Dopaminergic modulation of cortical motor network lateralization

Introduction Unilateral movements are primarily processed in contralateral cortical and subcortical areas and additionally in ipsilateral cerebellum, leading to an asymmetric pattern of neural activation. Decrease of lateralization is characteristic of aging (Naccarato et al., 2006; Wu et al., 2005), and disease, for example, in unilateral brain lesions or stroke (Carr et al., 1993; Rehme et al., 2011) and Parkinson's disease (PD; Wu et al., 2015). The explanation for imbalanced lateralization in drug-naive PD is an adaptive compensation, compatible with the finding that PD-associated deficient input from cortico-subcortical circuits is compensated by reduced cortical inhibition and increased cortical facilitation (Blesa et al., 2017). Here, we investigated the effect of dopamine depletion and substitution on cortical motor lateralization, with the hypothesis that lateralization decreases in advanced PD and that administration of levodopa, at least to a certain extent, reinstates lateralization. Methods We used fMRI to study motor activation in advanced PD patients and in healthy controls (HC) during unilateral upper and lower limb movements. Ten right-handed, left side symptom-dominant PD patients were tested in pseudo-randomized order after intake of their usual dopaminergic medication – 'ON' state – and after withdrawal of medication – 'OFF' state. Eighteen right-handed age-matched HC participated in a single session. We quantified activation lateralization using the average laterality index (AveLI; Matsuo et al., 2012) in three cortical motor regions of interest (ROIs): primary motor cortex (M1), supplementary motor area (SMA) and premotor cortex (PMC), during the four movement conditions. We compared AveLI between group pairs (PD OFF vs. HC, PD ON vs. HC, PD OFF vs. PD ON) within each ROI and movement condition. We estimated the effective connectivity between ROIs using bilinear dynamic causal modeling (DCM; Friston et al., 2003) and developed a measure to quantify the lateralization of the resulting connectivity networks to compare between groups. By constructing a group level parametric empirical Bayes (PEB) model (Friston et al., 2016) over all the subjects and conducting a search over nested models, we compared DCM parameter estimates between groups, thus providing the potential link between changes in motor lateralization and connectivity. Results In line with our predictions, motor activation lateralization as estimated with the AveLI showed a trend towards decrease in the PD OFF group compared to HC, in all three ROIs during left hand movement and in M1 during left foot movement (Fig. 1). Between-group differences were observed solely in conditions corresponding to movement of the more affected body side. Contrary to our hypothesis, dopamine substitution did not reinstate lateralization – in fact, AveLI in the PD ON group closely resembled that of the PD OFF group. Connectivity lateralization of input-specific modulation (DCM.B) networks was significantly lower in all conditions in the PD group as compared to HC. While on the body side more affected by PD, differences were found for both PD OFF and PD ON, input-specific modulation related to the less affected side was more altered in PD ON. PEB analysis revealed qualitatively more between-group differences in input-specific modulation on the more affected PD side and included many interhemispheric connections (Fig. 2). Conclusions Decreased lateralization is not only present in drug-naïve PD patients (Wu et al., 2015) but also in dopa-treated patients. Acute dopamine modulation does not alter lateralization. Decreased lateralization is evident in both fMRI activation amplitudes (as estimated with AveLI) and effective connectivity (as demonstrated through the DCM analysis)

Control of bacterial virulence through the peptide signature of the habitat

To optimize fitness, pathogens selectively activate their virulence program upon host entry. Here, we report that the facultative intracellular bacterium Listeria monocytogenes exploits exogenous oligopeptides, a ubiquitous organic N source, to sense the environment and control the activity of its virulence transcriptional activator, PrfA. Using a genetic screen in adsorbent- treated ( PrfA-inducing) medium, we found that PrfA is functionally regulated by the balance between activating and inhibitory nutritional peptides scavenged via the Opp transport system. Activating peptides provide essential cysteine precursor for the PrfA-inducing cofactor glutathione ( GSH). Non-cysteine-containing peptides cause promiscuous PrfA inhibition. Biophysical and co-crystallization studies reveal that peptides inhibit PrfA through steric blockade of the GSH binding site, a regulation mechanism directly linking bacterial virulence and metabolism. L. monocytogenes mutant analysis in macrophages and our functional data support a model in which changes in the balance of antagonistic Oppimported oligopeptides promote PrfA induction intra-cellularly and PrfA repression outside the host

Design and synthesis of amphiphiles with aromatic bodies for the selective separation of carbon nanotubes according to their helicity

Les propriétés électroniques des nanotubes de carbone monofeuillets (SWNTs) sont particulièrement intéressantes au point que ces objets pourraient être utilisés dans les ordinateurs de demain, à condition que l'homme réussisse à contrôler précisément leurSingle-Walled carbon NanoTubes (SWNTs) have been proved to show such unique electronic properties that they could integrate the next generations of computers, provided that their properties can be easily tuned. So far, all the manufacturing processes hav

ERP and behavioral indices of attractiveness in realistic female body pictures: a study on the effect of waist-to-hip ratio on visual processing

Waist-to-hip ratio (WHR) is defined as a human secondary sexual trait, affecting the attractiveness and conveying information about reproductive and genetic potential. To date, no electrophysiological indices have been found related to this aspect. The main goal of our research was to investigate the behavioral and electrophysiological indices linked to WHRs in female body processing and their relation to perceived sexual attractiveness in a healthy adult heterosexual population. We performed a behavioral rating task on attractiveness with 42 heterosexual subjects (20 males and 22 females) using 200 real female body pictures, seen from a back or front view, presenting 4 different WHRs (0.6, 0.7, 0.8 and 0.9). Consecutively we performed two 128-­‐channel EEG experiments with 18 heterosexual participants (9 males and 9 females). We presented WHR models from a front view with 4 different WHRs and scrambled pictures in a body decision task, in which participants were asked to reply manually to the targets (body or scrambled). In an attractiveness decision task, subjects looked at front views of female bodies with 2 different WHRs (0.7 and 0.9) while they rated them as “attractive” or “unattractive”. WHR variation modulated the reaction times and the behavioral ratings of the subjects, which showed a gradient of preference with bodies with medium (0.7) WHRs having the highest and bodies with high (0.9) WHRs having the lowest scores. WHR variation also affected P1 and N1 ERP components in terms of amplitude but not in terms of latency, and this modulation depended on the gender of the subject, the parameters of the task, and if the stimuli were targeted or untargeted. Our results also showed potential electrical sources behind some differences in the ERPs, revealing the possible role of the left middle frontal gyrus as a neural signature of WHR processing in men. Limitations of this study are discussed and perspectives for further analyses and future studies are suggested

FUNCTIONAL AND STRUCTURAL TOPOGRAPHY WITHIN CORTICO- SUBCORTICAL LOOPS IN PARKINSON'S DISEASE USING MAGNETIC RESONANCE IMAGING

Parkinson’s disease (PD) is a debilitating neurodegenerative disorder due to loss of dopamine producing cells in the substantia nigra. Given the fact that clinical symptoms emerge after a long preclinical period with gradual decline in dopamine production, there is pressing need to advance our understanding about the progression of motor and non- motor symptoms in symptomatic phase of PD. Recent theoretical work and animal models suggest a link between dopamine-dependent loss of neuronal specificity (LOS) in the basal ganglia (BG) and a broad range of symptoms in movement disorders. The overall goal of my thesis project was to test and validate this hypothesis in vivo using non-invasive magnetic resonance imaging (MRI). In a preparatory study for my main experiment, I evaluate how the spatial resolution of different MRI protocols impacts BGs motor somatotopy mapping. The second study tests the LOS hypothesis in PD patients and how functional segregation of motor somatotopy is affected by dopamine substitution. In a following study I expand the LOS hypothesis on the insular cortex, which shares major connections with the BG. My last experiment extends these findings to structural connectivity patterns of projections between thalamus, BG and cortex. I am truly convinced that my thesis project will contribute to advance our understanding of PD pathophysiology that helps monitoring and predicting clinical outcome. -- La maladie de Parkinson (MP) est une maladie neurodégénérative débilitante résultant de la perte des cellules dopaminergiques dans la substance noire. Etant donné l’émergence de symptômes cliniques après une longue période préclinique caractérisée par un déclin progressif de la production de dopamine, il est urgent de faire avancer notre compréhension de la progression des symptômes moteurs et non-moteurs dans la phase symptomatique de la MP. De récents travaux théoriques et modèles animaux suggèrent un lien entre une perte de la spécificité neuronale (PDS) dans les ganglions de la base (GB) dépendant de la dopamine et un large éventail de symptômes dans les troubles du mouvements. L’objectif général de mon projet de thèse était de tester et valider cette hypothèse in vivo en utilisant l’imagerie par résonance magnétique (IRM) non-invasive. Dans une étude préliminaire, j’ai évalué l’impact de la résolution spatiale de différents protocoles IRM sur la cartographie de la somatotopie motrice dans les GB. La deuxième étude teste l’hypothèse de la PDS chez des patients atteints de la MP et comment la ségrégation fonctionnelle de la somatotopie motrice est affectée par la substitution de dopamine. Dans l’étude suivante j’étends l’hypothèse de la PDS au cortex insulaire, qui partage d’importantes connections avec les GB. Ma dernière expérience étend ces découvertes aux patterns de connectivité structurelle entre le thalamus, les GB et le cortex. Je suis sincèrement convaincu que mon projet de thèse contribuera à l’avancée de notre compréhension de la pathophysiologie de la MP qui aide au suivi et à la prédiction de l’issue clinique

Conception et synthèse de tensioactifs à corps aromatiques pour la séparation sélective des nanotubes de carbone selon leur hélicité

Les propriétés électroniques des nanotubes de carbone monofeuillets (SWNTs) sont particulièrement intéressantes au point que ces objets pourraient être utilisés dans les ordinateurs de demain, à condition que l'homme réussisse à contrôler précisément leurs propriétés. Les nombreuses voies de synthèse connues des SWNTs ne conduisent qu'à des mélanges de nanotubes différents par leurs propriétés électroniques et leur géométrie. L'objet de cette thèse est de proposer un nouveau moyen pour trier les SWNTs en fonction de leur hélicité. Dans ce cadre, des tensioactifs à corps aromatiques ont été synthétisés et ont permis de séparer les SWNTs en fonction de leur structure. En outre, cette thèse avance des preuves que la séparation s'effectue grâce à la reconnaissance supramoléculaire par les tensioactifs aromatiques des SWNTs selon leur hélicité. Cette thèse a donc pour ambition de poser les bases d'une nouvelle approche pour le tri des SWNTs.Single-Walled carbon NanoTubes (SWNTs) have been proved to show such unique electronic properties that they could integrate the next generations of computers, provided that their properties can be easily tuned. So far, all the manufacturing processes have led to mixtures of SWNTs differing by their electronic properties and their geometry. This thesis proposes a new concept for the sorting of SWNTs according to their helicity. In this purpose, surfactants with aromatic cores have been designed and synthesised, they have then enabled to separate SWNTs according to their structure. Moreover, this separation is proved to occur thanks to the supramolecular recognition by the surfactants of the SWNTs according to their helicity. Thus, the purpose of this thesis is to lay the foundations of a new approach for the sorting of SWNTs

Design and synthesis of amphiphiles with aromatic bodies for the selective separation of carbon nanotubes according to their helicity

Les propriétés électroniques des nanotubes de carbone monofeuillets (SWNTs) sont particulièrement intéressantes au point que ces objets pourraient être utilisés dans les ordinateurs de demain, à condition que l'homme réussisse à contrôler précisément leurs propriétés. Les nombreuses voies de synthèse connues des SWNTs ne conduisent qu'à des mélanges de nanotubes différents par leurs propriétés électroniques et leur géométrie. L'objet de cette thèse est de proposer un nouveau moyen pour trier les SWNTs en fonction de leur hélicité. Dans ce cadre, des tensioactifs à corps aromatiques ont été synthétisés et ont permis de séparer les SWNTs en fonction de leur structure. En outre, cette thèse avance des preuves que la séparation s'effectue grâce à la reconnaissance supramoléculaire par les tensioactifs aromatiques des SWNTs selon leur hélicité. Cette thèse a donc pour ambition de poser les bases d'une nouvelle approche pour le tri des SWNTs.Single-Walled carbon NanoTubes (SWNTs) have been proved to show such unique electronic properties that they could integrate the next generations of computers, provided that their properties can be easily tuned. So far, all the manufacturing processes have led to mixtures of SWNTs differing by their electronic properties and their geometry. This thesis proposes a new concept for the sorting of SWNTs according to their helicity. In this purpose, surfactants with aromatic cores have been designed and synthesised, they have then enabled to separate SWNTs according to their structure. Moreover, this separation is proved to occur thanks to the supramolecular recognition by the surfactants of the SWNTs according to their helicity. Thus, the purpose of this thesis is to lay the foundations of a new approach for the sorting of SWNTs

Conception et synthèse de tensioactifs à corps aromatiques pour la séparation sélective des nanotubes de carbone selon leur hélicité

Les propriétés électroniques des nanotubes de carbone monofeuillets (SWNTs) sont particulièrement intéressantes au point que ces objets pourraient être utilisés dans les ordinateurs de demain, à condition que l'homme réussisse à contrôler précisément leurs propriétés. Les nombreuses voies de synthèse connues des SWNTs ne conduisent qu'à des mélanges de nanotubes différents par leurs propriétés électroniques et leur géométrie. L'objet de cette thèse est de proposer un nouveau moyen pour trier les SWNTs en fonction de leur hélicité. Dans ce cadre, des tensioactifs à corps aromatiques ont été synthétisés et ont permis de séparer les SWNTs en fonction de leur structure. En outre, cette thèse avance des preuves que la séparation s'effectue grâce à la reconnaissance supramoléculaire par les tensioactifs aromatiques des SWNTs selon leur hélicité. Cette thèse a donc pour ambition de poser les bases d'une nouvelle approche pour le tri des SWNTs.Single-Walled carbon NanoTubes (SWNTs) have been proved to show such unique electronic properties that they could integrate the next generations of computers, provided that their properties can be easily tuned. So far, all the manufacturing processes have led to mixtures of SWNTs differing by their electronic properties and their geometry. This thesis proposes a new concept for the sorting of SWNTs according to their helicity. In this purpose, surfactants with aromatic cores have been designed and synthesised, they have then enabled to separate SWNTs according to their structure. Moreover, this separation is proved to occur thanks to the supramolecular recognition by the surfactants of the SWNTs according to their helicity. Thus, the purpose of this thesis is to lay the foundations of a new approach for the sorting of SWNTs.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Novel Imaging Techniques to Study the Functional Organization of the Human Brain

Despite more than a century of investigation into the cortical organization of motor function, the existence of motor somatotopy is still debated. We review functional magnetic resonance imaging (fMRI) studies examining motor somatotopy in the cerebral cortex. In spite of a substantial overlap of representations corresponding to different body parts, especially in non-primary motor cortices, geographic approaches are capable of revealing somatotopic ordering. From the iconic homunculus in the contralateral primary cortex to the subtleties of ipsilateral somatotopy and its relations with lateralization, we outline potential reasons for the lack of segregation between motor representations. Among these are the difficulties in distinguishing activity that arises from multiple muscular effectors, the need for flexible motor control and coordination of complex movements through functional integration and artefacts in fMRI. Methodological advances with regard to the optimization of experimental design and fMRI acquisition protocols as well as improvements in spatial registration of images and indices aiming at the quantification of the degree of segregation between different functional representations are inspected. Additionally, we give some hints as to how the functional organization of motor function might be related to various anatomical landmarks in brain morphometry