Os potenciais evocados auditivos de tronco encefálico (PEATE) são um instrumento clínico muito útil na avaliação da maturação das vias auditivas em crianças nascidas pré-termo. Objetivos: Observar a maturação da via auditiva pela análise PEATE em crianças nascidas prétermo em três idades (4, 12 e 20 meses de idade). Casuística e Método: Coorte, individual, observacional, comparativo e contemporâneo. O fator em estudo foi crianças nascidas pré-termo e o desfecho à observação da maturação da via auditiva neste grupo, pela análise PEATE, em três avaliações (aos 4, 12 e 20 meses de idade), precedido de avaliação otorrinolaringológica e audiológica com objetivo de garantir que não apresentavam alteração auditiva. Resultados: Ingressaram 73 crianças pré-termo. Não foi encontrada diferença estatística (P>0,05) na comparação dos resultados entre os gêneros, bem como interaural. Houve diferença estatiticamente significante entre idade gestacional, as latências absolutas e intervalos interpicos nas três avaliações realizadas, ocorrendo uma diminuição das latências com o aumento da idade. Verificamos que a maturação da onda I foi mais rápida, e a maturação da onda V foi mais lenta. Podemos perceber que a maturação da via auditiva até o tronco encefálico segue o sentido caudorostral, sendo a da via periférica mais precoce, e a da rostral, mais tardia. Conclusão: Com base nos achados deste estudo, recomendamos que a aplicação do procedimento de avaliação audiológica através do PEATE em crianças nascidas pré-termo, pelo menos até os 20 meses de idade, seja realizado levando-se em conta a idade gestacional a fim de se obter análises fidedignas. / Brainstem Auditory Evoked Potential (BAEP) is a very useful clinical instrument in the evaluation of the auditory pathways maturation in preterm children. Objective: To observe the maturation of the auditory pathway with the use of the BAEP analysis in preterm children at three different ages (four, 12 and 20 months). Casuistry and Method: Group, individual, observational, comparative and contemporary. Preterm children and the outcome to observation of the auditory pathway maturation by the BAEP analysis in three evaluations (at 4, 12 and 20 months of age) were studied. The procedures were preceded by otolaryngological and auditory evaluation with the objective to guarantee the non presence of auditory alteration. Results: Seventy-three preterm children participated in the study. Statistically significant difference was not found (P> 0,05) in the comparison between genders and between ears. There was a statistically significant difference among gestational ages, absolute latencies and interpic intervals in the three evaluations conducted, occurring a reduction of latencies with age increase. We verified that maturation of wave I was faster and the maturation of wave V was slower. We could perceive that the maturation of the auditory pathway up to the brainstem follows the caudorostral direction, being the peripheral pathway more precocious and the rostral pathway more delayed. Conclusion: Based on the findings of this study, we recommend the application of the audiological evaluation procedure using BAEP in preterm children, at least until 20 months of age, by taking into account the gestational age in order to obtain reliable analyses.

Os potenciais evocados auditivos de tronco encefálico (PEATE) são um instrumento clínico muito útil na avaliação da maturação das vias auditivas em crianças nascidas pré-termo. Objetivos: Observar a maturação da via auditiva pela análise PEATE em crianças nascidas prétermo em três idades (4, 12 e 20 meses de idade). Casuística e Método: Coorte, individual, observacional, comparativo e contemporâneo. O fator em estudo foi crianças nascidas pré-termo e o desfecho à observação da maturação da via auditiva neste grupo, pela análise PEATE, em três avaliações (aos 4, 12 e 20 meses de idade), precedido de avaliação otorrinolaringológica e audiológica com objetivo de garantir que não apresentavam alteração auditiva. Resultados: Ingressaram 73 crianças pré-termo. Não foi encontrada diferença estatística (P>0,05) na comparação dos resultados entre os gêneros, bem como interaural. Houve diferença estatiticamente significante entre idade gestacional, as latências absolutas e intervalos interpicos nas três avaliações realizadas, ocorrendo uma diminuição das latências com o aumento da idade. Verificamos que a maturação da onda I foi mais rápida, e a maturação da onda V foi mais lenta. Podemos perceber que a maturação da via auditiva até o tronco encefálico segue o sentido caudorostral, sendo a da via periférica mais precoce, e a da rostral, mais tardia. Conclusão: Com base nos achados deste estudo, recomendamos que a aplicação do procedimento de avaliação audiológica através do PEATE em crianças nascidas pré-termo, pelo menos até os 20 meses de idade, seja realizado levando-se em conta a idade gestacional a fim de se obter análises fidedignas. / Brainstem Auditory Evoked Potential (BAEP) is a very useful clinical instrument in the evaluation of the auditory pathways maturation in preterm children. Objective: To observe the maturation of the auditory pathway with the use of the BAEP analysis in preterm children at three different ages (four, 12 and 20 months). Casuistry and Method: Group, individual, observational, comparative and contemporary. Preterm children and the outcome to observation of the auditory pathway maturation by the BAEP analysis in three evaluations (at 4, 12 and 20 months of age) were studied. The procedures were preceded by otolaryngological and auditory evaluation with the objective to guarantee the non presence of auditory alteration. Results: Seventy-three preterm children participated in the study. Statistically significant difference was not found (P> 0,05) in the comparison between genders and between ears. There was a statistically significant difference among gestational ages, absolute latencies and interpic intervals in the three evaluations conducted, occurring a reduction of latencies with age increase. We verified that maturation of wave I was faster and the maturation of wave V was slower. We could perceive that the maturation of the auditory pathway up to the brainstem follows the caudorostral direction, being the peripheral pathway more precocious and the rostral pathway more delayed. Conclusion: Based on the findings of this study, we recommend the application of the audiological evaluation procedure using BAEP in preterm children, at least until 20 months of age, by taking into account the gestational age in order to obtain reliable analyses.

After the findings were reported for the Women’s Health Initiative (WHI) study in the past decade, there has been a significant decline in the overall use of hormone replacement therapy (HRT) among women. However, there are still millions of middle-aged, menopausal women in the U.S. who are currently undergoing hormone therapy. Their reasons for continuing treatment include relief of severe menopausal symptoms, aid in the management of osteoporosis and reduction in the risk of colon cancer (Ness et al., 2005). The purpose of the following investigation was to evaluate the impact of HRT on the central and peripheral auditory systems both during and after treatment. Over the course of the study, hormone treatments were administered to female aging CBA/CaJ mice to observe what effects estrogen (E) and progestin (P) have on the peripheral and central auditory systems. Female CBA/CaJ middle age mice were ovariectomized and placed into 4 HRT groups (E, P, E+P and Placebo [Pb]). Hormone treatment lasted 6 months followed by a recovery/washout period of 1 month. During this time, electrophysiology tests such as auditory brainstem responses (ABR) and ABR gap in noise (GIN) were used to measure neural activity for the auditory nerve and brainstem. Distortion product otoacoustic emission (DPOAE) testing was also implemented to assess the functional status of the outer hair cells (OHC) and their ability to amplify sound in the cochlea. After 6 months of treatment, animals treated with E exhibited the least amount of changes in ABR thresholds and ABR GIN amplitudes than any other subject groups. Interestingly, P animals exhibited an abrupt increase in ABR thresholds only 3 months after treatment; however, for ABR GIN amplitude levels a progressive reduction observed throughout the study. E+P and Pb animals showed signs of accelerated age-related hearing loss (ARHL) with significantly elevated ABR thresholds and dwindling ABR GIN amplitude levels. No significant signs of recovery were observed for any of the hormone groups. Therefore, in the present murine investigation, the effects of HRT were long lasting. To further expand on the results obtained for the electrophysiology tests, molecular biology experiments were performed to evaluate the expression of IGF-1R and FoxO3 in the cochlea during hormone therapy, from both in vitro and in vivo perspectives. Both genes play significant roles in the PI3K/AKT pathway and were specifically chosen because of their role in anti-apoptotic responses and cell survival. It was hypothesized that E attenuates the effects of ARHL via the PI3K/AKT pathway by up-regulating IGF-1R and FoxO3 to counteract the effects of oxidative stress in the aging mammalian cochlea. qPCR experiments were performed with stria vascularis (SV) lateral wall cells extracted from the cochlea of each animal in the hormone groups post-treatment (in vivo) and in SVK-1 cells treated with HRT over various lengths of time (in vitro) to evaluate the expression levels of IGF-1R and FoxO3. In-vivo experiments showed that the E-treated animals had significantly higher IG-1R levels compared to the other subject groups after treatment was discontinued. Similarly, IGF-1R levels steadily increased for E-treated SVK-1 cells over the course of hormone therapy, compared to P and E+P cells. FoxO3 expression, on the other hand, declined for all of the hormone-treated cells groups, relative to control SVK-1 cells (in vitro), and no statistical differences were detected for FoxO3 levels among the post-treatment animals (in vivo). These findings indicate that there is cross talk between E and IGF-1R involving the PI3K/AKT pathway, which contributes to the delayed onset of ARHL observed during HRT with E. Meanwhile, FoxO3 may not play a role in neuro-protective properties in the cochlea during HRT, as initially hypothesized.

A brainstem-related abnormality in respiratory control appears to be one of the most compelling mechanisms for sudden infant death syndrome (SIDS). The elements calcium, copper, iron, potassium, magnesium, sodium, phosphorus, sulfur, and zinc were analyzed by inductively coupled plasma atomic emission spectroscopy in the brainstem of 30 infants who died from SIDS and 10 infants who died from other causes (control). No differences were found between SIDS and control for any element except for more calcium in the SIDS group. A multivariate analysis of the data failed to group the majority of SIDS and control subjects in different clusters. Further research is required to determine the biological significance of the higher calcium found in the SIDS group.,

Background: Iron deficiency, anemia, and iron excess have been associated with altered hearing functions in children and adults. Animal studies suggest that iron deficiency during pregnancy negatively affect fetal auditory development. The relationship between maternal iron status and auditory functions in healthy term newborns has not been clearly elucidated among humans. The goal of this pilot study was to determine the relationship between markers of iron status during pregnancy and brainstem auditory function in healthy neonates. Methods: Pregnant women who gave birth at the Montfort Hospital were recruited to take part in this study (n=6). Within two weeks after birth, their newborn’s hearing function was assessed by wave amplitude, latency and inter-latency from the Auditory Brainstem Response (ABR) test. Markers of iron status, namely hemoglobin (Hb) and mean corpuscular volume (MCV), were collected retrospectively for the first and second trimester from the women’s medical chart. Results: Overall, no significant relationship was observed between maternal Hb and MCV concentrations and newborns auditory function. Although two significant Spearman correlations were observed (MCV and inter-latency I-V; r=0.87; p=0.005 and Hb and amplitude V; r=0.89; p=0.04), these findings may be due to chance because of multiple testing and the small sample size. Conclusion: Although iron is a key nutrient involved in the brain and auditory system development, we were not able to demonstrate a relationship between iron status during pregnancy and newborn hearing function. Prospective or intervention studies with a larger sample size and with more specific iron markers (ex. ferritin) are required to confirm these findings.

Les circuits neuronaux responsables du sommeil paradoxal (SP) et de l'atonie musculaire qui le caractéristique sont l'objet de nombreuses recherches expérimentales, notamment en raison de l'existence de plusieurs pathologies invalidantes associées. Cette thèse de Neurobiologie s'inscrit plus spécifiquement dans la description anatomique et fonctionnelle du réseau neuronal responsable de l'atonie musculaire et son potentiel dysfonctionnement dans les troubles comportementaux en SP (RBD, REM sleep Behavior Disorder). Pour ce faire, nous avons combiné plusieurs techniques faisant appel à la neuroanatomie fonctionnelle, au traçage rétrograde de voies nerveuses, à l'hybridation in situ à la polysomnographie et à l'inactivation irréversible de populations neuronales ciblées moléculairement à l'aide de virus adéno-associés contenant des short hairpin RNAs (AAV-shRNA) chez le rat libre de ses mouvements. Nous avons ainsi montré que, contrairement à l'hypothèse généralement admise, le noyau sublatérodorsal pontique (SLD) n'est pas le générateur du SP. En effet, l'inactivation neurochimique de ses neurones glutamatergiques ou sa lésion totale diminuent les quantités de SP sans le supprimer, indiquant que le SLD n'est pas suffisant pour la genèse du SP. En revanche, ces expériences démontrent son implication directe dans la mise en place de l'atonie musculaire lors du SP. En effet, la déconnexion neurochimique des neurones glutamatergiques du SLD provoque pendant le SP l'apparition intermittente de tonus musculaire accompagné de comportements moteurs anormaux. En parallèle, nos travaux de thèse ont permis d'apporter des données expérimentales nouvelles sur la localisation, au sein de la formation réticulée bulbaire ventrale et non dans la moelle épinière, des interneurones GABA/glycine responsables de l'hyperpolarisation des motoneurones somatiques pendant le SP. En effet, ces neurones réticulaires sont exclusivement recrutés pendant le SP et envoient des projections monosynaptiques inhibitrices vers les motoneurones somatiques lombaires. De plus, leur déconnexion neurochimique ciblée déclenche des comportements moteurs anormaux sous-tendus par le maintien d'un tonus musculaire irrégulier pendant le SP. L'analyse actimétrique de ces comportements moteurs oniriques induits expérimentalement montre qu'ils sont très semblables à ceux observés après l'inactivation du SLD et à ceux décrits chez les patients RBD. Les données rapportées dans cette thèse permettent de mieux comprendre les mécanismes neurobiologiques générant le SP et ceux contribuant au contrôle moteur pendant le SP. Par la même occasion, nos travaux ont permis de valider deux modèles rongeurs du RBD humain, ouvrant ainsi des perspectives expérimentales pour l'élaboration de traitements ciblés de cette pathologie affectant le SP / A growing number of studies investigate the neuronal network responsible for paradoxical (PS) (or REM) sleep genesis and muscle atonia specific of this sleep state. The aim of this thesis was to characterize at the anatomical and functional levels the populations of neurons involved in generating muscle atonia during PS and their potential failure in REM sleep Behavior Disorder (RBD). For this purpose, we combined a large panel of experimental techniques such as functional neuroanatomy, retrograde tract-tracing, in situ hybridization, polysomnography and irreversible inactivation of genetically-targeted neurons with short-hairpin RNAs introduced in viral adenovectors (AAV-shRNA) in freely moving rats. We thus demonstrated for the first time that, in contrast to the currently admitted hypothesis, the pontine sublaterodorsal nucleus (SLD) is not the PS generator, since genetic inactivation of its glutamatergic neurons or its whole lesion diminish the quantities of but do not eliminate PS. This indicates that the SLD is not sufficient for PS generation. In contrast, our experiments clearly show that the SLD is responsible for muscle atonia because the specific inactivation of its glutamatergic neurons induces an irregular muscle tone concomitant to atypical motor behaviors during PS. In addition, we achieved original data about the location within the ventral medullary reticular formation, and not at spinal levels as often believed, of the glycine/GABA interneurons managing the sustained hyperpolarization of somatic motoneurons during PS. We indeed observed that these medullary neurons are selectively recruited during PS and send monosynaptic inhibitory efferents to the lumbar somatic motoneurons. Furthermore, their genetic inactivation is followed by an increase of abnormal motor behaviors underpinned by a sustained, although irregular, muscle tone. The actimetric analysis of these oneiric experimentally induced behaviors reveals that they are very similar to those observed after SLD inactivation or those reported in RBD patients. Taken together, data harvested during this Thesis help us to better understand the complex neurobiological mechanisms generating PS or specifically contributing to the control of the motor system during PS. At the same time, we validated two rodent models closely mimicking human RBD and thus opening new research fields for the development of targeted treatments for this pathology affecting REM sleep

Cette thèse porte sur la perception visuelle, auditive et audiovisuelle des voyelles nasales [ɑ̃] (« lent »),[ɔ̃] (« long ») et [ɛ̃] (« lin ») par des adultes devenus sourds, implantés cochléaires et implantés dutronc cérébral. L’étude sur la perception visuelle des voyelles, auprès de 22 adultes devenus sourds,redéfinit les sosies labiaux des voyelles nasales et propose une mise à jour de la classification desvisèmes. Trois études sur l’identification auditive des voyelles nasales auprès de 82, 15 et 10 adultesimplantés cochléaires mettent en évidence leur difficulté à reconnaitre les trois voyelles nasales, qu’ilsperçoivent comme des voyelles orales. Les analyses acoustiques et perceptives suggèrent que lesadultes implantés cochléaires s’appuient sur les informations fréquentielles des deux premiers picsspectraux mais négligent les informations d’intensité relative de ces pics. D’après l’étude menéeauprès de 13 adultes implantés du tronc cérébral, des informations acoustiques linguistiques sonttransmises par l’implant du tronc cérébral mais la fusion entre les informations auditives et visuellespourrait être optimisée pour l’identification des voyelles. Enfin, une enquête auprès de 179orthophonistes pointe le besoin d’une information sur la définition phonétique articulatoire actualiséedes voyelles [ɑ̃] et [ɛ̃]. / This thesis focuses on the visual, auditory and auditory-visual perception of french nasal vowels [ɑ̃](« lent »), [ɔ̃] (« long ») and [ɛ̃] (« lin ») by Cochlear Implant (CI) and Auditory Brainstem Implant(ABI) adults users. The study on visual perception of vowels, with 22 deafened adults, redefines thelip configuration of french nasal vowels and provides an update of the classification of vocalic visualphonemes. Three studies on auditory identification of nasal vowels with 82, 15 and 10 CI usershighlight their difficulty in recognizing the three nasal vowels, which they perceive as oral vowels.Acoustic and perceptual analyzes suggest that adults with CI rely on frequency informations of thefirst two spectral peaks but miss the informations of relative intensity of these peaks. The study with13 ABI users show that some linguistic acoustic cues are transmitted by the ABI but the fusion ofauditory and visual features could be optimized for the identification of vowels. Finally, a survey of179 Speech Language and Hearing Therapists show the need of an update on the phonetic articulationof french nasal vowels [ɑ̃] and [ɛ̃].

L’hyperacousie est définie comme une hypersensibilité aux sons d’intensité modérée. Il s’agit d’un trouble de la perception auditive qui a des répercussions néfastes sur la qualité de vie des patients. Un mécanisme impliquerait la modification du gain central des neurones auditifs centraux sous l'influence des régions cérébrales non auditives. Toutefois, la question de l'endroit où ces anomalies surviennent dans le système auditif reste ouverte, plus particulièrement lorsque l'hyperacousie survient sans perte auditive neurosensorielle. Nous avons utilisé un modèle animal d’hyperacousie réversible et sans perte audiométrique, induit par injection aigue de salicylate. Nous avons observé un raccourcissement significatif de la latence des ondes III et IV des PEA aux fréquences inférieures à 10 kHz corrélé à une diminution de 15 dB du seuil de réflexe de sursaut acoustique à basses fréquences. La diminution de l’efficacité du réflexe musculaire de l’oreille moyenne suite à l’injection de salicylate semble trop modérée pour expliquer l'hyperacousie, qui semble plutôt être causée par une altération du codage temporo-spatial de la sonie dans le tronc cérébral. L’hyperacousie fait partie des troubles de perception retrouvés dans la migraine, nous avons étudié les changements physiologiques auditifs dans un modèle animal de migraine induit par administration extradurale de soupe inflammatoire. Dans un contexte migraineux, aucun des paramètres modifiés par le salicylate n'est affecté de sorte que l'hypersensibilité au son est plutôt une phonophobie, réponse émotionnelle au son résultant d’une activation anormale du système limbique et du système nerveux autonome. / Hyperacusis is a disorder of loudness perception defined as decreased tolerance to ordinary environmental sounds that are felt as disagreeable, or even, unbearably painful. The idea that hyperacusis is underpinned by an increase in central auditory gain is now widely invoked. Besides, the neural bases of this gain abnormality remain unclear, as well as more generally the mechanisms of loudness perception. We used an animal model of reversible and hearing-loss-free hyperacusis induced by acute salicylate injection. We observed a significant shortening of the latency of ABR waves III and IV at frequencies below 10 kHz correlated to a 15 dB decrease of the threshold of acoustic startle reflex at low frequencies and without sensorineural hearing loss. The decreased effectiveness of middle ear muscle reflex following salicylate injection seems too moderate for explaining hyperacusis, which is more likely produced by impaired temporo-spatial loudness coding with a brainstem origin. Hyperacusis is one of the perceptual disorders found in migraine. We studied auditory physiological changes in an animal model of migraine induced by extradural administration of inflammatory soup. In a migraine context, none of the salicylate-induced changes was observed so that the reaction to sound is likely closer to phonophobia, an emotional response to sound resulting from abnormal activation of the limbic system and the autonomic nervous system.

Background: The efferent dorsal motor nucleus of the vagal nuclei complex may degenerate early in the course of Parkinson’s disease (PD), while efferent nucleus ambiguous, the principal source of parasympathetic vagal neurons innervating the heart, and afferent somatosensory nuclei remain intact.

Ventrolateral medullary neurons have important roles in cardiorespiratory coordination. A rostral extension of the ventral respiratory column (RVRC), including the retrotrapezoid nucleus (RTN), has neurons responsive to local perturbations of CO2 / pH. Respiratory-modulated firing patterns of RVRC neurons are attributed to influences of more caudal (CVRC) neurons. These circuits remain poorly understood. This study addressed the hypothesis that both local interactions and influences from the CVRC shape rostral neuron discharge patterns and responses. Spike trains from 294 rostral and 490 caudal neurons were recorded with multi-electrode arrays along with phrenic nerve activity in 14 decerebrate, vagotomized cats. Overall, 214 rostral and 398 caudal neurons were respiratory-modulated; 124 and 95, respectively, were cardiac-modulated. Subsets of these neurons were evaluated for responses to sequential, selective, transient stimulation of central and peripheral chemoreceptors and arterial baroreceptors. In 5 experiments, Mayer wave-related oscillations (MWROs) in neuronal firing rates were evoked, enhanced, or reduced following central chemoreceptor stimulation. Overall, 174 of the rostral neurons (59.5%) had short- time scale correlations with other RVRC neurons. Of these, 49 triggered cross-correlograms with RVRC targets yielding 330 offset features indicative of paucisynaptic actions from a total of 2,884 rostral pairs evaluated. Forty-nine of the CVRC neurons (10.0%) were triggers in 142 CVRC-RVRC correlograms - from a total of 8,490 - with offset features indicative of actions on RVRC neurons. Correlation linkage maps support the hypothesis that local circuit mechanisms contribute to the respiratory and cardiac modulation of RVRC neurons and their responses to chemoreceptor and baroreceptor challenges.