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Numbers convey different meanings when used in different contexts (Wiese, 2003). In a cardinal context, a number will tell us how many entities are in a set and convey quantity meaning. In an ordinal context, a number will refer to the relative position (or rank) of one element within a sequence; non-numerical ordered series (e.g. the letters of the alphabet) can also be used to provide meaningful order information. Because quantity and order are linked up with each other in the cognitive number domain (the larger the quantity a number refers to, the later it is located in the conventional number sequence), the question of whether they rely on some common or distinct underlying mechanism(s) is theoretically relevant and was addressed in the present thesis. Experimental studies showed evidence of both similarities (similar distance and SNARC effects, recruitment of parietal and frontal regions, and conjoint impairment or preservation after brain damage) and dissociations (different developmental course, dissociation after cerebral lesion, and specific behavioural markers) between quantity and order neuro-functional processes. The aim of the present thesis was to clarify the relationship between numerical quantity and order processing and to test the hypothesis that they rely on (at least partially) dissociated mechanisms. We tested this hypothesis in a single case study, an electrophysiological study and in two behavioural experiments. In the neuropsychological study, we reported the case of patient CO, who showed Gerstmann syndrome after bilateral parietal damage and became unable to process sequence order relations (e.g. he couldn't recite the number sequence backwards, nor decide whether a number, letter, day or month comes before or after a given target in the corresponding sequence, and he was unable to verify the order of items in a pair). Nonetheless, the patient had largely preserved quantity processing abilities (he could compare numbers and dot patterns to find the smaller or larger, and showed a standard distance effect, he could produce a number smaller or larger than a given target, and match dot patterns with Arabic numerals). Overall, CO's pattern of performance was interpreted as reflecting the involvement of different mechanisms when processing quantity or sequence order relations. Our electrophysiological study corroborated this finding since different spatio-temporal patterns of the distance effect were observed when subjects had to process numbers in a quantity comparison task or in an order judgment task. Quantity processing elicited an early distance effect over the P2p component on left parietal sites, whereas the distance effect was slightly delayed and bilaterally distributed in the numerical order judgment task; and this latter task additionally recruited prefrontal regions on a later (P3-counterpart) component. Finally, our behavioural study further emphasized the involvement of different mechanisms underlying the processing of quantity and numerical order and provided some evidence about the nature of these specific mechanisms. In the number comparison (quantity) task, the standard distance effect was proposed to reflect the involvement of a magnitude comparison mechanism; whereas the reverse distance effect observed in the numerical order verification task was taken as evidence for the recruitment of a serial search (recitation) process. Besides, the pair-order effect was also found to specifically affect order but not quantity judgments. Taken together, the data collected in the present thesis lend further support to the hypothesis that quantity and numerical order rely on distinct processing mechanisms that can be damaged selectively after cerebral lesions, that recruit similar brain areas but with a different spatio-temporal course and that show specific behavioural markers.

Numbers convey different meanings when used in different contexts (Wiese, 2003). In a cardinal context, a number will tell us how many entities are in a set and convey quantity meaning. In an ordinal context, a number will refer to the relative position (or rank) of one element within a sequence; non-numerical ordered series (e.g. the letters of the alphabet) can also be used to provide meaningful order information. Because quantity and order are linked up with each other in the cognitive number domain (the larger the quantity a number refers to, the later it is located in the conventional number sequence), the question of whether they rely on some common or distinct underlying mechanism(s) is theoretically relevant and was addressed in the present thesis. Experimental studies showed evidence of both similarities (similar distance and SNARC effects, recruitment of parietal and frontal regions, and conjoint impairment or preservation after brain damage) and dissociations (different developmental course, dissociation after cerebral lesion, and specific behavioural markers) between quantity and order neuro-functional processes. The aim of the present thesis was to clarify the relationship between numerical quantity and order processing and to test the hypothesis that they rely on (at least partially) dissociated mechanisms. We tested this hypothesis in a single case study, an electrophysiological study and in two behavioural experiments. In the neuropsychological study, we reported the case of patient CO, who showed Gerstmann syndrome after bilateral parietal damage and became unable to process sequence order relations (e.g. he couldn't recite the number sequence backwards, nor decide whether a number, letter, day or month comes before or after a given target in the corresponding sequence, and he was unable to verify the order of items in a pair). Nonetheless, the patient had largely preserved quantity processing abilities (he could compare numbers and dot patterns to find the smaller or larger, and showed a standard distance effect, he could produce a number smaller or larger than a given target, and match dot patterns with Arabic numerals). Overall, CO's pattern of performance was interpreted as reflecting the involvement of different mechanisms when processing quantity or sequence order relations. Our electrophysiological study corroborated this finding since different spatio-temporal patterns of the distance effect were observed when subjects had to process numbers in a quantity comparison task or in an order judgment task. Quantity processing elicited an early distance effect over the P2p component on left parietal sites, whereas the distance effect was slightly delayed and bilaterally distributed in the numerical order judgment task; and this latter task additionally recruited prefrontal regions on a later (P3-counterpart) component. Finally, our behavioural study further emphasized the involvement of different mechanisms underlying the processing of quantity and numerical order and provided some evidence about the nature of these specific mechanisms. In the number comparison (quantity) task, the standard distance effect was proposed to reflect the involvement of a magnitude comparison mechanism; whereas the reverse distance effect observed in the numerical order verification task was taken as evidence for the recruitment of a serial search (recitation) process. Besides, the pair-order effect was also found to specifically affect order but not quantity judgments. Taken together, the data collected in the present thesis lend further support to the hypothesis that quantity and numerical order rely on distinct processing mechanisms that can be damaged selectively after cerebral lesions, that recruit similar brain areas but with a different spatio-temporal course and that show specific behavioural markers.

Locomotion requires visuospatial attention. However, the role and cortical control of visuospatial attention during locomotion remain unclear. Four experiments were conducted in this study to examine the role and cortical control of visuospatial attention during locomotion in healthy young adults. In the first experiment, we employed a visuospatial attention task at different phases of obstacle crossing during gait. The results suggested that toe-obstacle clearance was significantly reduced for the trailing limb when distraction interfered with visuospatial attention during the approaching phase of obstacle crossing. In the second experiment, subjects performed a visual Stroop task while approaching and crossing an obstacle during gait. The results for the second experiment indicated toe-obstacle clearance was significantly increased for the leading and trailing limbs. Taken together, it was found that different visual attention tasks lead to distinct modifications on obstacle crossing behaviors. In the third and fourth experiments, anodal transcranial direct current stimulation (tDCS) was applied over the right posterior parietal cortex (PPC) to examine the aftereffects on attention function and locomotor behavior. The results suggested that the orienting attention was significantly improved after anodal tDCS. In addition, the aftereffects of anodal tDCS potentially enhanced cognitive and motor performance while interacting with a challenging obstacle-crossing task in young healthy adults, suggesting that the right PPC contributes to attending visuospatial information during locomotion. This study demonstrated that visuospatial attention is critical for planning during locomotion and the right PPC contributes to this interplay of the neural processing of visuospatial attention during locomotion. This dissertation includes previously published and unpublished co-authored material.

Le cortex pariétal postérieur (PPC) est une structure clé de l’intégration sensori-motrice qui forme, avec les structures frontales auxquelles il est connecté, des réseaux pariéto-frontaux aux fonctions spécifiques. Il est ainsi impliqué dans la planification et le contrôle des mouvements de préhension visuo-guidés mais aussi dans le contrôle de l’attention spatiale. L’atteinte fonctionnelle du membre supérieur et la négligence spatiale sont deux conséquences fréquentes et invalidantes après un accident vasculaire cérébral (AVC). Dans ces deux situations, il est démontré que la connectivité cérébrale des réseaux pariéto-frontaux est modifiée au sein de l’hémisphère lésé, mais aussi vers et au sein de l’hémisphère non-lésé. Par ailleurs, ces modifications semblent impliquées dans la genèse et/ou les mécanismes de récupération de la négligence spatiale et de la déficience motrice. Cependant, la spécificité des modifications de connectivité du PPC controlésionnel reste partiellement méconnue, en particulier si on considère les régions fonctionnelles spécialisées qui y ont été identifiées chez le sujet sain. Ces dernières incluent notamment les parties antérieure et postérieure du sillon intra-pariétal (respectivement aIPS et pIPS) et le cortex pariéto-occipital supérieur (SPOC). Les objectifs de ce travail étaient (1) d’étudier les modifications de la connectivité intra- et inter-hémisphérique de ces trois zones chez des patients post-AVC comparativement à un groupe de sujets contrôles sains, (2) de déterminer les liens de la connectivité avec la sévérité des déficiences motrices et visuo-spatiales, et enfin (3) de juger de l’effet de la modulation du PPC sur ces dernières.Dans un premier temps, nous avons mesuré, au repos, la connectivité des réseaux pariétofrontaux au sein de l’hémisphère controlésionnel en utilisant une technique de stimulation magnétique transcrânienne à impulsion double (ppTMS). La deuxième étude s’est intéressée aux aspects fonctionnels (IRM fonctionnelle de repos) et structurels (mesure de la fraction d’anisotropie sur des séquences de diffusion) de la connectivité intra- et inter-hémisphérique du PPC controlésionnel. Nous avons enfin analysé l’effet de la modulation inhibitrice du PPC controlésionnel (rTMS en mode thetaburst continu (cTBS)) sur les paramètres du mouvement de pointage avec le membre supérieur parétique.La première étude a mis en évidence une hyperexcitabilité des connexions pariéto-frontales chez les patients négligents lorsque la stimulation conditionnante concernait le SPOC, ce d’autant plus que la négligence péripersonnelle était sévère. La connectivité aIPS-M1 n’était pas différente entre sujets hémiparétique et contrôles, et le degré de déficience motrice n’était pas lié aux données de connectivité. Le travail d’imagerie a montré que la connectivité fonctionnelle et structurelle du PPC controlésionnel était altérée chez les patients, au sein de l’hémisphère controlésionnel mais aussi vers l’hémisphère lésé, de manière différente selon les sites du PPC. Les données de connectivité fonctionnelle montraient des liens avec la sévérité de la négligence spatiale mais peu avec celle de la déficience motrice. Enfin, l’inhibition du PPC controlésionnel par un protocole de cTBS pourrait améliorer l’excitabilité de M1 du coté lésé et certains paramètres spatiaux et temporels du mouvement de pointage. Les patients post-AVC présentaient donc des modifications étendues de connectivité cérébrale du PPC controlésionnel, à la fois intra- et inter-hémisphériques. Alors que des liens entre connectivité et négligence ont été mis en évidence, il n’existait que peu de relation avec la déficience motrice, probablement parce qu’elle est déterminée par un nombre important d’autres facteurs. Enfin, ce travail ouvre de nouvelles pistes d’évolution des stratégies de modulation par les techniques de stimulation cérébrale non-invasives en post-AVC. / The posterior parietal cortex (PPC) is a key structure for sensorimotor integration. It forms with the frontal areas to which it is connected the parieto-frontal networks that have specialized functions. It is involved in the planning and online control of visually-guided prehension but also in the control of spatial attention. Upper limb impairment and spatial neglect are two frequent and disabling consequences of stroke. In these two deficiencies, it has been shown that cerebral connectivity in the parieto-frontal networks is modified within the lesioned hemisphere, but also towards and within the non-lesioned hemisphere due to an imbalance in the interhemispheric influences between parietal areas. Furthermore, these modifications seem to be involved in the genesis and/or the recovery of spatial neglect and motor deficiency. However, the changes in connectivity remain partly unknown, especially if we consider the different PPC functional areas identified in healthy subjects in the PPC (anterior and posterior parts of the intraparietal sulcus (respectively aIPS and pIPS) and the superior parieto-occipital cortex (SPOC)). The aims of the present work were (1) to study the modifications of intra- and interhemispheric cerebral connectivity of these 3 PPC areas in post-stroke patients vs healthy controls, (2) determine the relationship between connectivity data and the severity of motor and visuo-spatial deficiencies, and (3) study the effect of a modulation of the PPC on these deficiencies.We first assessed the connectivity of parieto-frontal networks within the contralesional hemisphere using a paired-pulse transcranial magnetic stimulation protocol (ppTMS). In a second study, we addressed the functional (resting state fMRI) and structural (fractional anisotropy on diffusion weighted imagery) intra- and interhemispheric connectivity of the contralesional PPC. We finally study the effect of an inhibitory modulation of the contralesional PPC (continuous theta-burst stimulation (cTBS)) on reaching parameters with the paretic upper limb in stroke patients.In the first study, we demonstrated an hyperexcitability of parieto-frontal connections in neglect patients when the conditioning stimulus was applied over the SPOC, especially when peripersonal neglect was severe. Connectivity between the aIPS and M1 was not different between patients and healthy controls and the severity of motor deficiency was not associated with connectivity. The neuroimaging study revealed that functional and structural connectivity from the contralesional PPC was altered in stroke patients, within the contralesional hemisphere but also to the lesioned hemisphere, in different ways depending on the PPC site considered. Functional connectivity showed some relationships with neglect severity but almost not with motor deficiency. Finally, the inhibition of the contralesional PPC lead by a cTBS protocol may increase lesioned M1 excitability and some spatiotemporal parameters of pointing movements.In conclusion, post-stroke patients showed wide modifications of cerebral connectivity of the contralesional PPC, both within the contralesional and toward the lesioned hemisphere. Whereas we identified links between connectivity and neglect severity, relationships were poorer with motor deficiency, certainly since this last is determined by several other factors. Finally, this work puts light on new perspectives of modulation protocols using non-invasive brain stimulation in stroke patients.

L'adaptation motrice permet d'ajuster la sortie motrice en réponse à des perturbations de l'environnement. Au début de l'adaptation, un processus stratégique conscient appelé recalibration a lieu. Ce processus implique le cervelet et le cortex pariétal postérieur. Il permet de réduire les erreurs motrices en se basant sur le retour sensoriel. Les patients dystoniques ont des altérations du traitement de l'information somatosensorielle. Nous avons fait l'hypothèse que cela devait entrainer des anomalies d'adaptation au cours de la phase de recalibration. En utilisant l'imagerie par résonnance magnétique (IRMf) et la magnétoencéphalographie (MEG), nous avons enregistré l'activité cérébrale chez des patients ayant une crampe de l'écrivain et chez des volontaires sains, alors qu'ils réalisaient une tâche de pointage avec ou sans perturbation visuelle associée. L'étude en IRMf a révélé l'implication d'un réseau cérébello-pariétal postérieur dans la détection des erreurs motrices. Ce réseau était hypoactif chez les patients qui compensaient en recrutant un réseau alternatif plus cognitif mettant en jeu la mémoire visuo-spatiale et la représentation cognitive de la main. La MEG nous a permis d'analyser la dynamique temporelle des activations et de montrer en particulier que la préparation du mouvement est déjà anormale chez les patients; de réaliser une analyse fréquentielle de la communication cérébello-corticale. Cette analyse a révélé un défaut de cohérence dans la bande gamma, entre le cervelet et le cortex moteur et prémoteur ainsi qu'avec le cortex pariétal postérieur. L'ensemble de nos résultats suggère un désordre constitutionnel de ce réseau dans la dystonie. / Dystonia is a movement disorder characterized by prolonged muscle contractions causing involuntary repetitive twisting movements and abnormal postures. Motor adaptation shapes the motor output according to the changes in the environment. At its early stage, motor adaptation involves a strategic conscious process called “recalibration” that minimizes the perturbation and reduces the motor error based on online integration of sensory feedback. Sensorimotor processing is impaired in dystonia and we hypothesized that this may lead to deficits of the “recalibration” phase during motor adaptation. We used magnetoencephalography (MEG) and functional magnetic resonance imagery (fMRI) to record brain activation in patients with writer’s cramp and healthy volunteers using a classical rotation learning task. The fMRI study revealed that the cerebello-parietal network was directly implicated in motor error detection. In writer’s cramp, this network was underactivacted and patients relied more on cognitive networks based on visuospatial memory and cognitive representations of the hand. With MEG, (1) we reconstructed the temporal dynamic of activations in the cerebello-parietal network and demonstrated abnormal movement preparation in writer’s cramp patients; (2) we realized a spectral analysis of the cerebello-parietal communication. This analysis revealed decreased gamma coherence between the cerebellum, and the premotor and motor cortices and with posterior parietal cortex. All of our data suggest an underlying disorder of this network in dystonia.

This study investigated the effects of repeated administrations of nicotine (0.7 mg/kg) on dendritic morphology in the nucleus accumbens (NAcc), prefrontal cortex (Cg 3), and parietal cortex (Par 1). Animals were habituated for 3 days to a locomotor box, and after habituation, every second day for 5 weeks rats were placed into the locomotor chamber immediately after a subcutaneous injection of nicotine or saline. Rats demonstrated tolerance to an initial hypoactive response after each nicotine injection, and this was followed by an increase in activity after each injection (behavioral sensitization). This increase in activity was still present on a nicotine challenge after a 2-week abstinence period. One week after the nicotine challenge day, all rats were perfused and brains were removed. These brains we stained using Golgi-Cox procedures, and dendrites from the nucleus accumbens (N Acc), medial frontal cortex (Cg 3) and parietal cortex (Par 1) were analyzed using the camera lucida procedure. Results showed that rats receiving nicotine demonstrated an increase in dendritic length and spine density relative to controls in the NAcc and Cg3 brain areas, but not Par 1. The increase observed in the NAcc was significantly greater than what has been found with amphetamine or cocaine, and possible underlying mechanisms were discussed.

Path integration is a navigational process that humans and animals use to track changes in their position and orientation. Animal and computational studies suggest that a spatially-tuned navigation system supports path integration, yet this system is not well understood in humans. Here, the prediction was tested that path integration mechanisms and goal-directed navigation in humans would recruit the same key brain regions within the parietal cortex and medial temporal lobes as predicted by animal and computational models. The three experiments described in this dissertation used behavioral and functional magnetic resonance imaging methods in 131 adults (18-35 years) to examine behavioral and brain correlates of navigation. In a landmark-free environment, path integration mechanisms are utilized to update position and orientation to a goal. Experiment 1 examined neural correlates of these mechanisms in the human brain. The results demonstrated that successful first and third person perspective navigation recruited the anterior hippocampus. The posterior hippocampus was found to track distance and temporal proximity to a goal location. The retrosplenial and posterior parietal cortices were additionally recruited for successful goal-directed navigation. In a landmark-rich environment, humans utilize route-based strategies to triangulate between their position, landmarks, and navigational goal. Experiment 2 contrasted path integration and landmark-based strategies by adding a solitary landmark to a sparse environment. The results demonstrated that successful navigation with and without an orienting landmark recruited the anterior hippocampus. Activity in the bilateral posterior hippocampus was modulated by larger triangulation between current position, landmark, and goal location during first person perspective navigation. The caudate nucleus was additionally recruited for landmark-based navigation. Experiment 3 used functional connectivity methods coupled with two fMRI tasks to determine whether areas responsive to optic flow, specifically V3A, V6, and the human motion complex (hMT+), are functionally connected to brain regions recruited during first person perspective navigation. The results demonstrated a functional relationship between optic flow areas and navigationally responsive regions, including the hippocampus, retrosplenial, posterior parietal, and medial prefrontal cortices. These studies demonstrate that goal-directed navigation is reliant upon a navigational system supported by hippocampal position computations and orientation calculations from the retrosplenial and posterior parietal cortices.

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第12817号 / 論医博第2079号 / 新制||医||1004(附属図書館) / 31304 / 京都大学大学院医学研究科脳統御医科学系専攻 / (主査)教授 河野 憲二, 教授 金子 武嗣, 教授 大森 治紀 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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