Introduction: Assessing brain maturation in preterm neonates is essential for the health of the neonates. Machine learning methods have been introduced as a prospective assessment tool for neonatal electroencephalogram(EEG) signals. Explainable methods are essential in the medical field, and more research regarding explainability is needed in the field of using machine learning for neonatal EEG analysis. Methodology: This thesis develops an explainable machine learning model that estimates postmenstrual age in very preterm neonates from EEG signals and investigates the importance of the features used in the model. Dual-channel EEG signals had been collected from 14 healthy preterm neonates of postmenstrual age spanning 25 to 32 weeks. The signals were converted to amplitude-integrated EEG (aEEG) and a list of features was extracted from the signals. A regression tree model was developed and the feature importance of the model was assessed using permutation importance and Shapley additive explanations. Results: The model had an RMSE of 1.73 weeks (R2=0.45, PCC=0.676). The best feature was the mean amplitude of the lower envelope of the signal, followed by signal time spent over 100 µV. Conclusion: The model is performing comparably to human experts, and as it can be improved in multiple ways, this result indicates a promising outlook for explainable machine learning model applications in neonatal EEG analysis.

At the age of 13, the 2:1 ratio becomes evident. It entails the fact that after puberty, twice as many females as compared to males suffer from depressive episodes. Much research has been conducted to highlight key contributing factors that aid in the onset and the timing of the 2:1 ratio. Many researchers emphasize hormonal influences and the onset of puberty as key contributors, with theories such as the gonadic theory andthe interactional hypothesis both highlighting the role of hormones in the existence and the emergence of the 2:1 ratio during adolescence. Furthermore, a large variety of researchers emphasize females increased stress sensitivity and stress reactivity as key contributors to the 2:1 ratio. Critically, research concerning hormonal- and stress-related factors will be included. However, an additional focus will be on neurodevelopmental sex differences. This, as brain-based sex differences have been paid too little attention in theories and models concerning the emergence of the 2:1 ratio during adolescence. Results from research conducted to unravel the mystery of sex differences within the adolescent brain emphasize the impact of sex hormones on the maturational sexual differentiation occurring within the adolescent brain. It has been hypothesized that increases in female adolescent depression might occur in accordance with upsurges in peripheral estrogen levels, during puberty. This seems to suggest that there is an interaction between the effects of circulating ovarian hormones in relation to both sexual differentiation in brain organization and depression susceptibility. Hence, the point of this essay is to delineate key contributing factors that potentially govern the existence and onset of the 2:1 ratio during adolescence by emphasizing the areas of (a) sex-based neurodevelopmental factors, (b) hormonal factors and (c) stress-related factors.

One major reason of CNS pharmacotherapy's impediment is the existence of "barriers" between blood and CNS, especially the Blood-Brain Barrier (BBB), a neurovascular structure localized at the level of brain microvasculature. Main factors responsible for this barrier function are drug efflux transporters type ABC (ATP-Binding Cassette) and SLC (SoLute Carrier) expressed at BBB level and known to be at the origin of multi-drug resistance phenomenon. Recent researches aim at unraveling the signaling mechanisms regulating these transporters in order to modulate their activity and improve pharmacotherapy in brain diseases. For years, these transporters have been studied in adult organism. But, there is a wide spread belief that the BBB in embryo, fetus, new born and infant is "immature", implying caution in giving drugs to infants. However, current knowledge on the functional status of the BBB in immature organism remains very limited.This study was performed in the aim of understanding: 1) The ontogenesis of ABC and SLC transporters during brain maturation, 2) the functional role of four BBB drug efflux transporters (P-glycoprotein (P-gp), Breast Cancer Resistance Protein (bcrp), Organic Anion Transporter 3 (oat3), and Transporting Peptide 1a4 (oatp1a4) transporters) in children's brain, and 3) the mechanisms that regulate their functional expression under normal and pathological conditions, mostly under inflammatory conditions, because indeed alterations in structural and functional components of the BBB have been reported in a long list of CNS pathologies in adults. Our results showed changing properties of the BBB during ontogenesis, as well as an age-related differential regulation of BBB drug efflux transporters under normal and inflammatory conditions.These findings highlight the importance of considering an age-related response of CNS to drugs and of taking into account the specific properties of juvenile BBB during definition of therapeutic strategies designed to treat childhood brain diseases, and this in the clinical perspective of developing new drugs with enhanced efficacy in children's CNS.

L’échec thérapeutique des maladies cérébrales est lié, entre autres, à la présence de barrières entre le sang et le Système Nerveux Central (SNC), en particulier la Barrière Hémato-Encéphalique (BHE). La BHE est une structure neuro-vasculaire localisée au niveau des MicroVaisseaux Cérébraux (MVC) limitant l’entrée des molécules thérapeutiques dans le cerveau. Ce rôle barrière est dû à plusieurs facteurs, dont principalement, l’existence du côté luminal et/ou abluminal de la BHE de plusieurs transporteurs d’efflux, dont les transporteurs de type ABC (ATP Binding Casette) et SLC (SoLute Carrier) et qui sont à l’origine des phénomènes de résistance aux médicaments. Les études de recherche actuelles visent à identifier les voies de signalisation régulant l’activité de ces protéines d’efflux afin d’optimiser la pharmacothérapie cérébrale. Mais la majorité de ces études sont effectuées chez l’adulte. Très peu de données existent chez l’enfant.Cette étude a été réalisé dans la perspective de 1) Etudier l’ontogenèse des transporteurs ABC et SLC de la BHE au cours de la maturation cérébrale, 2) Elucider le rôle fonctionnel de quatre transporteurs d’efflux ((P-glycoproteine (P-gp), Breast Cancer Resistance Protein (bcrp), Organic Anion Transporter 3 (oat3), and Transporting Peptide 1a4 (oatp1a4) transporters) dans le cerveau des enfants et 3) Elucider les mécanismes qui régulent leur expression fonctionnelle dans des conditions normales et pathologiques, notamment inflammatoires, parce que des modifications dans les composantes structurales et fonctionnelles de l'unité neurovasculaire ont été rapportées dans une longue liste de pathologies du SNC chez les enfants et les adultes. Nos résultats ont montré l’existence de différences fonctionnelles, en terme de passage de molécules, entre la BHE pédiatrique et celle adulte. De plus, cette étude a mis en évidence une régulation différentielle liée à l'âge des transporteurs d'efflux de médicaments de la barrière dans des conditions normales et inflammatoires.Ces résultats fournissent des preuves sur l’intérêt de prendre en compte les propriétés spécifiques de la BHE pédiatrique et la distinguer de la BHE adulte lors des définitions des stratégies thérapeutiques destinées à traiter les maladies cérébrales chez les enfants. / One major reason of CNS pharmacotherapy’s impediment is the existence of “barriers” between blood and CNS, especially the Blood-Brain Barrier (BBB), a neurovascular structure localized at the level of brain microvasculature. Main factors responsible for this barrier function are drug efflux transporters type ABC (ATP-Binding Cassette) and SLC (SoLute Carrier) expressed at BBB level and known to be at the origin of multi-drug resistance phenomenon. Recent researches aim at unraveling the signaling mechanisms regulating these transporters in order to modulate their activity and improve pharmacotherapy in brain diseases. For years, these transporters have been studied in adult organism. But, there is a wide spread belief that the BBB in embryo, fetus, new born and infant is “immature”, implying caution in giving drugs to infants. However, current knowledge on the functional status of the BBB in immature organism remains very limited.This study was performed in the aim of understanding: 1) The ontogenesis of ABC and SLC transporters during brain maturation, 2) the functional role of four BBB drug efflux transporters (P-glycoprotein (P-gp), Breast Cancer Resistance Protein (bcrp), Organic Anion Transporter 3 (oat3), and Transporting Peptide 1a4 (oatp1a4) transporters) in children’s brain, and 3) the mechanisms that regulate their functional expression under normal and pathological conditions, mostly under inflammatory conditions, because indeed alterations in structural and functional components of the BBB have been reported in a long list of CNS pathologies in adults. Our results showed changing properties of the BBB during ontogenesis, as well as an age-related differential regulation of BBB drug efflux transporters under normal and inflammatory conditions.These findings highlight the importance of considering an age-related response of CNS to drugs and of taking into account the specific properties of juvenile BBB during definition of therapeutic strategies designed to treat childhood brain diseases, and this in the clinical perspective of developing new drugs with enhanced efficacy in children’s CNS.