Rozprawy doktorskie na temat „Human brain- Neuroimaging”

Thesis (Ph. D.)--Ohio State University, 2004.<br>Title from first page of PDF file. Document formatted into pages; contains xiv, 222 p. : ill. (some col.). Advisor: Pierre-Marie Luc Robitaille, Dept. of Emergency Medicine. Includes bibliographical references.

The human brain is composed of distributed networks that connect a disproportionately large neocortex to the brainstem, cerebellum and other subcortical structures. New methods for analyzing non-invasive imaging data have begun to reveal new insights into human brain organization. These methods permit characterization of functional interactions within and across brain networks, and allow us to appreciate points of departure between the human brain and non-human primates.<br>Psychology

Faire le bon choix, c’est trouver le bon compromis entre coût et bénéfice. Dans le cas de la gestion de l’effort physique, ce compromis prend une dimension temporelle. Pour comprendre comment la décision d’arrêter ou reprendre l’effort est prise, nous avons développé un paradigme expérimental chez le sujet humain sain et un modèle computationnel dans lequel le coût estimé augmente à l’effort car la fatigue affecte toute la commande motrice et diminue au repos quand nous récupérons. Le comportement reflète les variations de ce coût estimé et du compromis avec le bénéfice attendu. Grâce à la complémentarité de l’imagerie fonctionnelle par résonnance magnétique et de la magnétoencéphalographie (MEG), le coût estimé a été localisé dans les régions proprioceptives du cerveau : l’insula postérieure et le thalamus ventromédian. La MEG a également révélé que la désynchronisation du rythme beta moteur (13-30Hz) permet une reprise plus rapide de l’effort quand les enjeux sont importants. Cette gestion stratégique du repos est liée à l’utilité attendue qui peut être dissociée de l’utilité réelle. Nos résultats montrent que la gestion de l’effort est adaptée en ligne au coût estimé et modulée stratégiquement en fonction des coûts et bénéfices attendus. Les antalgiques (hypnose ou paracétamol) ont un effet limité sur ce processus, à l’inverse de la sérotonine (Escitalopram). Notre contribution, à l’interface entre médecine du sport, théorie de la décision et modèle d’accumulation utilisés en neurosciences, propose un mécanisme pour optimiser la gestion de l’effort physique en maximisant les gains et minimisant les dommages corporels<br>No pain, no gain: optimal decisions involve a tradeoff between cost and benefit. We propose that in physical effort allocation, this tradeoff is unfolded over time. We present a task to investigate this process in the laboratory with healthy humans and we suggest a computational model to account for decisions to stop and resume the effort. Costs increase during exertion, due to fatigue at all stages of the motor command and decrease during rest, due to recovery. We show that this dynamic may be captured by a cost-evidence variable and compared to the expected benefit. Functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) complementarily showed that cost-evidence may be implemented in proprioceptive regions of the brain: posterior insula and ventro-medial thalamus. In addition, MEG showed that motor beta (13-30 Hz) desynchronization mediates the effect of incentives to hasten effort resumption. This strategic invigoration of rest is supported by a behavioral dissociation: the expected utility (not the actual utility) modulates rest durations. Together, our results support that the behavior is adapted on the fly to cost-evidence levels and that this mechanism is modulated strategically according to the expected cost and benefit. This behavior was not affected by pain killers (hypnosis or paracetamol), but by serotonin (Escitalopram). This work bridges a gap between sport medicine, value-based decision-making and accumulation models in neuroscience in showing that accumulation and dissipation of cost-evidence can guide the optimization of effort allocation: this mechanism implements the maximization of benefit while the body costs are minimized

The study of brain nuclei in neuroimaging poses challenges owing to its small size. Many neuroimaging studies have been reported for effectively locating these nuclei and characterizing their functional connectivity with other regions of the brain. Hypothalamus, Locus Coeruleus, and Ventral Tegmental area are such nuclei found in the human brain, which are challenging to visualize owing to their size and lack of tissue contrast with surrounding regions. Resting-state functional magnetic resonance imaging (rsfMRI) analysis on these nuclei enabled researchers to characterize their connectivity with other regions of the brain. An automated method to successfully isolate voxels belonging to these nuclei is still a great challenge in the field of neuroimaging. Atlas-based segmentation is the most common method used to study the anatomy and the functional connectivity of these brain nuclei. However, atlas-based segmentation has shown inconsistency due to variation in brain atlases owing to different population studies. Therefore, in this study, we try to address the research problem of brain nuclei imaging using a clustering-based approach. Clustering-based methods separate of voxels utilizing their structural and functional homogeneity to each other. This type of method can help locate and cluster the voxels belonging to the nuclei. Elimination of erroneous voxels by the use of clustering methods would significantly improve the structural and functional analysis of the nuclei in the human brain. Since several clustering methods are available in neuroimaging studies, the goal of this study is to find a robust model that has less variability across different subjects. Non-parametrical statistical analysis was performed as functional magnetic resonance imaging (fMRI) based studies are corrupted with noise and artefact. Statistical investigation on the fMRI data helps to assess the significant experimental effects.

This research has advanced our understanding of how the brain controls muscle activity during walking, in healthy adults of different ages and people with Parkinson's disease. It has shown that there is direct brain control of leg muscles during the double support phase of gait in these populations. Moreover, this brain control is reduced in people with Parkinson's compared to healthy individuals, and standard anti-Parkinsonian medication does not counteract this deficiency.

In the behavioral sciences, the concept of phenotypic plasticity can be roughly categorized into two classes: developmental and activational plasticity. Developmental plasticity denotes the capacity of an individual carrying a specific genetic background to adopt different developmental trajectories under distinct settings. Complementarily, activational plasticity refers to the differential activation of adaptation mechanisms: an individual with high activational plasticity would be able to detect a wide range of environments, and to respond to it using a psychobiological phenotype from a relatively large catalogue. In this context, it is feasible postulating that several etiopathogenic mechanisms of depression-related phenotypes can be clarified by expanding on processes of biobehavioral plasticity in response to the experience. This expansion can be elaborated on the basis of both neurodevelopmental phenomena (developmental plasticity) and novel biological mechanisms detectable through neuroimaging and epigenetics approaches (activational plasticity). The present work expands on two specific hypotheses. First, depression-related psychopathological phenotypes are induced by factors altering the early neurodevelopment, and these long-lasting changes can be assessed in adulthood (depression and developmental plasticity). Secondly, the clinical manifestation of depression-related psychopathological phenotypes can be understood as activational plasticity deficits; these deficits can be assessed as neurobiological disease traits using novel epigenetic and neuroimaging techniques (depression and activational plasticity). The results of this work provide support to the neuroplasticity hypothesis of depression, from both developmental and activational perspectives. Developmentally, they suggest putative etiopathogenic pathways leading from an altered early neurodevelopment to an increased risk for depression-related phenotypes. By exploring and combining genetic, environmental and psychopathologic concepts, the feasibility of these results has been explained by combining the popular genetic pleiotropy hypothesis in psychiatry with a notion of disease-specificity liability driven by the environment. With regards to activational plasticity, this work has proposed novel genetic and epigenetic signatures potentially underlying the clinical manifestation of neuropsychiatric and neurocognitive features of depression (i.e., the genetics of DNMT3B and the epigenetics of DEPDC7); additionally, it has proposed new putative neurobiological mechanisms to explain depressive traits (i.e., a combination of differential and variable methylation, a genetically-mediated hippocampal communication deficit, and a new amygdalar synchrony failure driven by the genes).

By taking advantage of the advent of functional Magnetic Resonance Imaging (fMRI) this thesis argues that aesthetics belongs in the domain of neurobiology by investigating the different brain processes that are implicated in aesthetic perception from two perspectives. The first experiment explores a specific artistic style that has stressed the problem in the relationship between objects and context. This study investigates the neural responses associated with changes in visual perception, as when objects are placed in their normal context versus when the object-context relationship is violated. Indeed, an aim of this study was to cast a new light on this specific artistic style from a neuroscientific perspective. In contrast to basic rewards, which relate to the reproduction of the species, the evolution of abstract, cognitive representations facilitates the use of a different class of rewards related to hedonics. The second part investigates the hedonic processes involved in aesthetic judgments in order to explore if such higher order cognitive rewards use the same neural reward mechanism as basic rewards. In the first of these experiments we modulate the extent to which the neural correlates of aesthetic preference vary as a function of expertise in architecture. In the second experiment we aim to measure the more general effects of labelling works of art with cognitive semantic information in order to explore the neural modulation of aesthetic preference relative to this information. The main finding of this thesis is that stimulus affective value is represented separately in OFC, with positive reward (increasing aesthetic judgments) being represented in medial OFC and negative reward value is being represented in lateral OFC. Furthermore ventral striatum encode reward expectancy and the predictive value of a stimulus. These findings suggest a dissociation of reward processing with separate neural substrates in reward expectancy and stimulus affective value.

This study aims to shed light on how and when mechanisms of the human brain evolved to support complex cognition and language. The field of evolutionary cognitive archaeology asserts that prehistoric technologies, as products of past cognition in action, are informative of the minimum cognitive and linguistic abilities that hominins needed to possess for their production. Previous researchers attempted to reconstruct the neural correlates of two Early Stone Age (ESA) tool industries, the 2.6 million-year-old Oldowan industry and the 0.7 million-year-old late Acheulian industry, by using positron emission tomography (PET) to observe the functional activation occurring in the brains of trained and expert stone knappers after making these different tool types. Because of evidence for overlap between the knapping and language circuits of the brain and increased anterior frontal activity during Acheulian tool production, these researchers argued that their results 1) indicate increased cognitive demands for late Acheulian tool production relative to Oldowan tool production and 2) support a technological origin for language, meaning that certain language functions co-opted the neural substrate and functions that were already established for toolmaking and tool use. Because of the motion limiting aspects of PET, however, these studies were unable to record the hemodynamic response of naturalistic stone knapping in real-time. They also were unable to observe the functional activation associated with the earliest stage of learning, which is likely to differ from late stage learning or expertise. Furthermore, any conclusion regarding a technological origin for language is problematic if it relies on data obtained from participants who learned to knap with verbal instruction. To test these two claims, this dissertation utilized a neuroimaging technique called functional near-infrared spectroscopy (fNIRS) to explore the neural correlates of real-time, naturalistic Oldowan and Acheulian stone knapping at three different points in learning. Participants in the study were separated into two groups to learn ESA knapping skills. Both groups watched the same video tutorials that depicted an expert’s hands as he made stone tools, but those in the verbal group heard spoken instructions, while those in the nonverbal group watched a version with the sound turned off. Functional brain images were reconstructed from the digitized landmarks of each participant’s head and from the optical data. An analysis of variance (ANOVA) revealed a clearer distinction between the neural processes of Oldowan and Acheulian tool manufacturing tasks than has previously been demonstrated. Only the Acheulian task recruited a frontotemporal working memory network. Selection for individuals with increased working memory capacities, which would have allowed them to make increasingly complex tools to gain access to novel dietary items, may have spurred the evolution of larger brain size in the genus Homo during the early Pleistocene. The results also demonstrated that the presence or absence of language during training dictated which higher-order cognitive areas of the brain become engaged and at what point in training. Thus, the results of previous neuroarchaeological studies reflect a very specific condition of stone knapping skill acquisition that involves linguistic instruction, which may not be analogous to how skills were transmitted during the ESA. Finally, evidence of overlap between left hemisphere language and stone knapping circuits among the participants in the nonverbal group lends additional support for the technological origin for language hypothesis.

Genome wide association studies have provided evidence for a significant association between ZNF804A (zinc finger protein 804A) - specifically the intronic single nucleotide polymorphism (SNP) rs1344706 - and schizophrenia, but little is known about the function of the gene or the effects of the SNP. By studying post-mortem human brain tissue, I characterised ZNF804A immunoreactivity in adult and foetal human brain and investigated effects of diagnosis and rs1344706 genotype on ZNF804A mRNA and protein expression. Secondly, I looked in a large sample of healthy volunteers (n=922) at the effects of rs1344706 on brain structure using volumetry and voxel based morphometry (VBM). Furthermore, I recruited healthy volunteers who were either homozygous for the risk allele or homozygous for the non-risk allele (n=50). They participated in magnetoencephalography (MEG) and magnetic resonance (MR) sessions in which brain activity was measured during a working memory task, a visual processing task, and rest. Using magnetic resonance spectroscopy, also neurotransmitter levels were assessed. The experiments conducted for this thesis showed for the first time that ZNF804A immunoreactivity can be detected in both foetal and adult human brain and that it is mainly localised to layer III pyramidal cells, with a granular subcellular distribution throughout the cytoplasm. No effect of rs1344706 on mRNA and protein expression was found. In our structural MRI study, rs1344706 did not affect macroscopic brain structure as measured by volumetry and VBM, and given the large sample size, this seems a convincing negative. However, we did find that rs1344706 alters prefrontal-hippocampal connectivity, with increased connectivity being observed in risk homozygotes. Additionally, using MEG, we found an effect of ZNF804A genotype on hippocampal connectivity in the theta band (4-8Hz), with non-risk homozygotes displaying more connectivity. This finding provides a first clue as to the mechanisms that might underlie the previously observed effects of rs1344706 on prefrontal-hippocampal connectivity. Future studies will need to elucidate the actual function of the ZNF804A protein, in order to bridge the gap between the molecular and neuroimaging findings described in this thesis.

Comment les agents anesthésiques induisent-ils une perte de conscience lors de l’anesthésie générale? La dissection des mécanismes neuronaux de l’anesthésie générale représente un défi important en neurosciences. L’émergence de l’IRM fonctionnelle (IRMf) chez le primate non-humain donne l’occasion d’étudier l’activité neuronale à l’état éveillé et sous anesthésie en s’affranchissant des contraintes cliniques. Le développement récent de paradigmes auditifs, tel que le paradigme ‘local-global’, qui explore spécifiquement les réseaux cérébraux impliqués dans l’état conscient, nous a permis d’émettre l’hypothèse que la combinaison de l’IRMf chez le primate, de paradigmes auditifs et de protocoles d’anesthésie contrôlés par l’électroencéphalogramme (EEG), pourraient aider à disséquer les mécanismes neuronaux de l’anesthésie générale.Dans une première étape, étant donnée l’utilisation extensive de l’IRM dans notre travail, il était important d’étudier systématiquement l’effet des agents anesthésiques sur l’oxygénation vasculaire cérébrale, paramètre critique pour le signal IRMf. Nous avons donc réalisé une expérience préliminaire, faisant appel à l’IRM à ultra-haut champ magnétique chez le rongeur, afin de détecter les éventuels modifications du signal T2* induits par chacun des agents anesthésiques. Nous avons pu démontrer que le propofol et la kétamine, deux agents anesthésiques utilisés en clinique, affectaient moins l’oxygénation sanguine cérébrale que les anesthésiques volatils.Dans une deuxième étape, nous avons développé une « boîte à outils » pour l’IRMf chez le primate éveillé et anesthésié, et avons validé notre dispositif expérimental avec un paradigme auditif basé sur des sons simples (basse et haute fréquence).Dans une troisième étape, nous avons testé le paradigme auditif ‘local-global’ chez le macaque éveillé et avons pu démontrer que le cerveau du macaque est capable d’un codage prédictif hiérarchique à travers un espace de travail global, composé d’un réseau fronto-pariéto-cingulaire, montrant une forte homologie avec celui de l’Homme.Dans une quatrième étape, nous avons testé le paradigme auditif ‘local-global’, chez le macaque anesthésié et avons pu démontrer une désorganisation progressive de l’espace de travail global neuronal sous anesthésie. Cette désorganisation a été proportionnelle au niveau de sédation sous propofol, et complète sous sédation profonde à la kétamine. Ces résultats sont compatibles avec l’hypothèse selon laquelle le mécanisme de la perte de conscience sous anesthésie, est lié à une désorganisation de l’organisation fonctionnelle hiérarchique de l’espace de travail neuronal. Le cortex pariétal apparaît comme une cible commune aux deux agents anesthésiques.Dans la dernière étape, nous avons étudié le réseau cérébral par défaut (« default mode network ») chez le macaque éveillé et anesthésié. Nous avons pu démontrer que sous anesthésie, le cerveau présentait encore des patrons de connectivité distincts et riches, mais que ces patrons étaient fortement liés à l’organisation anatomique sous-jacente, alors que, à l’état éveillé cette organisation se caractérisait par un haut degré de flexibilité temporelle ce qui permet une exploration non-stéréotypée d’une plus grande variété d’états cérébraux.En conclusion, les agents anesthésiques entraînent une désorganisation de l’espace de travail global neuronal, avec pour conséquence l’altération des dynamiques temporelles de l’activité cérébrale spontanée, induisant ainsi une suppression de la conscience<br>How can anesthetics induce a loss of consciousness during general anesthesia? A major challenge in neuroscience is to dissect the mechanisms of general anesthesia, which is quite difficult to achieve in the clinical conditions. The dawning of monkey functional MRI (fMRI) in neuroscience is an important opportunity to investigate neuronal activity in awake and anesthetized conditions. The recent development of auditory paradigms, such as the ‘local-global’ paradigm, that specifically explore brain networks thought to be specific of the conscious state led us to hypothesize that the combination of primate fMRI, auditory paradigms and single-drug anesthetic protocols with electroencephalography (EEG) control would help dissect the neuronal mechanisms of general anesthesia. In a first step, because we planned an extensive use of fMRI in our work, it was key to screen anesthetic agents for their effects on brain vascular oxygenation, a critical parameter for fMRI signal. Thus we did a preliminary experiment using ultra-high field MRI in rodents to assess subtle changes of the T2* signal under different anesthetic conditions and could demonstrate that propofol and ketamine, both clinical anesthetics, affects less brain blood oxygenation than volatile agents. In a second step, we developed a toolbox for awake and anesthetized monkey fMRI and validated the experimental set-up with a simple sound paradigm (low and high frequency sounds). In the third step, we tested the ‘local-global’ auditory paradigm in awake monkeys and could demonstrate that the macaque brain was capable of hierarchical predictive coding through a hypothetical macaque Global Neuronal Workspace made of frontal, parietal and cingulate cortices, in a striking homology with humans. In the fourth step, we tested the ‘local-global’ auditory paradigm in anesthetized monkeys and could demonstrate a progressive disorganization of the macaque GNW under anesthesia when increasing the levels of propofol sedation, and a complete suppression of the macaque GNW under deep ketamine sedation. These results are compatible with the hypothesis that the mechanism of loss of consciousness under anesthesia is related to the disorganization of a hierarchical GNW, with the parietal cortex as a common target among anesthetics. In the final step we studied the default network by acquiring resting state in awake and anesthetized monkeys and could demonstrate that under anesthesia, the brain still exhibits distinct and rich connectivity patterns, but these patterns become strongly related to the underlying white-matter structural map in a monotonic manner, while the awake state is characterized by a high degree of temporal flexibility which allows for a non-stereotyped exploration of a greater variety of brain states. In conclusion, by disorganizing the GNW, anesthetics alter the temporal dynamics of spontaneous brain activity, and specifically its departure from mere random fluctuations along established anatomical routes, leading to consciousness suppression

Associative plasticity, which involves modification of synaptic strength by coactivation of two synaptic inputs, has been demonstrated in many species. Here I explore whether it is possible to induce associative plasticity within a corticocortical pathway in the human brain using a novel protocol that activates two brain areas repeatedly with double-site transcranial magnetic stimulation (TMS). The pathway between ventral premotor cortex (PMv) and primary motor cortex (M1) which computes hand movements for precision grasp was manipulated. First, I selectively potentiated physiological connectivity between the stimulated brain areas. The effects as assessed with paired-pulse TMS were in accordance with principles of spike timing-dependent plasticity (STDP), pathwayspecific and showed a different pattern of expression during rest and during performance of a naturalistic prehension task. Furthermore, I demonstrated that effects evolved rapidly, lasted for up to three hours and were reversible. In a follow-up study, the protocol‘s effects on network interactions were investigated using functional magnetic resonance imaging (fMRI), specifically focussing on functional connectivity of network nodes within the wider parietofrontal circuit controlling reaching-and-grasping. The study demonstrated that functional connectivity was causally modified between stimulated nodes and that those changes in coupling also affected parallel, functionally-related pathways. Comparison of neurophysiological (paired-pulse TMS) and functional (fMRI) connectivity between individuals revealed a linear relationship of these connectivity indices; the first can assess the physiological nature of the interaction, whereas the latter can elucidate global network effects, making the techniques complementary. Neurophysiological interactions of ipsilesional and contralesional PMv-M1 were tested in chronic subcortical stroke patients during grasping. Patients showed a diminished facilitatory influence of ipsilesional PMv on M1 compared to healthy controls which might contribute to their motor disability. Application of paired-associative TMS “normalised“ the reduced effective influence of ipsilesional PMv on M1 and this effect correlated with the patient‘s potential to improve their dexterity.

<p>The present thesis explored the neurobiological basis of three aspects of defense behaviors in humans. Positron emission tomography methodology was used, and changes in regional cerebral blood flow (rCBF) were measured as an index of neural activity. Firstly, brain function was studied in a group of patients suffering from combat-related posttraumatic stress disorder, using a symptom provocation paradigm with combat sounds in order to elicit fear. Exposure to auditory trauma reminders relative to neutral sounds was associated with increased rCBF in sensorimotor areas, the cerebellar vermis, the periaqueductal gray matter, and the right amygdala, whereas decreased activity was observed in the retrosplenial area of the posterior cingulate cortex. Secondly, the neural circuitry mediating the acoustic startle response and its habituation was studied in a group of healthy subjects. During acoustic startle stimulation as compared to a resting condition, increased rCBF was found in a medial posterior area of the pons corresponding to the nucleus reticularis pontis caudalis. As a result of startle repetition, altered activity was found in the cerebellum, pointing to its involvement in startle habituation. Thirdly, neural activity associated with startle modulation by phobic fear was studied in a group of subjects with specific animal phobias during exposure to pictures of their feared and non-feared objects, paired and unpaired with acoustic startle stimuli. As a result of startle potentiation, increased rCBF was found in the left amygdaloid-hippocampal region, and medially in the affective division of the anterior cingulate cortex. In conclusion, these results provide evidence for the involvement of limbic and paralimbic brain areas during fear provocation and fear-potentiated startle and for a similar neurocircuitry underlying startle in humans and animals.</p>

L’étude de la complexité de l’anatomie du cerveau humain nécessite la caractérisation des paramètres multimodaux et multi-échelle obtenus par des techniques de neuroimagerie récentes. Pour ce travail de thèse nous avons tiré profit d’un logiciel automatique actuel d’analyse surfacique d’images cérébrales afin d’extraire les phénotypes structuraux du cortex cérébral humain, c’est-à-dire l’épaisseur corticale, l’aire de la surface, la profondeur sulcale, la courbure et le contenu en myéline intracorticale. L’objectif principal de ce travail a été de caractériser des variables structurales multimodales sur une large base de données de plus de 450 adultes sains âgés de 18 à 57 ans (base de données BIL&amp;GIN) dans le but de décrire la variabilité interindividuelle de l’organisation structurale du cerveau et notamment la recherche de marqueurs de la maturation cérébrale et de la latéralisation. Nous avons tout d’abord pris l’exemple du gyrus de Heschl, support anatomique du cortex auditif primaire, qui possède une grande variabilité en lien avec l’existence de différents profils de duplication du gyrus couplée à de fortes différences interhémisphériques. Nous avons montré qu’une duplication partielle ou complète du gyrus de Heschl était associée à des modifications locorégionales d’épaisseur corticale, d’aire de la surface et de myéline localisée postérieurement à ce gyrus et dans le planum temporale, ces deux régions étant impliquées dans le traitement du langage. Dans une deuxième étude, nous avons recherché les modifications structurales du cortex associées à la maturation tardive (entre 18 et 30 ans) et à l’atrophie corticale liée au vieillissement. Nous avons montré que l’établissement d’un index de maturation basé sur l’intégration de l’épaisseur corticale et de la myéline intracorticale améliorait la discrimination entre les 2 profils de modifications de la substance grise pendant ces deux périodes de la vie. Finalement, nous avons caractérisé les asymétries corticales en utilisant un recalage surfacique des hémisphères qui s’affranchit des différences de morphologie sulcale et de position entre les deux hémisphères. Nous avons mis en évidence des régions pour lesquelles les asymétries d’épaisseur et de surface étaient concordantes (asymétrie gauche ou droite pour les deux variables anatomiques) et des régions pour lesquelles les asymétries étaient opposées (gauche pour l’une des variables et droite pour l’autre). Environ 20% des régions qui montraient une asymétrie d’épaisseur et d’aire présentaient des corrélations négatives entre ces variables. Il est frappant de constater que les deux régions ayant les asymétries les plus fortes, le planum temporale et le sillon temporal supérieur, ont des corrélations positives entre leurs asymétries d’épaisseur et d’aire. Le planum temporale possède une asymétrie gauche à la fois pour l’épaisseur et l’aire alors que le sillon temporal supérieur a une asymétrie droite pour les deux variables. Cette étude démontre qu’il existe des corrélations entre les asymétries d’épaisseur et d’aire qui sont caractéristiques de l’organisation du cortex. Ces régions sont des sites clé pour lesquels il reste maintenant à étudier la pertinence en tant que marqueurs de la latéralisation cérébrale et leurs corrélats fonctionnels<br>Studying the complexity of the human brain anatomy requires the characterization of multimodal and multiscale features obtained by recent in vivo neuroimaging techniques. In the present thesis, we benefited from up to date automated surface-based brain image analysis software to extract structural phenotypes of the human cerebral cortex, namely the cortical thickness, the surface area, the sulcal depth, the curvature and the intracortical myelin content. The principal aim of this work was to characterize multimodal structural variables on a large database of 450 healthy adults aged from 18 to 57 years (the BIL&amp;GIN database) in order to describe the inter-individual variability of brain structural organization and notably the research of candidate markers for brain maturation and lateralization. We first took the example of the Heschl’s gyrus hosting the primary auditory cortex and having high variability due to the presence of different pattern of gyrus duplication coupled with strong interhemispheric differences. We showed that the partial or complete duplication of the Heschl’s gyrus was associated to loco-regional modifications in terms of cortical thickness, surface area and myelin located posteriorly to this gyrus and in the planum temporale, this two regions being implied in language processing. In a second study, we investigated the cortical structural modifications associated to late maturation (between 18 and 30 years) and cortical atrophy linked to aging. We revealed that the computation of a maturation index based on an integration of cortical thickness and intracortical myelin improved the discrimination of two different patterns of grey matter changes during these different stages of life. Finally, we characterized cortical asymmetries using a specific hemisphere surface matching which removed differences in sulcal morphology and position between both hemispheres. We highlighted regions where thickness and surface area asymmetries were concordant (leftward or rightward asymmetry for both anatomical variables) and regions of opposite asymmetries (leftward for one and rightward for the other). About 20% of regions that showed cortical thickness and surface area asymmetries presented negative correlation between these variables. It is striking that the two regions with the strongest anatomical asymmetries; the planum temporale and the superior temporal sulcus had rather positive asymmetry correlations. The planum temporale presented a leftward asymmetry of both cortical thickness and area while the superior temporal sulcus showed a right asymmetry of the two variables. This study demonstrated that there were correlations between thickness and surface area asymmetries, characteristics of the cortex organization. These areas are key sites for which it now remains to study the anatomical relevance as markers of brain lateralization and its functional correlates

Indiana University-Purdue University Indianapolis (IUPUI)<br>The time course and biological mechanisms by which breast cancer (BC) and/or alterations in estrogen status lead to cognitive and brain changes remain unclear. The studies presented here use neuroimaging, cognitive testing, genetics, and biomarkers to investigate how post-chemotherapy interval (PCI), chemotherapy-induced amenorrhea (CIA), and genetic variation in the estrogen pathway affect the brain. Chapter 1 examines the association of post-chemotherapy interval (PCI) with gray matter density (GMD) and working memory-related brain activation in BC survivors (mean PCI 6.4, range 3-10 years). PCI was positively associated with GMD and activation in the right frontal lobe, and GMD in this region was correlated with global neuropsychological function. In regions where BC survivors showed decreased GMD compared to controls, this was inversely related to oxidative DNA damage and learning and memory scores. This is the first study to show neural effects of PCI and relate DNA damage to brain alterations in BC survivors. Chapter 2 demonstrates prospectively, in an independent cohort, decreased combined magnitudes of brain activation and deactivation from pre-to post-chemotherapy in patients undergoing CIA compared to both postmenopausal BC patients undergoing chemotherapy and healthy controls. CIA’s change in activity magnitude was strongly correlated with change in processing speed, suggesting this activity increase reflects effective cognitive compensation. These results demonstrate that the pattern of change in brain activity from pre- to post-chemotherapy varies according to pre-treatment menopausal status. Chapter 3 presents the effects of variation in ESR1, the gene that codes for estrogen receptor-α, on brain structure in healthy older adults. ESR1 variation was associated with hippocampus and amygdala volumes, particularly in females. Single nucleotide polymorphism (SNP) rs9340799 influenced cortical GMD and thickness differentially by gender. Apolipoprotein E (APOE)-ε4 carrier status modulated the effect of SNP rs2234693 on amygdala volumes in women. This study showed that genetic variation in estrogen relates to brain morphology in ways that differ by sex, brain region and APOE-ε4 carrier status. The three studies presented here explore the interplay of BC, estrogen, and cognition, showing that PCI, CIA, and ESR1 genotype influence brain phenotypes. Cognitive correlates of neuroimaging findings indicate potential clinical significance of these results.

‘To move things is all mankind can do. ... whether whispering a syllable or felling a forest.’ - Charles Sherrington --- The human motor system is one of the most complicated systems in the human body. This complex system of interactions and collaborations between different regions of the human nervous system enables humans to interact with their external environment. Several parts of the human central nervous system are required to communicate effectively to send signals to the target muscles to carry out the final voluntary or involuntary movements. At the level of the central nervous system (CNS), motor planning and control form the essential element of any voluntary movements and several models have been suggested to describe these processes. Internal models, and specifically the ‘forward model’ is one of the most recognised theories of human motor control function. In this thesis, I have investigated two different movement disorders in which motor dysfunction is suggested to be involved in motor planning level in one disorder and motor execution in the other. I used several novel MRI methods to elucidate the neuro-mechanisms and brain regions likely to be involved in motor impairment in these two disorders, developmental coordination disorder (DCD) and (Freidreich’s ataxia) FRDA. Integral to this process was an endeavor to investigate human motor control theory and examine its pathological aspects through the window of neuroimaging.

Tese de doutoramento, Engenharia Biomédica e Biofísica, Universidade de Lisboa, Faculdade de Ciências, 2015<br>In the last decade directed functional connectivity analysis has been increasingly adopted as a method to study the information transfer in the human brain. However, its use with functional neuroimaging data has faced several limitations and controversies, especially when applied to functional magnetic resonance imaging (fMRI) data. This thesis presents a study of directed functional connectivity metrics and their application to datasets from two of the most widely used functional neuroimaging techniques, electroencephalography (EEG) and fMRI. Since a major part of this work focuses on testing and benchmarking connectivity metrics in controlled simulations, an initial study was performed on known generative models, with varying degrees of biophysical fidelity, for the former datasets. Its results suggested that less realistic models are more suitable for large simulations, due to their computational efficiency, or for testing novel metrics, due to their increased control over simulated causal relations. The following study provided a thorough performance assessment of directed functional connectivity metrics in broad experimental simulations with synthetic fMRI data. Our conclusions argued in favor of their applicability in the context of fMRI, provided that a stringent set of experimental specifications is met. The two succeeding studies proposed a novel framework for causal inference, oriented to EEG data, with the use of adaptive data analysis. Their findings suggested that this new framework is able to not only provide improved frequency localization but also to restrict causal analysis to components with physical meaning. The last study provided the opportunity to apply some of the knowledge gathered throughout these studies in the analysis of intracranial EEG data from a patient with infantile spams. From studying the causal relations in the recorded data it was possible to delineate a seizure onset zone that is consistent, and even more specific, with regions determined clinically or by novel localization strategies.<br>Na última década a análise de conectividade funcional direccionada tem sido progressivamente adoptada no estudo da conectividade do cérebro humano. No entanto, a sua utilização com dados de neuroimagem funcional tem enfrentado uma série de limitações e controvérsias, especialmente quando aplicado a dados de ressonância magnética funcional (fMRI). Esta dissertação apresenta um estudo de métricas de conectividade funcional direccionada e na sua aplicação a registos de duas das técnicas de neuroimagem funcional mais utilizadas, electroencefalografia (EEG) e fMRI. Uma vez que uma grande parte deste trabalho consiste em testar e avaliar estas métricas recorrendo a simulações controladas, foi realizado um estudo inicial sobre os modelos generativos mais recorrentes na literatura, com diferentes graus de fidelidade biofísica, para EEG e fMRI. Os resultados sugeriram que os modelos menos realistas são mais adequados para grandes simulações, devido a requisitos computacionais baixos, ou para testar novas métricas, devido ao maior controle sobre as relações causais simuladas. O segundo estudo consistiu numa avaliação do desempenho da análise de conectividade funcional direccionada em simulações extensas com dados de fMRI sintéticos. As conclusões argumentaram a favor da aplicabilidade a dados fMRI, desde que um rigoroso conjunto de especificações experimentais seja cumprido. Os dois estudos seguintes propõem uma nova abordagem para a inferência causal através da análise de dados adaptativa. Os resultados sugerem que esta abordagem é capaz de, não só proporcionar uma melhor localização em frequência, mas também de restringir a análise causal a componentes com significado físico. No último estudo são efectuadas análises de causalidade em registos EEG intracranianos de um paciente com espasmos infantis. A partir do estudo das relações causais nestes registos, foi possível delinear uma zona epileptogénica consistente, e ainda mais específica, com as regiões determinadas clinicamente ou por novas estratégias de localização.

BACKGROUND: The potential pathogenesis between the presence and severity of chronic cerebrospinal venous insufficiency (CCSVI) and its relation to clinical and imaging outcomes in brain parenchyma of multiple sclerosis (MS) patients has not yet been elucidated. The aim of the study was to investigate the relationship between CCSVI, and altered brain parenchyma venous vasculature visibility (VVV) on susceptibility-weighted imaging (SWI) in patients with MS and in sex- and age-matched healthy controls (HC). METHODS: 59 MS patients, 41 relapsing-remitting and 18 secondary-progressive, and 33 HC were imaged on a 3T GE scanner using pre- and post-contrast SWI venography. The presence and severity of CCSVI was determined using extra-cranial and trans-cranial Doppler criteria. Apparent total venous volume (ATVV), venous intracranial fraction (VIF) and average distance-from-vein (DFV) were calculated for various vein mean diameter categories: < .3 mm, .3-.6 mm, .6-.9 mm and > .9 mm. RESULTS: CCSVI criteria were fulfilled in 79.7% of MS patients and 18.2% of HC (p < .0001). Patients with MS showed decreased overall ATVV, ATVV of veins with a diameter < .3 mm, and increased DFV compared to HC (all p < .0001). Subjects diagnosed with CCSVI had significantly increased DFV (p < .0001), decreased overall ATVV and ATVV of veins with a diameter < .3 mm (p < .003) compared to subjects without CCSVI. The severity of CCSVI was significantly related to decreased VVV in MS (p < .0001) on pre- and post-contrast SWI, but not in HC. CONCLUSIONS: MS patients with higher number of venous stenoses, indicative of CCSVI severity, showed significantly decreased venous vasculature in the brain parenchyma. The pathogenesis of these findings has to be further investigated, but they suggest that reduced metabolism and morphological changes of venous vasculature may be taking place in patients with MS.