La contribution du stress et de l'hyperactivation dans l'insomnie pendant la ménopause.

Cette thèse s’intéresse à la contribution de facteurs potentiellement associés à l’insomnie durant la ménopause à l’aide de deux études distinctes. La première étude s’appuie sur les données d’une enquête épidémiologique de cinq années auprès de 3 419 adultes à partir desquels un échantillon de 873 femmes âgées de 40 à 60 ans a été sélectionné. Quatre questionnaires portant sur la qualité de sommeil, la sévérité de l’insomnie, la réactivité du sommeil au stress et la prédisposition à l’activation ont été utilisés dans deux volets distincts. Le volet transversal avait pour but de comparer le sommeil entre des femmes pré et postménopausées et d’observer si la réactivité du sommeil au stress et la prédisposition à l’activation étaient des prédicteurs des difficultés de sommeil pour chacun des groupes. Le volet longitudinal avait pour objectif de suivre l’évolution prospective des difficultés de sommeil et d’examiner si ces difficultés de sommeil étaient modérées par les facteurs d’activation et de réactivité pendant la transition ménopausique. Les résultats transversaux montrent que les femmes postménopausées rapportaient une moins bonne qualité de sommeil et une sévérité d’insomnie plus élevée que les femmes préménopausées. Ces difficultés de sommeil étaient prédites par la réactivité du sommeil au stress et la prédisposition à l’activation. Au regard des résultats longitudinaux, ceux-ci indiquent que la transition ménopausique avait un effet négatif sur le sommeil. Toutefois, la réactivité du sommeil au stress et la prédisposition à l’activation ne semblaient pas modérer la relation entre la transition ménopausique et les difficultés de sommeil. D’autres facteurs biologiques liés à la ménopause, tels que les bouffées de chaleur, pourraient être en lien avec le développement des difficultés de sommeil. Toutefois, aucune information sur leurs présences n’était disponible dans cette base de données. C’est pourquoi la seconde étude visait à étudier la contribution de facteurs préexistants (hyperactivation et stress) et biologiques (bouffées de chaleur) dans le développement de l’insomnie pendant la ménopause. Cette étude impliquait le recrutement d’un échantillon de 63 femmes péri et postménopausées (âgées de 45 à 55 ans), classifiées en trois groupes distincts : sans insomnie, avec de l’insomnie ayant commencé lors de la périménopause et avec de l’insomnie ayant commencé au moins 3 ans avant la périménopause. L’admissibilité des participantes était jugée lors d’une entrevue téléphonique, une entrevue face-à-face (questionnaires, entrevue diagnostique) et une nuit d’enregistrement polysomnographique pour détecter d’autres troubles du sommeil. Les ii participantes incluses étaient invitées pour une seconde nuit d’enregistrement afin d’évaluer le sommeil, les bouffées de chaleur et l’activation physiologique (ex. cardiovasculaire). Le sommeil, les bouffées de chaleur, les niveaux d’activation et de stress étaient ensuite évalués durant une semaine à l’aide de mesures subjectives (questionnaires, agenda) et objectives (actigraphie, cortisol salivaire). Selon les résultats, les deux groupes avec insomnie rapportaient une activation somatique et cognitive à l’heure du coucher, un impact des événements de stress diurnes et une fréquence des bouffées de chaleur nocturnes subjectives plus élevés que les femmes sans insomnie. De plus, les femmes avec de l’insomnie précédant la ménopause avaient des taux de cortisol salivaire plus élevés que les femmes avec insomnie récente et celles sans insomnie. Les analyses de médiation ont révélé une relation entre le stress quotidien et les réveils subjectifs, par le biais des bouffées de chaleur et d’activation cognitive au coucher. Néanmoins, les résultats de la nuit d’enregistrement polysomnographique ne montrent aucune différence sur les mesures du sommeil et d’activation entre les trois groupes. L’ensemble des résultats de cette thèse souligne la contribution de facteurs de vulnérabilité psychobiologique dans le développement des difficultés de sommeil pendant la ménopause. D’autres recherches sont encore à effectuer, afin de mieux comprendre l’étiologie de l’insomnie pendant cette période et d’adapter les interventions actuelles à cette population.This thesis investigates the contribution of factors potentially associated with menopausal insomnia using two separate studies. The first study is based on data from a fiveyear epidemiological survey of 3,419 adults from which a sample of 873 women aged 40 to 60 years was selected. Four annual surveys on sleep quality, insomnia severity, sleep reactivity and arousal predisposition were used to address two questions. The purpose of the cross-sectional component was to compare sleep quality and insomnia severity between reproductive and postmenopausal women and to examine whether sleep reactivity and arousal predisposition were predictors of sleep disturbances for each group. The objective of the longitudinal component was to follow the prospective evolution of sleep disturbances and to examine whether these sleep disturbances were moderated by arousal predisposition and sleep reactivity during menopausal transition. Cross-sectional results showed that postmenopausal women reported poorer quality of sleep and higher severity of insomnia than reproductive women. Sleep disturbances were predicted by sleep reactivity and arousal predisposition. The longitudinal results indicated that the menopausal transition had a negative effect on sleep. However, sleep reactivity and arousal predisposition did not appear to moderate the relationship between menopausal transition and sleep disturbances. Other biological factors related to menopause, such as hot flashes, may be related to the development of sleep difficulties. However, no information on their occurrence was available in this database. Therefore, the second study aimed to investigate the contribution of predisposing psychological (arousal and stress) and biological (hot flashes) factors in the development of menopausal insomnia. This study involved the recruitment of a sample of 63 peri and postmenopausal women (aged 45–55 years), classified into three distinct groups: without insomnia, with insomnia that began during the menopausal transition and with insomnia that began at least 3 years before the menopausal transition. Participants’ eligibility was evaluated during a telephone interview, a face-to-face interview (questionnaires, diagnostic interview) and one night’s polysomnography recording to detect other sleep disorders (e.g., sleep apnea). Included participants were then invited for a second night recording to assess sleep, hot flashes and physiological arousal (e.g., cardiovascular). Sleep, hot flashes, arousal and stress levels were then assessed over a one-week period using subjective (questionnaires, diary) and objective (actigraphy, salivary cortisol) measures. The results show that the two groups with insomnia reported higher somatic and cognitive arousal at bedtime, higher impact of daytime stress events, and higher frequency of subjective hot flashes than women without insomnia. In addition, women with premorbid insomnia showed higher salivary cortisol levels at bedtime compared to good sleepers and menopausal insomnia group. Mediation analyses revealed that subjective reports of hot flashes mediated the relationship between daily stress and subjective awakenings in the three groups, whereas cognitive pre-sleep arousal mediated this relationship for the insomnia groups only. However, results from the physiological recording showed no differences in sleep and arousal measurements between the three groups. Overall results of this thesis underline the contribution of psychobiological vulnerability factors in the development of sleep difficulties during the menopause. Further research needs to be carried out to better understand the etiology of menopausal insomnia and to adapt current interventions to this population

L’érythropoïétine cérébrale: une nouvelle molécule contre la dépression hypoxique chez le nouveau-né et l’adulte

Durant l’hypoxie, l’érythropoïétine (Epo) agit sur le système nerveux central (SNC) pour réduire la dépression respiratoire. Mais nous ignorons si la présence de l’Epo endogène dans le SNC agit comme un stimulant respiratoire sexe-spécifique chez le nouveau-né et l’adulte, en hypoxie et en hypercapnie. Des souris âgées de 9 jours et de 3 mois reçoivent une injection intracisternale de l’antagoniste de l’Epo (sEpoR) ou d’un contrôle. 24h après, nous enregistrons les paramètres métaboliques et ventilatoires par pléthysmographie avec une période en normoxie, hypercapnie et différents cycles d’hypoxie. D’après nos résultats, sEpoR produit une dépression respiratoire en normoxie et en hypoxie, en raison d’une diminution de la fréquence respiratoire chez la femelle et du volume courant chez le mâle adulte et nouveau-né. De plus, une différence sexe-spécifique est remarquée en hypoxie seulement chez l’adulte. Cependant, ces résultats ne sont pas retrouvés en hypercapnie. L’Epo endogène est donc un important stimulant respiratoire en hypoxie.The erythropoietin (Epo) acts on the central nervous system (CNS) to reduce respiratory depression. However, we do not know whether the presence of endogenous Epo in the CNS acts as a respiratory stimulant sex-specific in newbons and adults, in hypoxia and in hypercapnia. Old mice 9 days and 3 months receive intracisternal injection of the antagonist Epo (sEpoR) or a control. 24 hours after we record the metabolic and ventilatory parameters by plethysmography with a period in normoxie, different cycles of hypoxia and in hypercapnia. According to our results, sEpoR produce a respiratory depression in normoxie and in hypoxia, due to a decrease in the respiratory frequency in the female and tidal volume in the male all both ages. In normoxia, sex-specific difference is noticed in two ages, but in hypoxia, only adults. However, this effect is not present in hypercapnia. Endogenous Epo is an important respiratory stimulant in hypoxia

Sleep disturbances during the menopausal transition : the role of sleep reactivity and arousal predisposition

Background Sleep disturbances are common during the menopausal transition and several factors can contribute to this increased incidence. This study examined the association between sleep reactivity, arousal predisposition, sleep disturbances, and menopause. Methods Data for this study were derived from a longitudinal, population-based study on the natural history of insomnia. A total of 873 women (40–60 years) were divided into two groups according to their menopausal status at baseline: reproductive (n = 408) and postmenopausal (n = 465). Participants were evaluated annually throughout the five-year follow-up period. Four questionnaires were used to examine sleep quality, insomnia severity, sleep reactivity, and arousal predisposition. The data were analyzed using two approaches: cross-sectional with a multivariate analysis and binary regression, and longitudinal with a linear mixed models using menopausal groups (3) x time (5) design. Results Cross-sectional analyses showed that postmenopausal women reported significantly more severe insomnia and poorer sleep quality than reproductive women. Sleep reactivity and arousal predisposition were significant predictors of sleep disturbances. Longitudinal analyses revealed increased sleep disturbances in the two years before and after the menopausal transition. Sleep reactivity and arousal predisposition did not moderate the temporal relationship between menopausal transition and sleep disturbances. Conclusion More sleep disturbances were reported during the menopausal transition, but those difficulties were not explained by sleep reactivity and arousal predisposition. These results suggest the involvement of other psychophysiological factors in the development of sleep disturbances during the menopause

Evaluation of a virtual agent to train medical students conducting psychiatric interviews for diagnosing major depressive disorders

Background: A psychiatric diagnosis involves the physician's ability to create an empathic interaction with the patient in order to accurately extract semiology (i.e., clinical manifestations). Virtual patients (VPs) can be used to train these skills but need to be evaluated in terms of accuracy, and to be perceived positively by users. Methods: We recruited 35 medical students who interacted in a 35-min psychiatric interview with a VP simulating major depressive disorders. Semiology extraction, verbal and non-verbal empathy were measured objectively during the interaction. The students were then debriefed to collect their experience with the VP. Results: The VP was able to simulate the conduction of a psychiatric interview realistically, and was effective to discriminate students depending on their psychiatric knowledge. Results suggest that students managed to keep an emotional distance during the interview and show the added value of emotion recognition software to measure empathy in psychiatry training. Students provided positive feedback regarding pedagogic usefulness, realism and enjoyment in the interaction. Limitations: Our sample was relatively small. As a first prototype, the measures taken by the VP would need improvement (subtler empathic questions, levels of difficulty). The face-tracking technique might induce errors in detecting non-verbal empathy. Conclusion: This study is the first to simulate a realistic psychiatric interview and to measure both skills needed by future psychiatrists: semiology extraction and empathic communication. Results provide evidence that VPs are acceptable by medical students, and highlight their relevance to complement existing training and evaluation tools in the field of affective disorders.Bordeaux Region Aquitaine Initiative for NeurosciencePhénotypage humain et réalité virtuelleInitiative d'excellence de l'Université de Bordeau

Chronic overexpression of cerebral Epo improves the ventilatory response to acute hypoxia during the postnatal development

Clinicians observed that the treatment of premature human newborns for anemia with erythropoietin (Epo) also improved their respiratory autonomy. This observation is in line with our previous in vitro studies showing that acute and chronic Epo stimulation enhances fictive breathing of brainstem-spinal cord preparations of postnatal day 3-4 mice during hypoxia. Furthermore, we recently reported that the antagonization of the cerebral Epo (by using the soluble Epo receptor; sEpoR) significantly reduced the basal ventilation and the hypoxic ventilatory response of 10 days old mice. In this study, we used transgenic (Tg21) mice to investigate the effect of the chronic cerebral Epo overexpression on the modulation of the normoxic and hypoxic ventilatory drive during the post-natal development. Ventilation was evaluated by whole body plethysmography at postnatal ages 3 (P3), 7 (P7), 15 (P15) and 21 (P21). In addition Epo quantification was performed by RIA and mRNA EpoR was evaluated by qRT-PCR. Our results showed that compared to control animals the chronic Epo overexpression stimulates the hypoxic (but not the normoxic) ventilation assessed as VE/VO2 at the ages of P3 and P21. More interestingly, we observed that at P7 and P15 the chronic Epo stimulation of ventilation was attenuated by the down regulation of the Epo receptor in brainstem areas. We conclude that Epo, by stimulating ventilation in brainstem areas crucially helps tolerating physiological (e.g., high altitude) and/or pathological (e.g., respiratory disorders, prematurity, etc.) oxygen deprivation at postnatal ages

A Virtual Patient to Train Semiology Extraction and Empathic Communication Skills for Psychiatric Interview

Psychiatric diagnostic relies on physician’s ability to create an empathic interaction with the patient (i.e., engage the patient in the conversation with empathic sentences, while keeping an emotional distance) in order to accurately extract semiology (i.e., clinical manifestations). Virtual patients (VPs) offer new ways to train these skills but need to be validated in terms of accuracy to measure the skills of interest, and be perceived positively by its users. We recruited 34 medicine students, who interacted with a VP suffering from depressive disorders. Results suggest good abilities for the students to use empathic sentences to communicate with the VP, but results varied regarding semiology extraction, students having a specialty in psychiatry performing better than their counterparts. Additionally, results suggest that students managed to keep an emotional distance during the interaction with the VP, but they let their emotions out when answering semiology questions. Positive feedbacks and limitations raised by students during debriefing interviews provide suggestions for improvements and ideas for future works