Évaluation du contrôle sensorimoteur chez les patients ayant une scoliose idiopathique de l'adolescent - Vers un biomarqueur des troubles sensorimoteur basé sur la stimulation vestibulaire galvanique

La scoliose est la pathologie déformante du rachis la plus courante de l’adolescence. Dans 80 % des cas, elle est idiopathique, signifiant qu’aucune cause n’a été associée. Les scolioses idiopathiques répondent à un modèle multifactoriel incluant des facteurs génétiques, environnementaux, neurologiques, hormonaux, biomécaniques et de croissance squelettique. Comme hypothèse neurologique, une anomalie vestibulaire provoquerait une asymétrie d’activation des voies vestibulospinales et des muscles paravertébraux commandés par cette voie, engendrant la déformation scoliotique. Certains modèles animaux permettent de reproduire ce mécanisme. De plus, des anomalies liées au système vestibulaire, comme des troubles de l’équilibre, sont observées chez les patients avec une scoliose. La stimulation vestibulaire galvanique permet d’explorer le contrôle sensorimoteur de l’équilibre puisqu’elle permet d’altérer les afférences vestibulaires. L’objectif de cette thèse est d’explorer le contrôle sensorimoteur en évaluant la réaction posturale provoquée par cette stimulation chez les patients et les participants contrôle. Dans la première étude, les patients sont plus déstabilisés que les contrôles et il n’y a pas de lien entre l’ampleur de l’instabilité et la sévérité de la scoliose. Dans la deuxième étude, à l’aide d’un modèle neuromécanique, un poids plus grand aux signaux vestibulaires a été attribué aux patients. Dans la troisième étude, un problème sensorimoteur est également observé chez les jeunes adultes ayant une scoliose, excluant ainsi que le problème soit dû à la maturation du système nerveux. Dans une étude subséquente, des patients opérés pour réduire leur déformation du rachis, montrent également une réaction posturale de plus grande amplitude à la stimulation comparativement à des participants contrôle. Ces résultats suggèrent que l’anomalie sensorimotrice ne serait pas secondaire à la déformation. Finalement, un algorithme a été développé pour identifier les patients ayant un problème sensorimoteur. Les patients montrant un contrôle sensorimoteur anormal ont également une réponse vestibulomotrice plus grande et attribuent plus de poids aux informations vestibulaires. Globalement, les résultats de cette thèse montrent qu’un déficit sensorimoteur expliquerait l’apparition de la scoliose mais pas sa progression. Le dysfonctionnement sensorimoteur n’est pas présent chez tous les patients. L’algorithme permettant une classification de la performance sensorimotrice pourrait être utile pour de futures études cliniques.

Hemophagocytic Lymphohistiocytosis Complicating Myelodysplasia

We describe a 62-year-old patient with a 4-year history of myelodysplasia who later developed striking features that included massive splenomegaly, rapidly evolving visual loss and a sensorimotor polyneuropathy. This led us to consider the diagnosis of haemophagocytic lymphohistiocytosis (HLH). Upon further investigation, we found that he fulfilled the necessary diagnostic criteria for HLH, including the presence of haemophagocytosis of erythroid precursors on bone marrow smear.

Movement Sonification: Effects on Motor Learning beyond Rhythmic Adjustments

Motor learning is based on motor perception and emergent perceptual-motor representations. A lot of behavioral research is related to single perceptual modalities but during last two decades the contribution of multimodal perception on motor behavior was discovered more and more. A growing number of studies indicates an enhanced impact of multimodal stimuli on motor perception, motor control and motor learning in terms of better precision and higher reliability of the related actions. Behavioral research is supported by neurophysiological data, revealing that multisensory integration supports motor control and learning. But the overwhelming part of both research lines is dedicated to basic research. Besides research in the domains of music, dance and motor rehabilitation, there is almost no evidence for enhanced effectiveness of multisensory information on learning of gross motor skills. To reduce this gap, movement sonification is used here in applied research on motor learning in sports. Based on the current knowledge on the multimodal organization of the perceptual system, we generate additional real-time movement information being suitable for integration with perceptual feedback streams of visual and proprioceptive modality. With ongoing training, synchronously processed auditory information should be initially integrated into the emerging internal models, enhancing the efficacy of motor learning. This is achieved by a direct mapping of kinematic and dynamic motion parameters to electronic sounds, resulting in continuous auditory and convergent audiovisual or audio-proprioceptive stimulus arrays. In sharp contrast to other approaches using acoustic information as error-feedback in motor learning settings, we try to generate additional movement information suitable for acceleration and enhancement of adequate sensorimotor representations and processible below the level of consciousness. In the experimental setting, participants were asked to learn a closed motor skill (technique acquisition of indoor rowing). One group was treated with visual information and two groups with audiovisual information (sonification vs. natural sounds). For all three groups learning became evident and remained stable. Participants treated with additional movement sonification showed better performance compared to both other groups. Results indicate that movement sonification enhances motor learning of a complex gross motor skill-even exceeding usually expected acoustic rhythmic effects on motor learning.

MRI indices of functional recovery following intracerebral implantation of a human neural stem cell line in a pre-clinical model of ischaemic stroke

Stem cell therapy for ischaemic stroke is an emerging field in light of an increasing number of patients surviving with permanent disability. Several allogenic and autologous cells types are now in clinical trials with preliminary evidence of safety. Some clinical studies have reported functional improvements in some patients. After initial safety evaluation in a Phase 1 study, the conditionally immortalised human neural stem cell line CTX0E03 is currently in a Phase 2 clinical trial (PISCES-II). Previous pre-clinical studies conducted by ReNeuron Ltd, showed evidence of functional recovery in the Bilateral Asymmetry test up to 6 weeks following transplantation into rodent brain, 4 weeks after middle cerebral artery occlusion. Resting-state fMRI is increasingly used to investigate brain function in health and disease, and may also act as a predictor of recovery due to known network changes in the post-stroke recovery period. Resting-state methods have also been applied to non-human primates and rodents which have been found to have analogous resting-state networks to humans. The sensorimotor resting-state network of rodents is impaired following experimental focal ischaemia of the middle cerebral artery territory. However, the effects of stem cell implantation on brain functional networks has not previously been investigated. Prior studies assessed sensorimotor function following sub-cortical implantation of CTX0E03 cells in the rodent post-stroke brain but with no MRI assessments of functional improvements. This thesis presents research on the effect of sub-cortical implantation of CTX0E03 cells on the resting- state sensorimotor network and sensorimotor deficits in the rat following experimental stroke, using protocols based on previous work with this cell line. The work in this thesis identified functional tests of appropriate sensitivity for long-term dysfunction suitable for this laboratory, and investigated non-invasive monitoring of physiological variables required to optimize BOLD signal stability within a high-field MRI scanner. Following experimental stroke, rats demonstrated expected sensorimotor dysfunction and changes in the resting-state sensorimotor network. CTX0E03 cells did not improve post-stroke functional outcome (compared to previous studies) and with no changes in resting-state sensorimotor network activity. However, in control animals, we observed changes in functional networks due to the stereotaxic procedure. This illustrates the sensitivity of resting-state fMRI to stereotaxic procedures. We hypothesise that the damage caused by cell or vehicle implantation may have prevented functional and network recovery which has not been previously identified due to the application of different functional tests. The findings in this thesis represent one of few pre-clinical studies in resting-state fMRI network changes post-stroke and the only to date applying this technique to evaluate functional outcomes following a clinically applicable human neural stem cell treatment for ischaemic stroke. It was found that injury caused by stereotaxic injection should be taken into account when assessing the effectiveness of treatment.

Functional heterogeneity of medial posterior parietal cortex of macaque monkey

The posterior parietal cortex (PPC) of primates represents a remarkable platform that has evolved over time to solve some of the computational challenges that we face in the everyday life, such as sensorimotor integration, spatial attention, and motor planning. With the aim of further investigating the multifaceted functional characteristics of medial PPC, we conducted three studies to explore the visuomotor, somatic, visual, and attention-related properties of two PPC areas: V6A, a visuomotor area part of the dorsomedial visual stream, and PE, an area strongly dominated by somatomotor input, residing mainly on the exposed surface of the superior parietal lobule. In the first study, we tested the impact of visual feedback on V6A grasp-related activity during arm movements towards objects of different shapes. Our results demonstrate that V6A is modulated by both grip type and visual information during grasping preparation and execution, with a predominance of cells influenced by grip type. In the second study, we explored the influence of depth and direction information on reach-related activity of neurons in the so far largely neglected medial part of area PE. We observed a remarkable trend in medial PPC, going from the joint coding of depth and direction signals caudally, in area V6A, to a largely segregated processing of the two signals rostrally, in area PE. In the third study, we used a combined fMRI-electrophysiology experiment to investigate the neuronal mechanisms underlying covert shift of attention processes in area V6A. Our preliminary results reveal that half of the cells showed shift-selective activity when the monkey covertly shifted its attention towards the receptive field. All together these findings highlight the role of the medial PPC in integrating information coming from different sources (vision, somatosensory and motor) and emphasize the involvement of action-related regions of the dorsomedial visual stream in higher level cognitive functions.

Variety, flexibility, and use of abstract concepts. A multiple grounded perspective.

The nature of concepts is a matter of intense debate in cognitive sciences. While traditional views claim that conceptual knowledge is represented in a unitary symbolic system, recent Embodied and Grounded Cognition theories (EGC) submit the idea that conceptual system is couched in our body and influenced by the environment (Barsalou, 2008). One of the major challenges for EGC is constituted by abstract concepts (ACs), like fantasy. Recently, some EGC proposals addressed this criticism, arguing that the ACs comprise multifaced exemplars that rely on different grounding sources beyond sensorimotor one, including interoception, emotions, language, and sociality (Borghi et al., 2018). However, little is known about how ACs representation varies as a function of life experiences and their use in communication. The theoretical arguments and empirical studies comprised in this dissertation aim to provide evidence on multiple grounding of ACs taking into account their varieties and flexibility. Study I analyzed multiple ratings on a large sample of ACs and identified four distinct subclusters. Study II validated this classification with an interference paradigm involving motor/manual, interoceptive, and linguistic systems during a difficulty rating task. Results confirm that different grounding sources are activated depending on ACs kind. Study III-IV investigate the variability of institutional concepts, showing that the higher the law expertise level, the stronger the concrete/emotional determinants in their representation. Study V introduced a novel interactive task in which abstract and concrete sentences serve as cues to simulate conversation. Analysis of language production revealed that the uncertainty and interactive exchanges increase with abstractness, leading to generating more questions/requests for clarifications with abstract than concrete sentences. Overall, results confirm that ACs are multidimensional, heterogeneous, and flexible constructs and that social and linguistic interactions are crucial to shaping their meanings. Investigating ACs in real-time dialogues may be a promising direction for future research.

Ethics in the flesh: formalizing moral values in embodied cognition

Values are beliefs or principles that are deemed significant or desirable within a specific society or culture, serving as the fundamental underpinnings for ethical and socio-behavioral norms. The objective of this research is to explore the domain encompassing moral, cultural, and individual values. To achieve this, we employ an ontological approach to formally represent the semantic relations within the value domain. The theoretical framework employed adopts Fillmore’s frame semantics, treating values as semantic frames. A value situation is thus characterized by the co-occurrence of specific semantic roles fulfilled within a given event or circumstance. Given the intricate semantics of values as abstract entities with high social capital, our investigation extends to two interconnected domains. The first domain is embodied cognition, specifically image schemas, which are cognitive patterns derived from sensorimotor experiences that shape our conceptualization of entities in the world. The second domain pertains to emotions, which are inherently intertwined with the realm of values. Consequently, our approach endeavors to formalize the semantics of values within an embodied cognition framework, recognizing values as emotional-laden semantic frames. The primary ontologies proposed in this work are: (i) ValueNet, an ontology network dedicated to the domain of values; (ii) ISAAC, the Image Schema Abstraction And Cognition ontology; and (iii) EmoNet, an ontology for theories of emotions. The knowledge formalization adheres to established modeling practices, including the reuse of semantic web resources such as WordNet, VerbNet, FrameNet, DBpedia, and alignment to foundational ontologies like DOLCE, as well as the utilization of Ontology Design Patterns. These ontological resources are operationalized through the development of a fully explainable frame-based detector capable of identifying values, emotions, and image schemas generating knowledge graphs from from natural language, leveraging the semantic dependencies of a sentence, and allowing non trivial higher layer knowledge inferences.