Submitted by Fabíola Silva (fabiola.silva@famerp.br) on 2016-05-31T15:59:39Z No. of bitstreams: 1 magaliaparecidaoratemenezesdasilva_dissert.pdf: 1848544 bytes, checksum: bf5d6434181a9f1108fd8f5a3dc4fcf0 (MD5) / Made available in DSpace on 2016-05-31T15:59:39Z (GMT). No. of bitstreams: 1 magaliaparecidaoratemenezesdasilva_dissert.pdf: 1848544 bytes, checksum: bf5d6434181a9f1108fd8f5a3dc4fcf0 (MD5) Previous issue date: 2015-07-02 / Introduction: Mutations in the otoferlin gene (OTOF) can account for Auditory Neuropathy. Objective: To investigate the prevalence of mutations in OTOF gene in patients with and without Auditory Neuropathy. Casuistic and Methods: This original cross-sectional study evaluated 16 index cases with auditory neuropathy; 13 patients with sensorineural hearing loss and 20 normal-hearing subjects. DNA was extracted from peripheral blood leukocytes, and the OTOF gene sites were amplified by PCR-RFLP. Results: Out of the 16 index cases, 9 (56%) are female and 7 (44%) are male. Out of the 13 deaf patients, 7 (54%) are male and 6 (46%) female. Among the 20 listeners, 13 (65%) are male and 7 (35%) female. Thirteen (81%) index cases had wild-type genotype (AA) and 3 (19%), had the heterozygous AG genotype for IVS8-2A-G (intron 8) mutation. The 5473C-G (exon 44) mutation was found in a heterozygous state (CG) in 7 (44%) index cases and 9 (56%) had the wild-type allele (CC). Of these mutants, two (25%) are compound heterozygote for the mutations found in intron 8 and exon 44. All patients (100%) with hearing loss and listeners do not have mutations. Conclusion: Differences at the molecular level are found in patients with and without Auditory Neuropathy. / Introdução: Mutações no gene da otoferlina (OTOF) são responsáveis pela Neuropatia Auditiva. Objetivo: Investigar a prevalência de mutações no gene OTOF em pacientes com e sem Neuropatia Auditiva. Casuística e Método: Estudo original em corte transversal no qual foram avaliados 16 casos índice com Neuropatia Auditiva, 13 pacientes com deficiência auditiva sensorioneural (DASN) e 20 indivíduos ouvintes. DNA foi extraído de leucócitos do sangue periférico e regiões do gene OTOF foram analisadas pela técnica PCR-RFLP. Resultados: Dos 16 casos índice, 9 (56%) são do gênero feminino e 7 (44%) do masculino. Dos 13 pacientes com DASN, 7 (54%) são masculinos e 6 (46%) femininos. Dos 20 ouvintes, 13 (65%) são masculinos e 7 (35%) femininos. Treze (81%) casos índice apresentam o genótipo selvagem (AA) e 3 (19%), o genótipo heterozigoto AG para a mutação IVS8-2A-G (intron 8). A mutação 5473C-G (exon 44) foi encontrada em heterozigose (CG) em 7 (44%) dos casos índice e 9 (56%) apresentam o genótipo selvagem (CC). Destes mutantes, dois (25%) são heterozigotos compostos para as mutações encontradas no intron 8 e exon 44. Os pacientes com DASN e os ouvintes não apresentam mutações (100%). Conclusão: Existem diferenças, ao nível molecular, em pacientes com e sem Neuropatia Auditiva.

INTRODUÇÃO: Nos usuários de Implante Coclear (IC), o registro do potencial de ação composto do nervo auditivo evocado eletricamente (ECAP) representa o modo mais efetivo para se avaliar o estado do nervo auditivo em resposta ao estímulo elétrico e a interação entre o eletrodo e o tecido neural. Modificações nas respostas neurais ao longo do tempo têm implicação direta nos mapeamentos das crianças, principalmente durante os primeiros meses de uso do IC. OBJETIVO. Estudar o ECAP em crianças ao longo do primeiro ano de uso do IC. Por meio da Telemetria de Respostas Neurais, as características do ECAP foram analisadas em 13 crianças, implantadas com idades inferiores a três anos de idade. RESULTADOS. Durante o primeiro ano de uso do IC, houve aumento estatisticamente significante para a amplitude do pico N1, nos eletrodos basais, entre o segundo e o terceiro retorno. Não foram obtidas diferenças significantes para a latência do pico N1, para o slope e para o p-NRT, entre os retornos. Discretas alterações foram mais evidentes para os eletrodos basais. A análise entre os eletrodos mostrou que os eletrodos apicais apresentaram maiores amplitudes do N1 e valores do p-NRT, estatisticamente, inferiores aos limiares dos eletrodos apicais. Houve prevalência das respostas com morfologia do tipo Ia para os eletrodos E10, E15 e E20 e do tipo Ic para o eletrodo E5. No primeiro retorno, o tempo de recuperação do nervo auditivo de seu estado refratário foi, para a maioria dos sujeitos, igual a 1000 Mius para o E5, e igual a 2000 Mius para os eletrodos E5, E10 e E15. No terceiro retorno, o tempo de recuperação do E5 aumentou para 2000 Mius e, no E20, diminui para 1000 Mius, para a maioria dos sujeitos. A comparação entre os diferentes modelos revelou que o Implante Coclear N24 R (CS) apresentou as maiores amplitudes, os maiores slopes e as menores latências e menores valores de p-NRT. CONCLUSÃO. Ao longo do primeiro ano de uso do IC, a estimulação elétrica liberada pelos eletrodos intracocleares não causou alterações significativas às características do ECAP, exceto pelo aumento da amplitude do pico N1. / INTRODUCTION: In Cochlear Implant (CI) users, the recording of the electrically evoked compound action potential (ECAP) of the auditory nerve represents the most effective way to assess the auditory nerve in response to electrical stimulus and the interaction between the electrode and the neural tissue. Changes in neural responses, over time, have direct implication in mappings of children, mainly during the first months of CI use. OBJECTIVE: To study ECAP in children during the first year of CI use. Through Telemetry of Neural Responses, the ECAP characteristics have been analyzed in 13 children. The children who were implanted were younger than three years old. RESULTS: During the first year of CI use there was a significant statistical growth for the amplitude of N1 peak, in basal electrodes, between the second and third returns. There were not any significant differences obtained for N1 peak latency, neither for the slope nor for p-NRT, among the returns. The analysis among the electrodes has shown that the apical ones have presented higher N1 amplitudes and p-NRT values, statistically lower than the thresholds of apical electrodes. Responses with Ia type morphology have prevailed for electrodes E10, E15 and E20, and Ic type for electrode E5. In the first return, recovery time of the refractory state of the auditory nerve was in most subjects equals to 1000 Mius for E5, and equals to 2000 Mius for electrodes E5, E10 and E15. In the third return, recovery time of E5 increased to 2000 Mius and in E20 decreased to 1000 Mius, in most subjects. The comparison of the different models has shown that the Cochlear Implant N24 R (CS) has presented the highest amplitudes, the highest slopes and the lowest latencies, and the lowest p-NRT values. CONCLUSION: During the first year of CI use, the electrical stimulation released by intracochlear electrodes did not cause significant changes of ECAP characteristics, except in the increase of N1 peak amplitude.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 118-136).

INTRODUÇÃO: Nos usuários de Implante Coclear (IC), o registro do potencial de ação composto do nervo auditivo evocado eletricamente (ECAP) representa o modo mais efetivo para se avaliar o estado do nervo auditivo em resposta ao estímulo elétrico e a interação entre o eletrodo e o tecido neural. Modificações nas respostas neurais ao longo do tempo têm implicação direta nos mapeamentos das crianças, principalmente durante os primeiros meses de uso do IC. OBJETIVO. Estudar o ECAP em crianças ao longo do primeiro ano de uso do IC. Por meio da Telemetria de Respostas Neurais, as características do ECAP foram analisadas em 13 crianças, implantadas com idades inferiores a três anos de idade. RESULTADOS. Durante o primeiro ano de uso do IC, houve aumento estatisticamente significante para a amplitude do pico N1, nos eletrodos basais, entre o segundo e o terceiro retorno. Não foram obtidas diferenças significantes para a latência do pico N1, para o slope e para o p-NRT, entre os retornos. Discretas alterações foram mais evidentes para os eletrodos basais. A análise entre os eletrodos mostrou que os eletrodos apicais apresentaram maiores amplitudes do N1 e valores do p-NRT, estatisticamente, inferiores aos limiares dos eletrodos apicais. Houve prevalência das respostas com morfologia do tipo Ia para os eletrodos E10, E15 e E20 e do tipo Ic para o eletrodo E5. No primeiro retorno, o tempo de recuperação do nervo auditivo de seu estado refratário foi, para a maioria dos sujeitos, igual a 1000 Mius para o E5, e igual a 2000 Mius para os eletrodos E5, E10 e E15. No terceiro retorno, o tempo de recuperação do E5 aumentou para 2000 Mius e, no E20, diminui para 1000 Mius, para a maioria dos sujeitos. A comparação entre os diferentes modelos revelou que o Implante Coclear N24 R (CS) apresentou as maiores amplitudes, os maiores slopes e as menores latências e menores valores de p-NRT. CONCLUSÃO. Ao longo do primeiro ano de uso do IC, a estimulação elétrica liberada pelos eletrodos intracocleares não causou alterações significativas às características do ECAP, exceto pelo aumento da amplitude do pico N1. / INTRODUCTION: In Cochlear Implant (CI) users, the recording of the electrically evoked compound action potential (ECAP) of the auditory nerve represents the most effective way to assess the auditory nerve in response to electrical stimulus and the interaction between the electrode and the neural tissue. Changes in neural responses, over time, have direct implication in mappings of children, mainly during the first months of CI use. OBJECTIVE: To study ECAP in children during the first year of CI use. Through Telemetry of Neural Responses, the ECAP characteristics have been analyzed in 13 children. The children who were implanted were younger than three years old. RESULTS: During the first year of CI use there was a significant statistical growth for the amplitude of N1 peak, in basal electrodes, between the second and third returns. There were not any significant differences obtained for N1 peak latency, neither for the slope nor for p-NRT, among the returns. The analysis among the electrodes has shown that the apical ones have presented higher N1 amplitudes and p-NRT values, statistically lower than the thresholds of apical electrodes. Responses with Ia type morphology have prevailed for electrodes E10, E15 and E20, and Ic type for electrode E5. In the first return, recovery time of the refractory state of the auditory nerve was in most subjects equals to 1000 Mius for E5, and equals to 2000 Mius for electrodes E5, E10 and E15. In the third return, recovery time of E5 increased to 2000 Mius and in E20 decreased to 1000 Mius, in most subjects. The comparison of the different models has shown that the Cochlear Implant N24 R (CS) has presented the highest amplitudes, the highest slopes and the lowest latencies, and the lowest p-NRT values. CONCLUSION: During the first year of CI use, the electrical stimulation released by intracochlear electrodes did not cause significant changes of ECAP characteristics, except in the increase of N1 peak amplitude.

[Truncated abstract] The present study investigated whether any of the characteristics of the compound action potential (CAP) waveform or the spectrum of the neural noise (SNN) recorded from the cochlea, could be used to examine abnormal spike generation in the type I primary afferent neurones, possibly due to pathologies leading to abnormal hearing such as tinnitus or tone decay. It was initially hypothesised that the CAP waveform and SNN contained components produced by the local action currents generated at the peripheral ends of the type I primary afferent neurones, and that changes in these local action currents occurred due to changes in the membrane potential of these neurones. It was further hypothesised that the lateral olivo-cochlear system (LOCS) efferent neurones regulate the membrane potential of the primary afferent dendrites to maintain normal action potential generation, where instability in the membrane potential might lead to abnormal primary afferent firing, and possibly one form of tinnitus. We had hoped that the activity of the LOCS efferent neurones could be observed through secondary changes in the CAP waveform and SNN, resulting from changes in the membrane potential of the primary afferent neurones. The origins of the neural activity generating the CAP waveform and SNN peaks, and the effects of the LOCS on the CAP and SNN were experimentally investigated in guinea pigs using lesions in the auditory system, transient ischemia and asphyxia, focal and systemic temperature changes, and pharmacological manipulations of different regions along the auditory pathway. ... Therefore, the CAP and SNN are altered by changes in the propagation of the action potential along the primary afferent neurones, by changes in the morphology of the tissues surrounding the cochlear nerve, and by changes in the time course of the action currents. If the CAP waveform is not altered, the amplitude of the 1kHz speak in the spontaneous SNN can be used as an objective measure of the spontaneous firing rate of the cochlear neurones. However, because the SNN contains a complex mixture of neural activity from all cochlear neurones, and the amplitude of the spontaneous SNN is variable, it would be difficult to use the spontaneous SNN alone as a differential diagnostic test of cochlear nerve pathologies. To record extratympanic electrocochleography (ET ECochG) from humans, a custom-designed, inexpensive, low-noise, optically isolated biological amplifier was built. Furthermore, a custom-designed extratympanic active electrode and ear canal indifferent electrode were designed, which increased the signal-to-noise ratio of the ECochG recording by a factor of 2, decreasing the overall recording time by 75%. The human and guinea pig CAP waveforms recorded in the present study appeared similar, suggesting that the origins of the human and guinea pig CAP waveforms were the same, and that experimental manipulations of the guinea pig CAP waveform can be used to diagnose the cause of abnormal human ECochG waveforms in cases of cochlear nerve pathologies.

Différents éléments vasculo-nerveux participent à la constitution de l'angle ponto-cérébelleux. Dans certaines conditions pathologiques dont la genèse est encore imparfaitement connue actuellement, des conflits peuvent apparaître entre des vaisseaux battants autour du tronc cérébral et des nerfs crâniens. L'objectif de ce travail en trois parties distinctes est consacré à certaines bases anatomiques et physiologiques permettant de mieux appréhender ces conflits vasculo-nerveux. La première partie s'intéresse à la morphogenèse du système vertébrobasilaire. La conception d'un logiciel original de reconstruction tridimensionnelle a permis la modélisation de quatre embryons à partir de coupes histologiques. Les images obtenues permettent de confirmer la morphogenèse décrite dans la littérature et jette les bases d'une étude plus exhaustive. La deuxième partie démontre pour la première fois la mobilité physiologique du nerf vestibulo-cochléaire au niveau de l'angle ponto-cérébelleux, par l'utilisation d'une séquence IRM en contraste de phase. Les directions crânio-caudale et antéro-postérieure et leur amplitude ont été étudiées. Ces mouvements sont dépendants de l'onde de pouls. De façon plus générale, ils peuvent être modélisés sous la forme d'une corde oscillant entre le tronc cérébral et le fond du méat acoustique interne. La troisième partie traite d'une étude de faisabilité qui jette les bases informatiques permettant d'apprécier le vieillissement artériel par la variabilité morphologique du point de confluence des artères vertébrales. Au laboratoire, nous avons conçu un programme de normalisation à partir des scanographies de neuf patients. Il autorise ainsi la création d'un tronc cérébral moyen, et la comparaison de la topographie de ces points de confluence. / Several vascular and nervous structures are located within the cerebello-pontine angle. In certain pathological conditions, microvascular compression syndroms may occur, where an artery or a vein is compressing a cranial nerve. The purpose of this work in three parts is to investigate some anatomical and physiological bases of these microvascular compression syndroms. The first part focuses on the vertebrobasilar system morphogenesis. A special designed 3D reconstruction original software allowed us to reformate four human embryos from histological serial sections. The three-dimensional views are confirming the classical features thus creating the basis of a larger study based on multiple embryos. The second part shows for the first time the physiological motion of the vestibulo-cochlear nerve at the level of the cerebello-pontine angle, with the help of a phase-contrast MRI sequence. The cranio-caudal and antero-posterior directions and their amplitudes have been studied. These motions are cardiac-cycle-dependant. We used an "oscillating string" model to explain the VCN motion between the brain stem and the fundus of the internal acoustic meatus. The third part of this work is focused on a preliminary study of the variability of the vertebro-basilar arterial fusion along the lifetime. An original software has been designed and allowing the normalisation from nine post-contrast cerebral CT scanners. A ?mean? brain stem was obtained and visualized in front of nine arterial fusion points.

Introduction: Auditory neuropathy spectrum disorder (ANSD) is a disorder characterized by impaired temporal coding of acoustic signals due to a deficiency in neural synchrony or neural transmission. Despite variations in speech perception outcomes within both patients and studies, current evidence demonstrates that children with ANSD, who use hearing aids (HAs) or cochlear implants (CIs), generally achieve speech perception performance comparable to peers with sensorineural hearing loss (SNHL). However, limited studies have reported factors that have prognostic value for auditory intervention outcomes. The objectives of this doctoral thesis, consisting of three consecutive associated projects on children with ANSD, were (1) to determine factors with predictive value for post-intervention (CIs and/or HAs) outcomes through a retrospective study, (2) to systematically summarize and critically appraise existing evidence of the prognostic value of early auditory electrophysiologic tests and MRI findings for CI outcomes through a systematic review (SR), and (3) to systematically overview, summarize, and critically appraise evidence of CI outcomes through an umbrella review of current SRs (overview of SRs). -- Methods: For the first project, the records of 38 children with ANSD between 5 and 18 years old, 63.20% males, who used CIs (71%) and/or HAs, identified at the Children's Hospital of Eastern Ontario (CHEO) were reviewed. For the second and third projects, the SRs were guided by the PRISMA 2020 statement, and electronic databases were searched without restrictions on language, publication status, or year of publication. In the second project, studies on children with ANSD (including those with cochlear nerve deficiency [CND]), cochleovestibular nerve (CVN) abnormalities, or SNHL reporting the relevance of preoperative and/or postoperative electric compound action potential (eCAP), electric auditory brainstem response (eABR), and/or MRI results to CI outcomes were included. The methodological quality and strength of evidence were assessed using the Crowe Critical Appraisal Tool (CCAT) and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) tool, respectively. In the third project, all SRs that reported CI outcomes in children with ANSD were included. The methodological quality of the selected SRs was evaluated using the Assessment of Multiple Systematic Reviews 2 (AMSTAR-2) checklist, and the risk of bias in evidence was assessed using the Risk of Bias in Systematic Reviews (ROBIS) tool. -- Results: In the retrospective chart review (first project), ages at HL diagnosis and CI activation and the length of follow-up with CI/HA showed a significant relationship with open-set speech perception outcomes (i.e., the scores of Phonetically Balanced Kindergarten [PBK] test with word and phoneme speech materials and Hearing in Noise Test [HINT] in quiet and noise conditions). Using a Forward Linear Multiple Regression Model, the length of follow-up with CI/HA and bilateral amplification showed prognostic value for speech perception performance. In the second project, 25 papers were included in the review. While it was difficult to draw a firm conclusion about the eCAP findings, current evidence strongly supports the prognostic value of eABR and MRI for post-CI speech perception outcomes. According to the eight SRs selected for the third project, children with ANSD achieve CI outcomes comparable to their peers with SNHL. However, in children with postsynaptic ANSD (i.e., those with CND), cochlear nerve hypoplasia is associated with better speech recognition outcomes compared to cochlear nerve aplasia, especially in the absence of additional disabilities and/or medical comorbidities (ADs/MCs). -- Conclusion: Children with ANSD, especially those without cochlear nerve aplasia and ADs/MCs, achieve speech perception outcomes comparable to their peers with SNHL. In addition, age at HL diagnosis, age at CI activation, the length of follow-up with CI/HA, bilateral amplification, and eABR and MRI findings are associated with or have predictive value for intervention outcomes. The findings of the SRs should be interpreted with caution given the low quality of evidence and risk of bias in the studies selected for SRs.