Inaug.-Diss.--München, 1934. / Lebenslauf. "Literaturverzeichnis": p. iii-iv.

Inaug.-Dis.--Königsberg. / Vita. "Theses": l p. at end.

As virtual experiences are rapidly substituting a significant proportion of in-person interactions during the COVID pandemic, it is critical to monitor the effect of screen exposure time on developing children’s behavior and nervous system. Screen use boosts information accessibility and, therefore, may delay the development of the inhibitory control networks in children, who are vulnerable to immediate reward-orientated tendencies and not yet capable of controlling their impulsivity. Therefore, it was hypothesized that as children become more exposed to screens, the development of the inhibitory control network would be delayed and their reward sensitivity will be augmented. Using the ABCD Study Data Repository, 8,334 children’s behavioral and neural data (aged 9-11) were included. Robust mediation analysis and correlation analysis were used to investigate how Screen Time interacts with children’s reward-orientated tendency (e.g. Behavioral approach system, BAS) and the brain's inhibitory network. Intrinsic Frontoparietal Network-Striatum (FPN-Striatum) connectivity strength was used as neural indices of the inhibitory control quality in children. Results showed that Screen Time significantly mediated the relationship between BAS and both waves of the intrinsic inhibitory process. A higher BAS was linked to a longer Screen Time and weaker inhibitory network connectivity. This complete/full mediation model indicates that Screen Time negatively influenced the strength of FPN-Striatum connectivity. In conclusion, the study revealed specific behavioral and neural correlates of screen exposure using a large database, and suggested that increasing screen exposure time may impair the inhibitory capability and increase impulsivity in children. / M.S. / The current study explored the effect of daily screen exposure in pre-adolescent children to provide an important springboard for future work in protecting developing children against the negative impacts of screen use, which has increased significantly during the COVID-19 pandemic. Over 8,000 children’s data from the Adolescent Brain Cognitive Development (ABCD) project was included and found that an increased daily screen exposure time is linked to an inefficient inhibitory control system in the brain. As children’s inhibitory control systems are still developing, this negative effect further hinder the maturation of inhibitory-control systems two years later. Given that the virtual movement is irreversible, the results provide scientific evidence that a balance between screen time and non-screen activities is required for developing children.

La neuromodulation apporte une extraordinaire richesse à la dynamique des réseaux de neurones. Parmi les neuromodulateurs du système nerveux central, la noradrénaline permettrait de faciliter l'adaptation du comportement face aux variations des contraintes environnementales en modulant l'attention, cette fonction au coeur de la cognition qui nous permet de sélectionner l'information la plus pertinente en fonction de notre but. Ce processus complexe qui opère à chaque instant à la fois dans l'espace et le temps, constitue une étape essentielle dans cette adaptation comportementale. Cependant, à ce jour, les mécanismes par lesquels ce neuromodulateur exerce ses effets sur le cerveau sain demeurent mal connus. Mon travail de thèse a pour objectif d'examiner les déterminants comportementaux et les marqueurs neuronaux de l'effet stimulant des agonistes noradrénergiques. La question posée était : "Comment la noradrénaline agit-elle pour optimiser l'attention?" Pour répondre à cette question, j'ai choisi de combiner la pharmacologie, l'analyse du comportement, et l'imagerie par résonnance magnétique fonctionnelle chez le singe. Un des principaux résultats de mes travaux est que l'administration d'agents noradrénergiques induit une large réorganisation des réseaux cérébraux, qui pourrait être à l'origine de l'optimisation des réponses comportementales observées parallèlement / Neuromodulation provides an extraordinary wealth to the dynamics of neural networks. Among the neuromodulators of the central nervous system, noradrenaline would facilitate behavioral adaptation facing variations of environmental constraints by modulating attention, this function at the heart of cognition that allows us to select the most relevant information based our goal. This complex process that operates at every moment both in space and time, is an essential step in this behavioral adaptation. However, to date, the mechanisms by which this neuromodulator exerts its effects on healthy brain remain unknown. My thesis aims to examine the behavioral and neural markers of the boosting effect of noradrenergic agonists. The question asked was: "How does noradrenaline optimize attention?" To answer this question, I chose to combine pharmacology, behavior analysis, and functional Magnetic Resonance Imaging in monkeys. One of the main results of my work is that the administration of noradrenergic agents induced a large-scale brain networks reorganization, which could be responsible for optimizing behavioral responses observed in parallel

In the introduction, I discuss the problems scholars experience in trying to define the concept of Roman friendship. I argue that amicitia cannot be equated with patronage, and present justification based on some primary literature. Brief words are then offered on the sociology of friendship, and an attempt is made to relate ideas from modern sociology to ancient friendship. The first chapter is based on the Letters of Pliny the Younger, and begins with an analysis of the vocabulary employed by Pliny in describing his friendships. This is considered in conjunction with prosopographical data in order to establish the connection between vocabulary and practice. The derived results are used to conclude that friendship in the Roman world was more involved than simply patronage, and that it was one of the driving forces behind Roman social behaviour as it helps to integrate different levels of society. Chapter two follows a similar methodology, with the correspondence of Fronto as its focus. The conclusions drawn in this chapter are used to reinforce the arguments presented in the first. Also included in chapter two is a brief discussion of the ancient philosophical approaches to friendship, and a solution is presented to resolve the differences between philosophical ideals and the reality of friendship. The third chapter begins with an examination of the secondary literature on the concept of friendship with the emperor. I maintain that scholarship is lacking in this field because it neglects the personal nuances such relationships could have. The chapter then turns to Pliny’s Panegyricus to determine his attitude regarding this issue, which is used as evidence against some modern interpretations of aristocratic perceptions of the emperor. Pliny’s exchanges with Trajan are subsequently analyzed, and it is argued that it was as subject/ruler that Pliny and Trajan defined their association. Chapter four discusses the relationship Fronto shared with the Antonine emperors. I contend that Fronto related differently with each and experienced different levels of intimacy, which points to the importance of personal connections, even with people as uniquely powerful as emperors. I also conclude from this that even emperors were not above the rules and practices of friendship. The concluding remarks draw attention to the advantages of exploring Roman social relationships through the prism of friendship, as opposed to the traditional perspective of patronage. Some future avenues of research are also suggested.

Le diagnostic différentiel de Démence Fronto-Temporale (DFT) vs Maladie d’Alzheimer (MA) n’est pas toujours facile à établir, et peuvent être confondus avec ceux de l’Aphasie Primaire Progressive (APP) » (Snowden et al. 2011) puisque l’anomie est présente dans les deux pathologies (Assal et al. 2009, Barkat-Defadas et al. 2008, Léger et al. 2007). La MA peut se décrire comme une démence dégénérative, avec une perte de tissu neuronal plutôt dans les lobes pariétal et temporal, résultant dans des difficultés dans les domaines de l’attention, les fonctions exécutives, la mémoire, les compétences pour apprendre, le langage, le calcul, et les fonctions viso-spatiales (Robin et al. 2003). De l’autre coté, la DFT est une démence qui atteint plutôt les lobes frontal et temporal elle peut se classifier d’après trois variantes: variante comportementale (DFTbf), Aphasie primaire progressive (APP) et démence sémantique (DS) (Kertesz et al 2003). Dans les deux cas nous pouvons trouver des troubles communs du à la perte du tissu dans les régions temporales, dans les étapes initiales de la maladie. L’analyse du langage chez des patients avec DFT et MA, et la corrélation de celui-ci avec le profil psycholinguistique permettra l’isolement des caractéristiques cliniques propres du profil des patients, a fin de proposer des critères plus spécifiques pour disjoindre le profil clinique de langage entre la DFT et la MA.La présente thèse sera réalisée en co-tutelle entre l’hôpital San Ignacio / Pontificia Universidad Javeriana et l’Université Lumière-Lyon2. Ce projet poursuit trois objectifs : (i) recueillir des données psycholinguistiques et de langage (tenant compte des années de scolarité et la sévérité du cours de la maladie), (ii) étudier et isoler les variantes linguistiques, qui peuvent influencer erronément la différence des critères de diagnostique entre la DFT et MA; (iii) raffiner les critères de diagnostique de la DFT et MA. 75 sujets ont été évalués (FTD n = 63, AD = 12, 22 sujets contrôles). Le test d'afastie (BAT) (Paradis 1989) a été utilisé pour identifier la discrimination auditive, la compréhension des structures syntaxiques (auditive et lecture), la production de phrases, la compréhension des narrations, la lecture de phrases, ainsi qu'une analyse des erreurs selon la structure syntaxique. En outre, nous évaluons les fonctions exécutives et les tests cognitifs de base. Les échantillons de parole spontanée ont été transcrits en utilisant le format CHAT et analysés à l'aide des programmes CLAN. En adition aux analyses descriptives, une analyse de proximité des distances euclidiennes au carré a été effectuée ainsi que des corrélations et régréssions.Les résultats montrent que patients atteints de PPA ont eu la pire performance dans la plupart des tâches langagières. Les DFTvf montrent une bonne peormance pour les tâches standardisées, mais montrent des difficultées isolées pour la compréhension de structures syntaxiques de type négatif qui peut s’associer à l'incapacité de représenter une séquence temporelle de la phrase. Les résultats démontrent que le discours spontané nous permet de différencier tous les groupes de patients. Le discours de ces patients peut être distinctif et reflète non seulement les capacités linguistiques du sujet, mais aussi les autres fonctions cognitives. Même si la théorie différencie les groupes PPA selon leur fluence, les résultats montrent qu’avec les variables qui portent sur la fluence de la parole qu'il n'est pas possible de différencier la variante non fluente et la logopénique. D'autres variables telles que les erreurs et la grammaire doivent être incluses dans les analyses pour obtenir le diagnostic différentiel des variantes de la APP. La parole spontanée démontre être un outil inestimable dans la pratique quotidienne du clinicien pour les diagnostics précoces et les critères pour un diagnostic différentiel entre la MA et la DFT – et ces trois variantes-. / Even though the large majority of cortical dementia is of the Alzheimer’s disease type, there are differential diagnosis limitations of current diagnostic criteria for early-onset Alzheimer disease (AD) and frontotemporal lobar degeneration (FTLD, all three variants: behavioural variant frontotemporal –FTDbv-, Primary progressive aphasia –PPA- and semantic dementia –SD-). Initially, either AD and FTD share cognitive declines and first complain includes memory and no language in FTLD or language and no memory in AD. For instance, word retrieval deficits are common in AD and are thought to reflect a degradation of semantic memory. Yet, the nature of semantic deterioration in AD and the underlying neural correlates of these semantic memory changes remain largely unknown (Wierenga, 2011). On the other hand, PPA, FTDbv and SD have, as well, common behavioural features: PPA, prior to word loss, may show apathy and semantic dementia patients have, long before, the pure meaning loss, a great decline on emotional and conduct process. Since new guidelines for the differential diagnosis of behavioural FTD (Raskovsky, 2011) and selective language features –nonfluent/agrammatic, semantic, syntax, narrative - of the language variants are being revised (Gorno-Tempini, 2011) the present project present a novel way to define criteria regarding cognition profile through language analysis in all: AD and FTDL all variants. In sum, isolation of pure clinical characteristics in order to enriched the clinic profile and subtract the pure linguistic features will facilitate better common clinical compromise besides language differences (Zanini et al. 2011, Hernández et al. 2011, Ardila& Ramos, 2008). The present study aims to study through the Javeriana University Memory Clinic (PUJMC) at the San Ignacio Hospital in Colombia, based on the experience in the last 14 years where almost 3000 patients have been studied, language semiology between AD, FDT – all three variants. This project has three objectives: (i) to collect psycholinguistic and language data (taking into account the years of schooling and the severity of the course of the disease), (ii) study and isolate linguistic variants that may erroneously influence the difference in diagnostic criteria between DFT and MA; (iii) refining the diagnostic criteria for FTD and MA. 75 subjects were assessed (FTD n= 63, AD= 12, 22 control sample subjects). Bilingual Aphasia Test (BAT) (Paradis 1989) was used in order to identify auditory discrimination, syntactic structures comprehension (auditory and by reading), sentences production, auditory and by reading, comprehension of narrative structures, sentences reading, as well as an analysis of errors according to the syntactic structure. Additionally, we assess executive functions and basic cognition battery. Spontaneous speech samples were transcribed using the CHAT format, and analysed using the CLAN programs Besides a descriptive analysis, a hierarchical clustering through a squared Euclidean distances was done, where patients groups were formed by similar clinical neighbors regardless the FTD variant. Results show that deep language analysis is useful when heterogeneity w/groups is present and depends (in all groups) on the disease stage. PPA patients had the worse performance. bvFTD executive passive structure difficulty is associated with executive functions: The inability to represent a temporal sequence of the phrase –not understanding if.. Then). Results demonstrate that spontaneous speech allow us to differentiate between all groups of patients. Discourse of these patients can be distinctive and it reflects not only the subject's linguistic abilities but other cognitive functions as well....

Background: Dementia presents challenges for whole families requiring on-going adaptation. Family relationships provide important benefits, thus understanding the impact of dementia for families is critical to facilitating their wellbeing. Behavioural variant Frontotemporal Dementia (bvFTD) brings specific challenges for relationships, however little is understood about how these are experienced or how families adjust. Aims: This research sought to develop an in-depth understanding of the inter-generational family experience of bvFTD over time. Method: Using a qualitative design, nineteen people were interviewed from seven families, including people living with bvFTD. Interviews occurred over three time points. Narrative analysis and grounded theory were used to understand how relationships are affected and the psycho-social coping processes involved in adjustment over time. Results: Four themes emerged; - Cohesive and connected --- distant and disconnected - Challenges to we/ I - Assimilating, adjusting and reconstructing --- resisting, denying, being stuck - A changing we / I --- an entrenched we / I Results illustrate the influence of pre-existing relationships on family experiences of bvFTD. Challenges to family relationships occurred, including changes in mutuality and increased responsibility. Levels of awareness and understanding, influenced by factors such as proximity impacted upon individual and family adjustment. Assimilating these changes was critical to developing strategies for managing the impact on the relationship and adapting to ‘a changing we’. For closest family members including partners, grief and loss were experienced resulting in the need for a parallel adaptation to a changing ‘I’. Acceptance and adaptation was critical to supporting the wellbeing of the person with bvFTD.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22693号 / 医博第4637号 / 新制||医||1045(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 高橋 淳, 教授 林 康紀, 教授 伊佐 正 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Résumé : La répétition de l’hexanucléotide GGGGCC est le facteur génétique le plus présent chez les patients atteints de démence fronto-temporale (DFT) et de sclérose latérale amyotrophique (SLA). Elle apparait au niveau du cadre de lecture ouvert 72 du chromosome 9 (C9orf72). D’une part, la DFT se caractérise par des troubles de la personnalité, du langage et du comportement causés principalement par une dégénérescence de neurones corticaux, thalamiques, hippocampiques et cérébelleux. D’autre part, les patients SLA sont atteints de paralysie des muscles squelettiques causée par la mort de motoneurones au niveau de la moelle épinière et du système moteur central. Ces deux pathologies partagent de nombreuses caractéristiques cliniques et génétiques, suggérant qu’il existe des mécanismes communs entre elles.D’abondantes inclusions cytoplasmiques de protéines issues de la traduction des ARN d’hexanucléotides ont été retrouvées dans le cerveau de patients décédés de SLA et de DFT. On appelle ces polypeptides : Protéines à Répétitions de Dipeptides (PRD), car ils ne sont composés que d’une suite de deux résidus : glycine-alanine (GA), glycine-proline (GP), glycine-arginine (GR), proline-arginine (PR) et proline-alanine (PA). La toxicité de ces PRD a été mise en évidence dans des modèles cellulaires, chez la drosophile mais aussi la souris. Cependant, peu d’études se sont concentrées sur la caractérisation biochimique de ces PRD.Le travail de cette thèse a consisté en la production et la caractérisation in vitro de PRD. J’ai réalisé la caractérisation biochimique de ces protéines et étudié leur capacité à s’auto-assembler au sein de l’équipe « Repliement des protéines in vitro et maladies conformationnelles » dirigée par Ronald Melki. Les PRD recombinants poly-GA, poly-PA et poly-GP ont été produits. Nous avons déterminé les conditions in vitro dans lesquelles ces protéines s’assemblaient. La morphologie des agrégats a été étudiée par microscopie électronique, tandis que la structure des protéines a été déterminée par spectromètre de dichroïsme circulaire pour la forme monomérique et par spectroscopie à infrarouge pour les assemblages.La toxicité, la propagation et la capacité de ces PRD à être internalisé sont testées dans des modèles cellulaires en collaboration avec l’équipe du Pr. Mimoun Azzouz de l’Université de Sheffield. / Abstract : The most common genetic factor between familial Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) is the repetition of (GGGGCC)n in the open reading frame 72 of chromosome 9 (C9orf72). FTD is characterized by personality, behavior and language disorders due to neuronal degeneration in the cortex, thalamus, hippocampus and cerebellum. ALS patients, on the other hand, exhibit motor symptoms primarily consisting of paralysis of the skeletal muscles caused by motoneuronal loss in the spinal cord and the central motor system. These pathologies have significant genetic and clinic overlaps suggesting common mechanisms.Large amounts of cytoplasmic inclusions of the Dipeptide Repeat Proteins (DRP), translated from C9orf72 RNA, were found in brains of patients who died from ALS or FTD.These proteins are constituted of repetitions of Dipeptides : glycine-alanine (poly-GA), glycine-proline (poly-GP), glycine-arginine (poly-GR), proline-arginine (poly-PR) and proline-alanine (poly-PA). The toxicity of the aggregated DRP has been shown in various cellular models as well as in drosophila and mice. Nevertheless, few studies have described the biochemistry of the DRP. The aim of my thesis is the in vitro caracterization of the DRP. I have characterized the biochemistry of these proteins and in particular their self-assembly abilities in Ronald Melki’s team « Proteins folding and conformational diseases ».Recombinant DRP of different lengths and nature have been produced to determined the in vitro conditions in which they assemble. The morphology of the related aggregates has been studied by transmission electron microscopy. Structure informations of DPR were obtained with Circular Dichroïsm spectrometry for monomers and Infrared spectroscopy for assemblies. Lastly, the toxicity and internalization abilities of these proteins and their assemblies are tested on culture cells in collaboration with Pr. Mimoun Azzouz of the University of Sheffield.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18854号 / 医博第3965号 / 新制||医||1007(附属図書館) / 31805 / 京都大学大学院医学研究科医学専攻 / (主査)教授 古川 壽亮, 教授 髙橋 良輔, 教授 富樫 かおり / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM