Children diagnosed with autism spectrum disorder often require early intensive behavioral interventions (EIBI) to learn new skills and decrease maladaptive behaviors. Discrete trial instruction (DTI) is a strategy behavior analysts often incorporate in EIBI programs. Researchers have demonstrated that DTI is very effective, but it requires intensive training for teachers to implement the strategy with high fidelity. Therefore, researchers have recently begun to investigate more time-efficient methods to train instructors to implement DTI. One method, e-learning, is a multi-media, computer-based training that typical includes audio narration, videos, and graphics. E-learning is a lowcost, time-efficient alternative to the traditional face-to-face training method. Very little research has been conducted thus far to evaluate the effectiveness of e-learning for teaching behavioral intervention techniques. Therefore, the purpose of this study was to investigate the use of e-learning to teach university students to implement discrete trial instruction with children with autism. Four participants completed the e-learning training package and we found that all participants’ fidelity when implementing DTI increased in role plays with an adult. All participants also were able to accurately implement DTI when teaching a child with autism and we observed generalization to untrained instructional programs. All participants were able to complete the training in an average of 2 hours and the social validity questionnaire indicated that participants felt the training was interesting and useful to help them learn how to implement DTI.

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No description available.

Communication is the exchange of thoughts and ideas from one person to another, often through the form of narratives. People communicate using speech, gesture, and drawing, or some multimodal combination of the three. Although there has been much research on how we understand and produce speech and pantomimes, there is relatively little on drawing, and even less on cross-modal communication. This dissertation presents novel empirical findings that contribute to a better understanding of the brain areas that mediate narrative communication across speech, pantomime, and drawing. Since the neuroscience of drawing was so understudied, I first used functional magnetic resonance imaging (fMRI) to investigate the existence of a basic drawing network in the human brain (Chapter 2). The drawing network was shown to contain three visual-motion areas that process the emanation of the visual image as drawing occurs. Next, to follow up on the poorly-characterized structural connectivity of these areas in the human dorsal visual stream, I used diffusion imaging to explore how these dorsal stream areas are connected (Chapter 3). The tractography results showed structural connectivity for two of the three predicted branches connecting the three visual-motion areas. Finally, I used fMRI to investigate how the basic drawing network is recruited during the more complex task of narrative drawing, and to find common brain areas among narrative speech, pantomime, and drawing (Chapter 4). Results suggest that people approached narratives in an intrinsically mentalistic fashion in terms of the protagonist, rather than as a mere description of action sequences. Together, these studies advance our understanding of the brain areas that comprise a basic drawing network, how these brain areas are interconnected, and how we communicate stories across three modalities of production. I conclude with a general discussion of my findings (Chapter 5). / Thesis / Doctor of Philosophy (PhD)

Yes / Introduction : Rheumatoid arthritis (RA) affects 1% of the population and is principally associated with joint inflammation. It is suggested however that muscle involvement may be one of the earliest clinical features of RA. It is therefore important that techniques exist to accurately assess muscle health in those with RA to enable successful treatment. This study assesses the inter-rater and intra-rater repeatability of Diffusion Tensor MRI (DTI), 2-Point Dixon fat fraction, and T2 relaxation of the thigh muscle in patients with RA using manual regions of interest (ROI). Methods: Nineteen patients (10/19 males; mean age 59; range 18-85) diagnosed with RA had an MRI scan of their hamstrings and quadriceps muscles to obtain fat fraction (FF), mean diffusivity (MD), fractional anisotropy (FA), and T2 quantitative measurements. Two raters (R#1 & R#2) (initials removed for review) independently contoured ROIs for each patient. R#1 repeated the ROI for the same 19 patients after a 6-month hiatus to assess intra-rater repeatability. Inter-rater and intra-rater repeatability for the ROI measurements were compared using Inter Class Correlation (ICC) and Bland-Altman plots. Results: There was excellent agreement for both inter-rater and intra-rater repeatability. ICC results ranged from 0.900-0.998 (P<0.001), and intra-rater ICC results ranged from 0.977-0.999 (P<0.001). Bland-Altman plots also showed excellent agreement. Conclusions: ICC measurements and Bland-Altman plots showed excellent repeatability and agreement with no statistically significant differences when assessing the inter-rater and intra-rater repeatability of FF, MD, FA, and T2 relaxation of the thigh muscle using manual regions of interest in patients with RA. Implications for practice: Manual ROI drawing does not introduce significant errors obtaining FF, MD, FA, and T2 MRI measurements in an RA population. / This research is funded by the NIHR infrastructure at Leeds.

L’objectif de cette thèse est de développer des méthodes IRM permettant d’étudier l’impact d’une ischémie focale transitoire sur le cerveau de rat nouveau-né. Les techniques utilisées sont l’imagerie à contraste renforcé par le manganèse (MEMRI), l’imagerie du tenseur de diffusion (DTI) ainsi que de façon préliminaire l’imagerie Q-ball (QBI). Le MEMRI après injection intra cérébrale a été utilisé afin d’étudier de manière dynamique le tractus cortico-thalamique, en parallèle le DTI a servi de marqueur de la structuration cérébrale. Les résultats ont montré une atteinte du tractus cortico-thalamique ipsi-latéral, sept et quatorze jours après ischémie. De manière générale le DTI a montré une structuration ralentie à la suite de l’ischémie. A partir de ces résultats la faisabilité d’une méthode d’acquisition rapide et de traitement de données Q-ball a été établie puis testée sur un animal immature. Les méthodes mises en place se sont révélées efficaces dans le suivi de la maturation cérébrale dans des conditions normales ainsi que pathologiques, ouvrant des perspectives d’études liées au développement cérébral. / The thesis aim is to develop MRI methods to study the impact of focal transient ischemia in neonatal rat brain. The principal techniques used are MEMRI (Manganese Enhanced MRI), DTI (Diffusion Tensor Imaging) and QBI (Q-Ball Imaging). MEMRI was used to observe in a dynamic way the cortico-thalamic manganese transport combined with the structural informations extracted from the DTI experiments. Results have shown a cortico-thalamic pathway disturbance, at seven and fourteen days after ischemia. Globally DTI results have shown a slowed brain structuration. From these results, the feasibility of a fast acquisition method and the post processing steps of Q-ball protocol was established and applied in an immature rat. The different MRI protocols developed during this thesis have shown good efficiency to follow the rat brain maturation, in healthy and pathological conditions, thus opening new perspectives for brain development studies.

Die Kapazität des Arbeitsgedächtnisses (AG) sagt die Leistungsfähigkeit in diversen anderen kognitiven Funktionen voraus. Zusätzlich werden altersbedingte Beeinträchtigungen in AG mit Defiziten in anderen kognitiven Funktionen assoziiert, was sich im hohen Alter in der Minderung der Selbständigkeit und des Leistungsniveaus in alltäglichen Aufgaben widerspiegelt. Das AG kann durch Trainingsmaßnahmen verbessert werden, und auch andere kognitive Funktionen können von AG-Training profitieren. Die Befundlage bezüglich dieser Transfereffekte deutet darauf hin, dass AG-Training auch Mechanismen zur Verbesserung der allgemeinen kognitiven Leistungsfähigkeit umfasst. Obwohl es zunehmend Hinweise für die Möglichkeit gibt, kognitive Funktionen durch AG-Training zu verbessern, sind die genauen Mechanismen von Training und Transfer noch unklar. In der vorliegenden Dissertation präsentiere ich vier Studien, in denen ich die genauen Mechanismen von AG-Training untersucht habe. Ich konnte zeigen, dass Training die Leistung in verschiedenen Tests zu exekutiven Funktionen verbessert, und dass der Transfer von Trainingseffekten statt auf die Förderung einer allgemeinen kognitiven Fähigkeit auf die Verbesserung in einem spezifischen Prozess zurückzuführen ist. Weiterhin habe ich zum ersten Mal gezeigt, dass bereits 16 Sitzungen eines AG-Trainings zu strukturellen Veränderungen in der weißen Substanz führen. Diese ließen sich in den Nervenbahnen nachweisen, die die mit AG assoziierten Hirnareale verbinden. Ich zeigte erstmals auch, dass altersbedingte Unterschiede in AG zwischen jungen und älteren Erwachsenen bereits nach 16 Trainingssitzungen ausgeglichen werden können. Die Befunde der vorliegenden Arbeit werden in Bezug auf die Flexibilität der kognitiven Funktionen und auf die Plastizität des zugrunde liegenden neuronalen Substrats diskutiert. Zusätzlich werden neue Ansichten für Modelle von Training- und Transfermechanismen vorgestellt. / Working memory (WM) is a cognitive function that is engaged in several everyday tasks. WM performance predicts performance in diverse other cognitive functions. Additionally, WM decline at old age is associated with age-related impairments in others cognitive functions, thus affecting autonomous performance of everyday tasks. It has been shown that WM can be improved with training interventions, and evidence has accumulated showing that also other cognitive functions can profit from WM training. The transfer findings indicate that WM training might enclose a mechanism to improve cognitive functions in general. Even though there exists a growing body of evidence on the possibilities to improve cognitive functions with WM training in different populations, the exact mechanisms of training and transfer have remained unclear. In the current dissertation I examine the prospects and precise mechanisms of WM training with four studies using the bi-modal dual n-back paradigm. I showed that dual n-back training improved performance in various tests tapping executive functions. I could also demonstrate that the mechanisms underlying transfer result from an improvement in a specific process tapped by the training task rather than in the boosting of a general cognitive ability. Consequently, transfer can occur to tasks if they engage the same specific process. Additionally, I provided primary evidence that only 16 sessions of WM training produces microstructural changes in white matter pathways connecting brain regions that support WM functions. I also showed for the first time that age-related differences in WM performance between young and older adults can be compensated for after only 16 training sessions. The findings of the present dissertation are discussed in relation to the flexibility of cognitive functions and the plasticity of the underlying neuronal substrate; additionally, new conceptions to models of training and transfer mechanisms are presented.

Introduction : L'électroconvulsivothérapie (ECT) est un traitement non pharmacologique du trouble dépressif résistant. Bien que son efficacité ait été démontrée dans cette indication, les mécanismes cérébraux qui sous-tendent ce processus restent très imprécis. Il n'existe actuellement pas de travail étudiant l'effet d'une ECT efficace au niveau des modifications structurofonctionnelles cérébrales. Il semble primordial de poursuivre l'étude des corrélats neuroanatomiques précoces et plus tardifs sous tendant les processus neurofonctionnels responsables de l'amélioration de la clinique. Méthodes : Il s'agit d'une étude mono centrique menée sur le CHU de Toulouse. Chez des patients présentant un trouble dépressif résistant, des évaluations cliniques et en IRM multimodale sont réalisées à 4 temps. La 1ère évaluation a lieu avant le début de la cure, la 2ème après une 1ère ECT, la 3ème après une 1ère ECT efficace et la 4ème après rémission.Résultats: Concernant le volume de l'hippocampe et de l'amygdale à la première visite n'était pas diffèrent du volume à la troisième visite (t(135) = .329, p = .94). Au contraire, il y avait une différence significatif entre le volume de deux structures entre la première et la quatrième visite (t(135) = -2.47, p = .039) et entre la troisième et la quatrième visite (t(135) = -3.51, p = .002). Concernant la diffusivité moyenne en tant que l'effet des visites tend vers la significativité pour la DM (F(2,136) = 2.67, p = .072). En IRM resting state, il existe une hypoconnectivité précoce entre (i) l'hippocampe Droit et le cortex Cingulaire antérieur dorsal (t = -6.20 ; pFDR : 0.0123) ; (ii) l'hippocampe Droit et le noyaux caudé gauche ( t = -7.69 ; pFDR : 0.0035) et (iii) le vermis cervelet et le precuneus (t = -5.93 p FDR : 0.0363). Il existe une hyperconnectivité entre V4 et V1 entre (i) le cortex orbito frontal médian droit et le gyrus occipital médian (t = 6.58 ; p FDR : 0.0146) et (ii) le gyrus frontal inférieur droit et le cortex fronto median gauche (t = 6.83 ; pFDR : 0.0104). Il existe une diminution significative des symptomes de depression entre la V4 et la V1 à l'échelle d'Hamilton (V4: 3,08 ET : 1,62 ; V1 : 23,17 ET : 3,21 ; p <0.001).Conclusion : Il semble exister des modifications structuro-fonctionnelle à l'issu de la cure d'ECT sans modifications structurelles et micro structurelles précoces. / Background: Electroconvulsive Therapy (ECT) is a non-pharmacological treatment of resistant depressive disorder. Although its efficacy has been demonstrated in this indication, the brain mechanisms underlying this process remain very imprecise. There is currently no work studying the effect of one effective ECT on cerebral structural changes. It seems essential to continue the study of the early and late neuroanatomical correlates underlying neurofunctional processes responsible for improving the clinic. Methods: This is a mono-centric study conducted on the Toulouse University Hospital. In patients with resistant depressive disorder, clinical and multimodal MRI assessments are performed at 4-step intervals. The first evaluation takes place before the beginning of the treatment, the 2nd after a 1st ECT, the 3rd after a 1st effective ECT and the 4th after remission. Results: Regarding the volume of the hippocampus and amygdala at the first visit was not different from the volume at the third visit (t (135) = .329, p = .94). On the contrary, there was a significant difference between the volume of two structures between the first and the fourth visit (t (135) = -2.47, p = .039) and between the third and fourth visits (t (135) = -3.51, p = .002). For mean diffusivity, the effect of visits showed a trend toward significance for MD (F (2.136) = 2.67, p = .072). In the MRI resting state, there is early hypoconnectivity between (i) the right hippocampus and the dorsal anterior cingulate cortex (t = -6.20, pFDR: 0.0123); (ii) right hippocampus and left caudate nucleus (t = -7.69, pFDR: 0.0035) and (iii) vermis cerebellum and precuneus (t = -5.93 p FDR: 0.0363). There is hyperconnectivity between V4 and V1 between (i) the right medial orbit frontal cortex and the medial occipital gyrus (t = 6.58; p FDR: 0.0146) and (ii) the right inferior frontal gyrus and left fronto medial cortex (t = 6.83, pFDR: 0.0104). There is a significant decrease in the symptoms of depression between V4 and V1 at the Hamilton scale (V4: 3.08 AND: 1.62, V1: 23.17 AND: 3.21, p <0.001). Conclusion: There appears to be structural-functional changes at the end of the ECT course. However, we do not find early structural and micro structural changes.

La stimulation transcrânienne par courant continu (tDCS) sert à moduler l’activité neuronale. Elle consiste à appliquer un faible courant constant entre deux électrodes placées sur le cuir chevelu. Deux montages semblent efficaces pour moduler les capacités cognitives et/ou soulager des symptômes cliniques. Cependant, les effets neurobiologiques de la tDCS sont encore mal connues. Ce travail de thèse a tenté de clarifier les mécanismes cérébraux de la tDCS chez les sujets sains, en particulier en lien avec le système dopaminergique. En utilisant un design randomisée en double aveugle, nous avons combiné une session de tDCS online avec plusieurs modalités d'imagerie (PET ou PET-IRM simultanée) chez le sujet au repos. Une première étude (n=32, 2mA, 20min) a montré que la tDCS bifrontale induit une augmentation de la dopamine extracellulaire dans le striatum ventral, impliqué dans le réseau de récompense-motivation, après la stimulation. Une seconde étude (n=30, 1mA, 30min) a montré que la tDCS fronto-temporale induit une augmentation de la dopamine extracellulaire dans la partie exécutive du striatum et une diminution de la perfusion dans une région du réseau du default mode (DMN), après la stimulation. L'analyse des données de cette étude est toujours en cours. Dans l’ensemble, ce travail fournit la preuve qu'une seule session de tDCS frontale peut impacter le système dopaminergique dans des régions connectées aux zones corticales stimulées. Par conséquent, les niveaux d'activité et réactivité dopaminergique doivent être de nouveaux éléments à considérer dans l’hypothèse globale de modulation de l’activité cérébrale par la tDCS frontale / Transcranial direct current stimulation (tDCS) is used to modulate neuronal activity in the brain. It consists in applying a small constant current between two electrodes placed over the scalp. Two frontal tDCS montages have shown promises in modulating cognitive abilities and/or helping to alleviate clinical symptoms. However, the effects of tDCS on brain physiology are still poorly understood. The aim of this thesis work was to clarify brain mechanisms underlying frontal tDCS in healthy subjects, specifically in relation to the dopaminergic system. Using a double blind sham-controlled design, we combined a single session of tDCS online with several imaging techniques (PET or simultaneous PET-MRI) with the subject at rest. A first study (n=32, 2mA, 20min) showed that bifrontal tDCS induced an increase in extracellular dopamine in the ventral striatum, involved in the reward-motivation network, after the stimulation period. A second study (n=30, 1mA, 30min) showed that fronto-temporal tDCS induced an increase in extracellular dopamine in the executive part of striatum as well as a decrease in perfusion in a region part of the default mode network (DMN), after the stimulation period. The data analysis of this study is still ongoing. Overall, the present work provides evidence that a single session of frontal tDCS impacts the dopaminergic system in regions connected to the stimulated cortical areas. Therefore, levels of dopamine activity and reactivity should be new elements to consider for a general hypothesis of brain modulation by frontal tDCS

Cette thèse a pour but de développer des techniques en imagerie par résonance magnétique(IRM) afin de détecter des altérations neurologiques à l’échelle microscopique dans des modèlesanimaux. Deux modèles chez la souris ont été étudiés en particulier: le modèle Glio6 de glioblastomehumain et le modèle MAP6, apparenté à la schizophrénie. Les méthodologies développées ont étécentrées autour de l’IRM du tenseur de diffusion (DTI) 3D rapide et à haute résolution spatiale pourdes applications ex vivo et in vivo chez le rongeur. Dans le modèle Glio6, la migration de cellulestumorales dans le corps calleux a été précocement détectée et quantifiée alors qu’aucun signe n’étaitvisible sur les IRM anatomiques classiques. La tractographie, imagerie des fibres de la matièreblanche, a permis d’identifier des déficits de certains tracts et de leurs connectivités dans le modèleMAP6. Des altérations inhomogènes ont été détectées, avec en particulier une réduction drastique dela voie cortico-spinale, résultats mettant en exergue le rôle primordial de la protéine MAP6 lors de laneuromorphogénèse. La méthode « Super Résolution » développée puis appliquée in vivo aux sourisMAP6, a permis d’obtenir en moins d’une heure une imagerie de tractographie comparable à celleobtenue ex vivo (en 59h), ce qui ouvre la voie à des suivis longitudinaux in vivo pour des études dudéveloppement du cerveau ou de l’évaluation de nouvelles thérapies. D’autre part, une méthode IRMcellulaire in vivo quantitative a été mise en place. Le principe repose sur la mesure combinée desrelaxivités cellulaires in vitro (pouvoir à réduire les temps de relaxation T2*, T2 et T1) pour convertir lestrois paramètres de la relaxation in vivo en concentrations cellulaires. En utilisant le modèle de gliomeU87 et des cellules U937 marquées magnétiquement, les résultats ont montré qu’une très large gammede concentrations cellulaires peut être quantifiée et que la biodistribution des cellules U937 autour dela tumeur est hétérogène, information essentielle pour étudier l’efficacité d’une thérapie cellulaire. / This thesis aims to develop magnetic resonance imaging (MRI) techniques to detectneurological damage at the microscopic level in animal models. Two mouse models were examined inparticular human glioblastoma model (Glio6) and a schizophrenia mouse model (MAP6 model). Themethodologies developed were centered around 3D fast diffusion tensor imaging (DTI) with highspatial resolution for ex vivo and in vivo applications in rodents. In Glio6 model, the migration oftumor cells in the corpus callosum was early detected and quantified while no signs were visible onconventional anatomical MRI. Tractography identified deficits of some tracts and their connectivity inthe MAP6 model. Inhomogeneous alterations were detected, especially with a drastic reduction of thecorticospinal pathway. Theses results highlight the crucial role of the MAP6 protein in the braindevelopment. The "Super Resolution" post-proccesing was developed and applied in vivo to MAP6mouse model. Tractography imaging comparable to that obtained ex vivo (in 59h) was obtained in lessthan one hour, paving the way for in vivo longitudinal studies as brain development studies orevaluation of new therapies. On the other hand, a in vivo cellular MRI method has been established.The principle is based on the combined measurement of cell relaxivities in vitro, to obtain in vivo cellconcentrations based on relaxation parameters. Using the U87 glioma model and U937 magneticallylabeled cells, the results showed that a wide range of cell concentrations can be quantified and thebiodistribution of U937 cells around the tumor is heterogeneous, information essential to study theeffectiveness of cell therapy.