Describing a comprehensive neurofunctional model of sentence comprehension has always been a complex challenge. On one hand, disentangling the subprocesses that are necessary for computing the meaning of a sentence and their neural underpinnings is insidious. Each subprocess is closely interconnected with the others, and isolating only one as if it were separable can undermine the investigation of the overall process above. On the other hand, available data on the neural basis of sentence processing are not straightforward. This thesis explores relevant contributions and attempts to highlight open questions regarding the neural basis of two key processes in sentence comprehension, namely morphosyntactic processing and thematic role assignment. It presents and discusses original data resulting from an experiment that, to our knowledge, represents the first investigation of the neural basis of these two processes in the same sentential context. Results demonstrate that morphosyntactic and thematic processing rely on functionally distinct neural correlates in the left hemisphere. Morphosyntactic aspects are mostly processed in a left prefrontal network including the left inferior frontal gyrus (IFG) and the middle frontal gyrus (MFG), whereas thematic role assignment correlates with a left parietal node including the left intraparietal sulcus (IPS). Moreover, it is argued that results support the view that these regions play a language-related rather than domain-general role in human cognition. Finally, two statistical approaches to the analysis of the same TMS language data (ANOVA and Linear Mixed Models – LMMs) are compared. Their outcomes are discussed and an attempt is made at accounting for similarities and differences. Results suggest that the two models should not be considered on a sort of quality hierarchy according to which one has greater or lesser explanatory power than the other. Rather, they both represent legitimate and reliable approaches to account for data variability.

Basierend auf der aktuellen Studienlage wurde versucht, Modellannahmen zum auditi- ven Sprachverständnisses weiter zu ergründen. Im Mittelpunkt stand dabei die Rolle des Gyrus angularis der sprachdominanten Hemisphäre bei der semantischen Integration von Worten in einen gegebenen Satzkontext. Zu diesem Zweck wurden 15 gesunde Proban- den mithilfe von repetitiver transkranieller Magnetstimulation (rTMS) in einem Sprach- verständnisexperiment untersucht. So konnte die funktionelle Relevanz der genannten Hirnregion in Abhängigkeit der Signalqualität des gehörten Satzes und des semanti- schen Kontextes untersucht werden. Zielparameter waren dabei der Anteil der korrekt wiederholten Wörter und Schlüsselwörter des Satzes sowie die Reaktionsgeschwindigkeit.

Ce travail de thèse a pour objectif d'aider à la compréhension neuropathophysiologique des troubles de l'humeur. Les nombreuses études s'intéressant à ce type de pathologie font face à un manque d'outil objectif de catégorisation de la maladie et donc à des difficultés dans le diagnostic différentiel. Les modifications neurofonctionnelles sont majoritairement basées sur deux modèles : le modèle de l'hypofrontalité, qui explique l'état dépressif par une diminution de l'activité des zones corticales frontales et une augmentation de celle des régions sous-corticales ; et le modèle de l'asymétrie interhémisphérique, intégré aux théories sur la latéralisation des émotions, qui fait du déséquilibre fonctionnel interhémisphérique (hémisphère droit plus actif que le gauche) le corrélat neurologique aux troubles de l'humeur. Malgré tous les efforts d'élimination de biais méthodologiques les chercheurs ne trouvent pas de consensus. Le but de cette recherche est de trouver des indicateurs objectifs du trouble dépressif par des techniques psychophysiques (oculométrie) et neurophysiologiques (excitabilité corticale). Nous avons donc suivi des patients recevant des traitements pharmacologiques ou des cures de stimulation magnétique transcrânienne (TMS) afin d'observer les effets de ces derniers et de voir si des déséquilibres, qu'ils soient intra- ou inter-hémisphériques, peuvent être mis en évidence et alors aider dans le choix du traitement. Nos résultats mettent en évidence la variabilité interindividuelle qui suppose que chaque patient peut présenter une pathophysiologie différente. Par ailleurs, le suivi de patients bipolaires dans les différentes phases thymiques suggère une inversion des déficits entre les phases maniaques et dépressives. Plusieurs corrélats pourraient donc engendrer une humeur dépressive et le choix d'une cure rTMS latéralisée pourrait être guidée par les modifications observées.

The present work introduces a synthesis of neocerebellar state estimation and feedforward control with multi-level language processing. The approach combines insights from clinical, imaging, and modelling work on the cerebellum with psycholinguistic and historical linguistic research. It finally provides the first experimental attempts towards the empirical validation of this synthesis, employing transcranial magnetic stimulation. A neuroanatomical locus traditionally seen as limited to lower sensorimotor functions, the cerebellum has, over the last decades, emerged as a widely accepted foundation of feedforward control and state estimation. Its cytoarchitectural homogeneity and diverse connectivity with virtually all parts of the central nervous system strongly support the idea of a uniform, domain-general cerebellar computation. Its reciprocal connectivity with language-related cortical areas suggests that this uniform cerebellar computation is also applied in language processing. Insight into the latter, however, remains an elusive desideratum; instead, research on cerebellar language functions is predominantly involved in the frontal cortical-like deficits (e.g. aphasias) seldom induced by cerebellar impairment. At the same time, reflections on cerebellar computations in language processing remain at most speculative, given the lack of discourse between cerebellar neuroscientists and psycholinguists. On the other hand, the fortunate contingency of the recent accommodation of these computations in psycholinguistic models provides the foundations for satisfying the desideratum above. The thesis thus formulates a neurolinguistic model whereby multi-level, predictive, associative linguistic operations are acquired and performed in neocerebello-cortical circuits, and are adaptively combined with cortico-cortical categorical processes. A broad range of psycholinguistic phenomena, involving, among others, "pragmatic normalization", "verbal/semantic illusions", associative priming, and phoneme restoration, are discussed in the light of recent findings on neocerebellar cognitive functions, and provide a rich research agenda for the experimental validation of the proposal. The hypothesis is then taken further, examining grammaticalization changes in the light of neocerebellar linguistic contributions. Despite a) the broad acceptance of routinization and automatization processes as the domain-general core of grammaticalization, b) the growing psycholinguistic research on routinized processing, and c) the evidence on neural circuits involved in automatization processes (crucially involving the cerebellum), interdisciplinary discourse remains strikingly poor. Based on the above, a synthesis is developed, whereby grammaticalization changes are introduced in routinized dialogical interaction as the result of maximized involvement of associative neocerebello-cortical processes. The thesis then turns to the first steps taken towards the verification of the hypothesis at hand. In view of the large methodological limitations of clinical research on cerebellar cognitive functions, the transcranial magnetic stimulation apparatus is employed instead, producing the very first linguistic experiments involving cerebellar stimulation. Despite the considerable technical difficulties met, neocerebellar loci are shown to be selectively involved in formal- and semantic-associative computations, with far-reaching consequences for neurolinguistic models of sentence processing. In particular, stimulation of the neocerebellar vermis is found to selectively enhance formal-associative priming in native speakers of English, and to disrupt, rather selectively, semantic-categorical priming in native speakers of Modern Greek, as well as to disrupt the practice-induced facilitation in processing repeatedly associated letter strings. Finally, stimulation of the right neocerebellar Crus I is found to enhance, quite selectively, semantic-associative priming in native speakers of English, while stimulation of the right neocerebellar vermis is shown to disrupt semantic priming altogether. The results are finally discussed in the light of a future research agenda overcoming the technical limitations met here.

This thesis investigated the processing of emotional stimuli by the visual system, and how the processing of emotions interacts with visual awareness. Emotions have been given ‘special’ status by some previous research, with evidence that the processing of emotions may be relatively independent of striate cortex, and less affected by disruption to awareness than processing of emotionally neutral images. Yet the extent to which emotions are ‘special’ remains questionable. This thesis focused on the processing of emotional stimuli when activity in V1 was disrupted using transcranial magnetic stimulation (TMS), and whether emotional properties of stimuli can be reliably discriminated, or affect subsequent responses, when visibility is low. Two of the experiments reported in this thesis disrupted activity in V1 using TMS, Experiment 1 with single pulses in an online design, and Experiment 2 with theta burst stimulation in an offline design. Experiment 1 found that a single pulse of TMS 70-130 ms following a presentation of a body posture image disrupted processing of neutral but not emotional postures in an area of the visual field that corresponded to the disruption. Experiment 2 did not find any convincing evidence of disruption to processing of neutral or emotional faces. From Experiment 1 it would appear that emotional body posture images were relatively unaffected by TMS, and appeared to be robust to disruption to V1. Experiment 2 did not add to this as there was no evidence of disruption in any condition. Experiments 3 and 4 used visual masking to disrupt awareness of emotional and neutral faces. Both experiments used a varying interval between the face and the mask stimuli to systematically vary the visibility of the faces. Overall, the shortest SOA produced the lowest level of visibility, and this level of visibility was arguably outside awareness. In Experiment 3, participants’ ability to discriminate properties of emotional faces under low visibility conditions was greater than their ability to discriminate the orientation of the face. This was despite the orientation discrimination being much easier at higher levels of visibility. Experiment 4 used a gender discrimination task, with emotion providing a redundant cue to the decision (present half of the time). Despite showing a strong linear masking function for the neutral faces, there was no evidence of any emotion advantage. Overall, Experiment 3 gave some evidence of an emotion advantage under low visibility conditions, but this effect was fairly small and not replicated in Experiment 4. Finally, Experiments 5-8 used low visibility emotional faces to prime responses to subsequent emotional faces (Experiments 5 and 6) or words (Experiments 7 and 8). In Experiments 5, 7 and 8 there was some evidence of emotional priming effects, although these effects varied considerably across the different designs used. There was evidence for meaningful processing of the emotional prime faces, but this processing only led to small and variable effects on subsequent responses. In summary, this thesis found some evidence that the processing of emotional stimuli was relatively robust to disruption in V1 with TMS. Attempts to find evidence for robust processing of emotional stimuli when disrupted with backwards masking was less successful, with at best mixed results from discrimination tasks and priming experiments. Whether emotional stimuli are processed by a separate route(s) in the brain is still very much open to debate, but the findings of this thesis offers small and inconsistent evidence for a brain network for processing emotions that is relatively independent of V1 and visual awareness. The network and nature of brain structures involved in the processing of subliminal and low visibility processing of emotions remains somewhat elusive.

Peripheral nerve stimulation (PNS) is commonly used to promote use-dependent cortical plasticity for rehabilitation of motor function in spinal cord injury. Pairing transcranial magnetic stimulation (TMS) with PNS has been shown to increase motor evoked potentials most when the two stimuli are timed to arrive in the cortex simultaneously. This suggests that a mechanism of timing-dependent plasticity (TDP) may be a more effective method of promoting motor rehabilitation. The following thesis is the result of applying a brain-computer interface to apply PNS in closed-loop simultaneously to movement intention onset as measured by EEG of the sensorimotor cortex to test whether TDP can be induced in incomplete spinal cord injured individuals with upper limb motor impairment. 4 motor incomplete SCI subjects have completed 12 sessions of closed-loop PNS delivered over 4-6 weeks. Benefit was observed for every subject although not consistently across metrics. 3 out of 4 subjects exhibited increased maximum voluntary contraction force (MVCF) between first and last interventions for one or both hands. TMS-measured motor map volume increased for both hemispheres in one subject, and TMS center of gravity shifted in 3 subjects consistent with studies in which motor function improved or was restored. These observations suggest that rehabilitation using similar designs for responsive stimulation could improve motor impairment in SCI.

Chez les personnes post-AVC (Accident Vasculaire Cérébral), spasticité, faiblesse et toute autre coactivation anormale proviennent de limitations dans la régulation de la gamme des seuils des réflexes d'étirement. Nous avons voulu savoir si les déficits dans les influences corticospinales résiduelles contribuaient à la limitation de la gamme des seuils et au développement de la spasticité chez les patients post-AVC. La stimulation magnétique transcranienne (SMT) a été appliquée à un site du cortex moteur où se trouvent les motoneurones agissant sur les fléchisseurs et extenseurs du coude. Des potentiels évoqués moteurs (PEM) ont été enregistrés en position de flexion et d'extension du coude. Afin d'exclure l'influence provenant de l'excitabilité motoneuronale sur l'évaluation des influences corticospinales, les PEM ont été suscités lors de la période silencieuse des signaux électromyographiques (EMG) correspondant à un bref raccourcissement musculaire juste avant l'enclenchement de la SMT. Chez les sujets contrôles, il y avait un patron réciproque d'influences corticospinales (PEM supérieurs en position d'extension dans les extenseurs et vice-versa pour les fléchisseurs). Quant à la plupart des sujets post-AVC ayant un niveau clinique élevé de spasticité, la facilitation corticospinale dans les motoneurones des fléchisseurs et extenseurs était supérieure en position de flexion (patron de co-facilitation). Les résultats démontrent que la spasticité est associée à des changements substantiels des influences corticospinales sur les motoneurones des fléchisseurs et des extenseurs du coude. / In post-stroke patients, spasticity, weakness and abnormal coactivation result from limitations in the range of regulation of stretch reflex thresholds. We investigated whether the deficits in residual corticospinal influences contribute to the limitation in the regulation of those thresholds and as a result to spasticity in post-stroke subjects. A single-pulse transcranial magnetic stimulation (TMS) was applied to the site of the motor cortex projecting to motoneurons of elbow flexors and extensors. Responses to TMS (motor evoked potentials or MEPs) were recorded at a flexion and an extension position of the elbow joint. To exclude the influence of background motoneuronal excitability on the evaluation of corticospinal influences, MEPs were elicited during the electromyographic (EMG) silent period produced by brief muscle shortening prior to TMS. In control subjects, corticospinal facilitation of flexor motoneurons was usually larger whereas that of extensor motoneurons was smaller during actively maintained flexion than when the extension position was maintained (reciprocal pattern of position-related changes in flexor and extensor MEPs). In most post-stroke subjects with high clinical spasticity scores, corticospinal facilitation of both flexor and extensor motoneurons was greater at the actively established flexion position (co-facilitation pattern). Results show that spasticity is associated with substantial changes in the corticospinal influences on flexor and extensor motoneurons. Corticospinal co-facilitation of the two groups of motoneurons may be related to the necessity to overcome resistance of spastic muscles during active changes in the elbow joint angle.

Les troubles du spectre autistique sont vraisemblablement liés à des altérations des circuits neuronaux au cours du développement. Des études en imagerie cérébrale ont mis en évidence des anomalies anatomo-fonctionnelles localisées notamment au niveau du sillon temporal supérieur (STS) dans l’autisme. Chez le sujet sain, le STS est impliqué dans la perception et la cognition sociale, dont les dysfonctionnements sont au coeur des symptômes autistiques. En effet, des anomalies de la perception sociale, notamment un manque de préférence par les yeux, ont été mises en évidence dans l’autisme. Dans cette thèse nous avons montré qu’il est possible de moduler l’activité neuronale du STS droit à l’aide de la stimulation magnétique transcranienne (TMS) avec un impact significatif sur la perception sociale, mesurée par l’eye-tracking. En effet, suite à une inhibition du STS, des jeunes volontaires sains regardent moins les yeux des personnages dans les scènes sociales. Par ailleurs, cette perception sociale a été corrélée au débit sanguin cérébral (DSC) au repos, mesuré en IRM avec la séquence arterial spin labelling. Ainsi, les volontaires sains qui regardaient le plus les yeux des personnages étaient ceux chez qui le DSC au repos était plus élevé au niveau des régions temporales droites. De plus, cette corrélation a été également observée chez des enfants avec autisme: les enfants qui regardaient le plus les yeux des personnages étaient ceux chez qui le DSC au repos était plus important au niveau des régions temporales droites. Enfin, les résultats préliminaires concernant l’application de la TMS chez des adultes avec autisme ouvrent des nouvelles perspectives thérapeutiques. / Autism is a pervasive developmental disorder associated with alterations of neural circuits. Neuroimaging studies in autism have revealed anatomo-fonctional abnormalities, particularly located within the superior temporal sulcus (STS). In normal subjects, STS is largely implicated in social perception and social cognition. Deficits in social cognition and particularly in social perception are the core symptoms of autism. Indeed, abnormalities of social perception have been described in adults and children with autism. These abnormalities are characterized by a lack of preference for the eyes. In this thesis, we have shown that it is possible to modulate neural activity within the right STS using a transcranial magnetic stimulation (TMS) protocol, with significant effects on social perception parameters, measured by eye-tracking during passive visualization of social scenes. Furthermore, social perception parameters were correlated with rest cerebral blood flow (CBF), measured with arterial spin labelling (ASL) MRI. We have shown that the healthy young volunteers who looked more to the eyes during passive visualization of social scenes were those who had higher rest CBF values within right temporal regions. In addition, this correlation was also observed in children with autism: children who looked more to the eyes during passive visualization of social scenes were those who had higher rest CBF values within right temporal regions. Finally, preliminary results concerning application of the TMS protocol in adults with autism open up new perspectives on innovate therapeutically strategies.

Micro-affordance effects have been reported for several different components of the reach-to-grasp action during both on-line and off-line visual processing. The presence of such effects represents a strong demonstration of the close relationship between perception, action, and cognition. In this thesis 7 experiments are described, which investigate different aspects of that relationship, with particular attention on the nature of object representations. In 5 behavioural experiments as well as in 1 Transcranial Magnetic Stimulation (TMS) experiment a stimulus-response compatibility paradigm is employed to examine the presence of micro-affordance effects arising during language processing of object names. The power and precision component of the reach-to-grasp action is investigated in relation to the compatibility of an object for grasping with either a power or a precision grasp. Overall, the results of the experiments discussed in the present thesis suggest that: a) object representations activated during language processing of object names are able to potentiate actions arising from the component of the reach-to-grasp action under investigation; b) such representations might be more semantic or „propositional‟ than depictive in nature, therefore more related to stored semantic knowledge of the object and its associated actions than to its detailed visual properties; c) this semantic information about objects seems to be automatically translated into specific motor activity, even in the absence of any intention to act; d) finally, such semantic, non-visual motor potentiation seems to be rapid and relatively short lived.

Training is associated with specific neural adaptations. Skill training has been associated with increases in corticospinal tract excitability, leading to long term adaptations within motor cortex. Neural adaptations associated with strength training are less well established. It is not known how they are affected by volume, intensity, rate of muscle activation, or rest period. We evaluated the acute neural adaptations to a single session of strength training with the goal of evaluating the influence of rate of muscle activation on neural adaptations at the cortical and spinal levels. Thirty subjects participated in a single session of maximal, isometric knee extensions with the right leg. The training consisted of 4 sets of 5 contractions, with sets separated by approximately 5 minutes. Subjects were randomized into a high rate of muscle-activation group (Ballistic), a low rate of muscle-activation group (Ramp), and a Control group that did all testing but no training. Cortical spinal tract excitability was assessed using transcranial magnetic stimulation, spinal excitability was assessed using peripheral nerve stimulation, and inhibition of motor cortex was assessed using short-interval intracortical inhibition. In addition, we measured changes in motor performance. These same measures were assessed 24 hours later. Results showed that an acute strength training session is associated with a depression in resting cortical spinal tract excitability, but no change in active excitability. This change was immediate, taking place after just 2 contractions. Training was also associated with an increase in the excitability of the monosynaptic reflex circuit within the spinal cord during muscle activation, but not at rest. After 24 hours, cortical motor tract excitability had returned to normal, but intracortical inhibition was decreased from the original measure. Subjects from all groups increased maximum rate of torque development from Day 1 to Day 2. These results indicate that strength-training is associated with neural adaptations, though the adaptations were different than those for skill training. Understanding these adaptations will allow coaches and clinicians to better design programs to optimize the strength potential of the nervous system along with that of the muscles.