Combinaison des approches psychopharmacologiques et d'imagerie cérébrale pour l’étude de la prise de décision individuelle et sociale chez l’Homme

The aim core of this thesis is to investigate different aspects of decision-making and flexibility in healthy and clinical populations. Specifically, we investigated the neural correlates of social decision-making in young healthy individuals, the influence of steroid hormones on cognitive flexibility in early menopausal women and cerebral dysfunctions involved in reward devaluation during decision-making process in individuals suffering of Parkinson disease. First, we studied the neural correlates of iniquity aversion when making a decision for oneself or on behalf of his own group and when facing a single individual or another group. Our results highlight influence of two distinct neural network involved in iniquity aversion during complex social exchange, outlining a neuronal explanation to interindividualintergroup discontinuity effect. Our second study, described the influence of hormone replacement therapy (i.e., HRT) on cognitive flexibility in early menopausal women. Many studies described a deleterious effect of steroid supplementation on executive cognitive functions, if it delayed after the onset of the menopause. However, “windows of opportunity” hypothesis suggests a benefic and neuroprotective effect against psychiatric disorders, if hormonal replacement therapy starts close to the beginning of menopause. Combining pharmacological and neuroimaging approaches, we showed a neuroprotective effect in brain structures involved in cognitive flexibility, in young menopausal women. Finally, our last study highlights the effect of dopaminergic treatment in Parkinsonians patients developing impulsive control disorder (i.e., hypersexuality). Preliminary results showed influence of these two factors on distinct subsystems involved in evaluation of different types of costs (i.e., effort/delay) associated with subsequent rewards. This thesis demonstrates the value of combining pharmacology studies and fMRI in order to better understand to which extent hormonal and dopaminergic treatments affect the brain mechanisms during individual and social decision-makingLe but de cette thèse était d’étudier les mécanismes cérébraux sous-tendant la prise de décision sociale chez des sujets sains, l’influence des hormones stéroïdiennes gonadiques sur la flexibilité cognitive et les dysfonctionnements cérébraux sous-tendant la dévaluation de récompenses dans la maladie de Parkinson. Lors de notre premier protocole, nous avons étudié comment le fait de prendre une décision pour soi ou pour un groupe auquel nous appartenons, et lorsque nous faisons face à un seul individu ou à un groupe, influence notre aversion à l’iniquité et les régions cérébrales engagées. Nos résultats ont montré l’influence de deux réseaux cérébraux distincts dans l’aversion à l’iniquité lors de ces interactions sociales, définissant une signature cérébrale à l’effet de « discontinuité interpersonnelle/intergroupe». Notre seconde étude visait à déterminer l’influence d’un traitement hormonal substitutif sur la flexibilité cognitive, chez les femmes récemment ménopausées. De nombreuses études ont montré un effet délétère d’une supplémentation hormonale sur les fonctions cognitives, si celle-ci débute tardivement après la ménopause. Cependant, une récente hypothèse a proposé que le traitement hormonal puisse être bénéfique et neuroprotecteur contre des maladies psychiatriques, s‘il débute lors d’une courte durée à la suite du début de ménopause. Dans une étude combinant pharmacologie et IRMf, nous avons démontré une modulation par traitement hormonal sur les régions impliquées dans le contrôle cognitif chez des femmes récemment ménopausées. Notre dernière étude évalue l’effet d’un traitement dopaminergique et la présence d’un trouble du contrôle des impulsions particulier (i.e., l’hypersexualité) chez des patients atteints par la maladie de Parkinson. Nos résultats préliminaires ont montré l’influence de ces facteurs sur des régions frontales et sous-corticales spécifiques impliquées dans des choix, nécessitant l’évaluation de différents coûts (i.e., effort/attente) menant à des récompenses plus ou moins importantes. Notre thèse démontre l’intérêt de combiner les études de pharmacologie et d’IRMf pour comprendre comment les traitements hormonaux et dopaminergiques influencent les mécanismes cérébraux de la décision individuelle et social

Towards a comprehensive understanding of p75 neurotrophin receptor functions and interactions in the brain

The role of neurotrophins in neuronal plasticity has recently become a strong focus in neuroregeneration research field to elucidate the biological mechanisms by which these molecules modulate synapses, modify the response to injury, and alter the adaptation response. Intriguingly, the prior studies highlight the role of p75 neurotrophin receptor (p75(NTR)) in various injuries and diseases such as central nervous system injuries, Alzheimer's disease and amyotrophic lateral sclerosis. More comprehensive elucidation of the mechanisms, and therapies targeting these molecular signaling networks may allow for neuronal tissue regeneration following an injury. Due to a diverse role of the p75(NTR) q in biology, the body of evidence comprising its biological role is diffusely spread out over numerous fields. This review condenses the main evidence of p75(NTR) for clinical applications and presents new findings from published literature how data mining approach combined with bioinformatic analyses can be utilized to gain new hypotheses in a molecular and network level.Peer reviewe

Towards a comprehensive understanding of p75 neurotrophin receptor functions and interactions in the brain

The role of neurotrophins in neuronal plasticity has recently become a strong focus in neuroregeneration research field to elucidate the biological mechanisms by which these molecules modulate synapses, modify the response to injury, and alter the adaptation response. Intriguingly, the prior studies highlight the role of p75 neurotrophin receptor (p75NTR) in various injuries and diseases such as central nervous system injuries, Alzheimer's disease and amyotrophic lateral sclerosis. More comprehensive elucidation of the mechanisms, and therapies targeting these molecular signaling networks may allow for neuronal tissue regeneration following an injury. Due to a diverse role of the p75NTR in biology, the body of evidence comprising its biological role is diffusely spread out over numerous fields. This review condenses the main evidence of p75NTR for clinical applications and presents new findings from published literature how data mining approach combined with bioinformatic analyses can be utilized to gain new hypotheses in a molecular and network level.</p

A comprehensive p75 neurotrophin receptor gene network and pathway analyses identifying new target genes

P75 neurotrophic receptor (p75NTR) is an important receptor for the role of neurotrophins in modulating brain plasticity and apoptosis. The current understanding of the role of p75NTR in cellular adaptation following pathological insults remains blurred, which makes p75NTR's related signaling networks an interesting and challenging initial point of investigation. We identified p75NTR and related genes through extensive data mining of a PubMed literature search including published works related to p75NTR from the past 20 years. Bioinformatic network and pathway analyses of identified genes (n=235) were performed using ReactomeFIViz in Cytoscape based on the highly reliable Reactome functional interaction network algorithm. This approach merges interactions extracted from human curated pathways with predicted interactions from machine learning. Genome-wide pathway analysis showed total of 16 enriched hierarchical clusters. A total of 278 enriched single pathways were also identified (pPeer reviewe

Studying individual and social decision making in Humans combining psychopharmacological and neuroimaging approaches

Le but de cette thèse était d’étudier les mécanismes cérébraux sous-tendant la prise de décision sociale chez des sujets sains, l’influence des hormones stéroïdiennes gonadiques sur la flexibilité cognitive et les dysfonctionnements cérébraux sous-tendant la dévaluation de récompenses dans la maladie de Parkinson. Lors de notre premier protocole, nous avons étudié comment le fait de prendre une décision pour soi ou pour un groupe auquel nous appartenons, et lorsque nous faisons face à un seul individu ou à un groupe, influence notre aversion à l’iniquité et les régions cérébrales engagées. Nos résultats ont montré l’influence de deux réseaux cérébraux distincts dans l’aversion à l’iniquité lors de ces interactions sociales, définissant une signature cérébrale à l’effet de « discontinuité interpersonnelle/intergroupe». Notre seconde étude visait à déterminer l’influence d’un traitement hormonal substitutif sur la flexibilité cognitive, chez les femmes récemment ménopausées. De nombreuses études ont montré un effet délétère d’une supplémentation hormonale sur les fonctions cognitives, si celle-ci débute tardivement après la ménopause. Cependant, une récente hypothèse a proposé que le traitement hormonal puisse être bénéfique et neuroprotecteur contre des maladies psychiatriques, s‘il débute lors d’une courte durée à la suite du début de ménopause. Dans une étude combinant pharmacologie et IRMf, nous avons démontré une modulation par traitement hormonal sur les régions impliquées dans le contrôle cognitif chez des femmes récemment ménopausées. Notre dernière étude évalue l’effet d’un traitement dopaminergique et la présence d’un trouble du contrôle des impulsions particulier (i.e., l’hypersexualité) chez des patients atteints par la maladie de Parkinson. Nos résultats préliminaires ont montré l’influence de ces facteurs sur des régions frontales et sous-corticales spécifiques impliquées dans des choix, nécessitant l’évaluation de différents coûts (i.e., effort/attente) menant à des récompenses plus ou moins importantes. Notre thèse démontre l’intérêt de combiner les études de pharmacologie et d’IRMf pour comprendre comment les traitements hormonaux et dopaminergiques influencent les mécanismes cérébraux de la décision individuelle et socialeThe aim core of this thesis is to investigate different aspects of decision-making and flexibility in healthy and clinical populations. Specifically, we investigated the neural correlates of social decision-making in young healthy individuals, the influence of steroid hormones on cognitive flexibility in early menopausal women and cerebral dysfunctions involved in reward devaluation during decision-making process in individuals suffering of Parkinson disease. First, we studied the neural correlates of iniquity aversion when making a decision for oneself or on behalf of his own group and when facing a single individual or another group. Our results highlight influence of two distinct neural network involved in iniquity aversion during complex social exchange, outlining a neuronal explanation to interindividualintergroup discontinuity effect. Our second study, described the influence of hormone replacement therapy (i.e., HRT) on cognitive flexibility in early menopausal women. Many studies described a deleterious effect of steroid supplementation on executive cognitive functions, if it delayed after the onset of the menopause. However, “windows of opportunity” hypothesis suggests a benefic and neuroprotective effect against psychiatric disorders, if hormonal replacement therapy starts close to the beginning of menopause. Combining pharmacological and neuroimaging approaches, we showed a neuroprotective effect in brain structures involved in cognitive flexibility, in young menopausal women. Finally, our last study highlights the effect of dopaminergic treatment in Parkinsonians patients developing impulsive control disorder (i.e., hypersexuality). Preliminary results showed influence of these two factors on distinct subsystems involved in evaluation of different types of costs (i.e., effort/delay) associated with subsequent rewards. This thesis demonstrates the value of combining pharmacology studies and fMRI in order to better understand to which extent hormonal and dopaminergic treatments affect the brain mechanisms during individual and social decision-makin

Editorial for “Ensemble Learning for Early‐Response Prediction of Antidepressant Treatment in Major Depressive Disorder”

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Hormone therapy at early post-menopause increases cognitive control-related prefrontal activity

Clinical data have been equivocal and controversial as to the benefits to the brain and cognition of hormone therapy (HT) in postmenopausal women. Recent reevaluation of the role of estrogens proposed that HT may effectively prevent the deleterious effects of aging on cognition, and reduces the risks of dementia, including Alzheimer's disease, if initiated early at the beginning of menopause. Yet, little is known about the effects of HT on brain activation related to cognitive control, the ability to make flexible decisions in relation to internal goals. Here, we used fMRI to directly test for a modulation of sequential 17 beta estradiol (2 mg/day) plus oral progesterone (100 mg/day) on task switching-related brain activity in women at early postmenopause. The results showed that HT enhanced dorsolateral prefrontal cortex recruitment during task switching. Between-subjects correlation analyses revealed that women who engaged more the dorsolateral prefrontal cortex showed higher task switching performance after HT administration. These results suggest that HT, when taken early at the beginning of postmenopause, may have beneficial effect on cognitive control prefrontal mechanisms. Together, these findings demonstrate that HT can prevent the appearance of reduced prefrontal cortex activity, a neurophysiological measure observed both in healthy aging and early dementia