no treatment to cure these diseases or slow down their progression. In order to identify new genes responsible for DOA, our team was interested in the YWHAH gene localized at the OPA5 locus, coding the 14-3-3eta protein, a gene strongly expressed in RGCs. The screening of YWHAH in DNAs without mutation in OPA1, OPA3 and mtDNA allowed us to identify two heterozygous mutations in patients presenting a DOA associated to a severe deafness.As 14-3-3eta plays a role in apoptosis, we studied patient fibroblasts and found that they present a marked susceptibility to apoptosis. Moreover, the mutated alleles of 14-3-3eta lost their ability to confer resistance to cell death. In order to evaluate the effects of the 14-3-3eta mutations on the visual and auditory functions, we have generated an animal model mimicking a human mutation. The 14-3-3eta hetero and homozygous mice present a stable auditory impairment of 15 to 20 decibels, whereas only the homozygous mice present an alteration of the visual function at 12 months, with affected interneurones and photoreceptors. Even if the mutant mouse does not present a phenotype as dramatic as in human, its study shed light on 14-3-3eta involvement in neuronsensorial functions

In der vorliegenden Arbeit wurden einseitig mit Human-Cochlea-Implantat versorgte Meerschweinchen verwendet, die auf dem anderen Ohr normalhörend waren und mit einer einseitig vertäubten, aber nicht elektrostimulierten Kontrollgruppe verglichen wurden. Untersucht wurde der Einfluss von drei unterschiedlichen Stimulationsraten und drei Stimulationsintensitäten während einer einseitigen Elektrostimulation. Dabei wurde zunächst der Einfluss der Elektrostimulation auf die Hörschwellen mittels Hirnstammaudiometrie (ABR) untersucht. Anschließend wurden die Zelldichten in der aufsteigenden Hörbahn (dorsaler Nucleus Cochlearis, Colliculus Inferior, medialer Kniehöcker und auditorischer Cortex) im Hirnschnitt unter Verwendung einer Hämalaun-Eosin Färbung bestimmt. Ein Zusammenhang zwischen der verwendeten Stimulationsrate und den in der zentralen Hörbahn gefundenen Zelldichten wurde ebenso wenig gezeigt wie ein Zusammenhang mit den mittels ABR ermittelten Hörschwellen der normalhörenden Seite. Dagegen wurde jedoch ein Zusammenhang zwischen den in der Elektrostimulation verwendeten Stimulationsintensitäten und den ermittelten Zelldichten festgestellt. Die niedrigste verwendete Stimulationsintensität führte zu einer bilateralen Konservierung der Zelldichten in der gesamten untersuchten Hörbahn, wogegen eine Elektrostimulation mit der höchsten Stimulationsintensität zum Teil einen bilateralen Zellverlust im dorsalen Nucleus Cochlearis, medialen Kniehöcker und im auditorischen Cortex zur Folge hatte. Dieser Zellverlust führte in dem Untersuchungszeitraum nicht zu einer signifikanten Veränderung der Hörschwelle. / In this study, human cochlear implants (CI) were implanted unilaterally in the cochlea of guinea pigs that were normal hearing on the contralateral side. Electro-stimulation was used on the cochlea with the implanted CI. They were compared to an unilaterally implanted but not electro-stimulated control group. This study investigates the effect of three different stimulation-rates and three different stimulation-intensities in unilateral electro-stimulation. The effect of the electro-stimulation on the hearing thresholds was determined using auditory brainstem recordings (ABR). Afterwards, cell densities in the ascending auditory pathway (dorsal cochlear nucleus, inferior colliculus, medial geniculate body and auditory cortex) were measured in brain slices stained with hematoxylin and eosin. No evidence was found of a connection between the different stimulation rates of electro-stimulation in the cochlea with a CI and cell densities seen in the central auditory pathway. Furthermore, there were no links found between hearing thresholds determined by ABR and the different parameters that were used for the electro-stimulation. However a significant effect of the different stimulation intensities on the cell densities identified in the auditory pathway was demonstrated. The lowest intensity used in the electro stimulation led to a bilateral preservation of cell densities in the entire auditory pathway whereas electro-stimulation with the highest intensity induced a significant cell loss in the auditory pathway (dorsal cochlear nucleus, the medial geniculate body and the auditory cortex). Interestingly, this cell loss was not accompanied by significant changes in the auditory threshold.

Introdução: A apneia obstrutiva do sono (AOS) provoca modificações na arquitetura normal do sono, fragmentando-o de forma crônica com hipóxias intermitentes levando, a longo prazo, a sérias consequências na saúde. Acredita-se que a ocorrência de eventos respiratórios durante o sono como apneia e hipopneia pode prejudicar o mecanismo de transdução da orelha interna e a transmissão de impulsos nervosos ao longo da via auditiva que são altamente dependentes do fornecimento do oxigênio. Contudo, essa associação não se encontra bem estabelecida na literatura. Adicionalmente, sujeitos com AOS poderiam apresentar alterações na função de transferência acústica da orelha média devido ao desequilíbrio pressórico existente nas vias aéreas superiores durante o sono, característico da fisiopatologia da doença. Objetivo: Comparar os achados da avaliação auditiva entre os indivíduos portadores e não portadores de AOS. Método: A casuística foi composta por 38 adultos do sexo masculino, média de idade de 35,8 (±7,2) e foram divididos em quatro grupos experimentais pareados por idade e índice da massa corpórea. Os grupos foram classificados com base na polissonografia em: controle (n=10), AOS leve (n=11), AOS moderada (n=8) e AOS grave (n=9). Todos os sujeitos do estudo negaram história pregressa de risco para perda auditiva. Todos os sujeitos foram submetidos à audiometria convencional, timpanometria, pesquisa de reflexos acústicos ipsi e contralaterais, imitância acústica de banda larga com estímulo clique de 226 a 8000 Hz para obtenção da energia de absorvância (EA), emissões otoacústicas por produto de distorção e potenciais evocados auditivos de tronco encefálico. Os resultados foram submetidos às análises estatísticas e o nível de significância adotado foi de 5% para todos os testes. Resultados: As medidas da EA não mostraram diferença significante entre os grupos quando considerados somente o fator grupo (sem AOS, AOS leve, moderada e grave). Para o efeito de interação entre os fatores grupo e frequência, o valor da média da EA do grupo com AOS de grau moderado foi significativamente maior do que do grupo com AOS de grau leve (p=0,003) em 8000 Hz. O grupo com AOS de grau grave apresentou menores valores das médias das amplitudes das EOAPD quando comparados aos dos grupos controle, AOS de grau leve e AOS de grau moderado (p=0,02, p=0,03 e p=0,01, respectivamente). Não houve diferença significante nos valores das latências absolutas das ondas I, III e V, e interpicos I-III, III-V e I-V entre os grupos. Observou-se associação entre a presença da AOS e alteração da latência absoluta da onda V (p=0,03). Foi observada associação entre AOS de grau moderado e alteração da latência da onda V (p=0,01). Conclusão: A presença da AOS está associada à presença de alteração na condução nervosa do estímulo acústico na via auditiva em tronco encefálico. A presença de AOS de grau grave prejudicou a função coclear. De maneira geral, a função de transferência acústica da orelha média é similar entre os adultos com e sem AOS / Introduction: The obstructive sleep apnea (OSA) can change the normal sleep architecture, fragmenting it chronically with intermittent hypoxias and, to the long time, inducing to serious consequences to health. It is believed that the occurrence of respiratory events during sleep with the presence of apnea and hipopneia can damage the transduction mechanism of the inner ear and nerve impulses transmission along the auditory pathways, which are highly dependent on the oxygen supply. However, this association is not well established. Moreover, the acoustic transference function of middle ear could show alterations, due to the pressure changes that occur in upper airway during the sleep, typical of OSA pathophysiology. Objective: To compare the findings of the hearing evaluations between subjects with OSA and without OSA. Method: A total of 38 subjects of the male sex, mean age 35.8 (±7.2), were divided into four groups, which were matched for age and body mass index. The groups were classified by the means of polissomnography in without OSA (n=10), mild OSA (n=11), moderate OSA (n=8) and severe OSA (n=9). All the subjects denied a history of risk for hearing loss. These subjects were submitted to: conventional audiometry, tympanometry, ipsilateral, contralateral acoustic reflex, wideband acoustic immittance for measurements of energy of absorbance (EA) with click stimulus of 226 to 8000 Hz, distortion product of otoacoustic emissions (DPOAE) and click evoked auditory brainstem responses (ABR). The recorded data of each analysis were conducted to an appropriate statistical test and was adopted the significant level of 5% for all the tests. Results: The EA data did not showed statistical differences among the groups when considering only the OSA severity factor (without, mild, moderate or severe). For the interaction between OSA severity and frequency factors, the mean value of EA of moderate OSA group was significant higher than the mild OSA group (p=0.003) in 8000 Hz. The severe OSA group presented lower mean values of amplitudes of DPOAE when compared to the control group, mild and moderate OSA groups (respectively, p=0.02, p=0.03 and p=0.01). For ABR, no differences was observed in latencies waves I, III and V, and interpeaks I-III, III-V and I-V values among the groups. Conclusion: The presence of OSA is associated with the presence of alterations in the nerve conduction of acoustic stimuli in the auditory pathway in the brainstem. The presence of severe OSA impaired the DPOAE responses. In general, the acoustic transference function of middle ear is similar between the adults with and without OSA

INTRODUÇÃO: A literatura evidencia as diferenças anatômicas do osso temporal em crianças quando comparadas à adultos. Mais e mais a literatura enfatiza a importância de que as crianças com surdez congênita devem ser implantadas cada vez mais precocemente. Estudos anátomo-radiológicos são importantes para o desenvolvimento de técnicas cirúrgicas que possibilitem implantar crianças recém natas. Técnicas de implante coclear percutâneo (através de robótica) tem sido desenvolvidas na Universidade de Vanderbilt. Criamos então nossa principal pergunta \"Seria possível implantar crianças recém natas através de implante percutâneo?\" e procuraremos respondê-la no curso desse trabalho. OBJETIVO: Aferir as medidas do recesso do nervo facial e sua relação com a cóclea visando simular o trajeto da broca através desse recesso, para realização da cocleostomia, objetivando o implante coclear percutâneo. CASUÍSTICA E METODOLOGIA: Estudo experimental realizado com 9 espécimes de natimortos com idade gestacional entre 32 e 40 semanas, submetidos à tomografia computadorizada com individualização e reconstrução do nervo facial, cadeia ossicular, membrana timpânica, cóclea e labirinto, seguido da definição da trajetória da broca até a escala timpânica, utilizando o software Improvise. RESULTADOS: As medidas da trajetória da broca até o nervo facial, variaram de 0.58 a mais próxima e, 1.71 a mais distante; quando analisamos os resultados obtidos para cadeia ossicular, temos uma variação que vai de 0.38 até 1.49. A membrana timpânica se encontra entre 0.85 e 1.96 de distância da trajetória simulada da broca. A trajetória da cortical do osso temporal até a escala timpânica, variou de 5.92 a 12.65. CONCLUSÃO: As medidas da relação, entre a broca e as estruturas anatômicas da orelha média e, a simulação da trajetória, mostraram que é possível executar com segurança a técnica de implante coclear percutâneo em crianças a partir de 32 semanas de gestação / INTRODUCTION: Literature shows changes in the temporal bone anatomy in children when compared with adults. More and more literature emphasizes the importance of children with congenital deafness should be implanted increasingly early. Anatomical radiologic studies are important for the development of surgical techniques that allow implanting new born. Percutaneous cochlear implant technique (through robotics) was developed in Vanderbilt University. So we created our main question \" Is it possible to implant new born children using the percutaneous technique? \" and we\'ll try to answer it in the course of this work. PATIENTS AND METHODS: Experimental study done in 9 stillbirth specimens with 32 and 40 weeks of age, submitted to CT study followed by reconstruction of the facial nerve, ossicular chain, tympanic membrane, labyrinth and cochlea. The CT evaluation and reconstruction was done with Improvise software, also used for measurements of the distances and in the simulation of the drill\'s trajectory (mm). RESULTS: The drill trajectory measurements to the facial nerve, ranged from 0.58 the nearest and the farthest 1.71, when we analyzed the results for ossicular chain, we have a range that goes from 0.38 to 1.49. The tympanic membrane is between 0.85 and 1.96 away from the simulated drill path. Cortical trajectory of the temporal bone to the scala tympani, ranged from 5.92 to 12.65. CONCLUSION: The measures of the relationship between the drill and the anatomical structures of the middle ear and the simulated trajectory, showed that it is possible to use safely the percutaneous cochlear implant technique in children of 32 weeks/old