京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18887号 / 医博第3998号 / 新制||医||1009(附属図書館) / 31838 / 京都大学大学院医学研究科医学専攻 / (主査)教授 河野 憲二, 教授 渡邉 大, 教授 大森 治紀 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Recent functional neuroimaging evidence suggests that recalling autobiographical memories, imagining fictitious autobiographical episodes, and taking the perspective of another person activate a similar network of brain regions. Results from the two studies presented here provide further evidence of this common neural network. Previous evidence also suggests that recalling autobiographical memories from a first person or from a third person perspective can influence the way in which those memories are experienced as well as the brain regions that are engaged; however, the effect of perspective on imagining autobiographical events remains unclear. Results from Study 1 indicated that brain regions implicated in both remembering and imagining were differentially engaged during these tasks depending on whether a first person or a third person perspective was taken. In addition, while recalling autobiographical memories from a third person perspective can result in the feeling that a past self is more like another person, imagining oneself in the position of another person can result in the feeling that that person is more similar to oneself; this suggests a possible link between perspective in memory and social perspective taking. In Study 2, we identified several brain regions exhibiting a pattern of increasing or decreasing activation as a function of whether socially interactive events were recalled from a first person perspective, by imagining oneself as one's partner, or from a third person perspective (i.e., as a function of distance from one's own perspective). Together, our findings suggest that perspective plays an important role in the way in which brain regions that are part of this common neural network are engaged during memory, imagination, and socially interactive tasks.

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Le Trouble de Stress Post-Traumatique (TSPT) est une pathologie fréquente, touchant près de 8 % de la population générale. Cette pathologie psychiatrique s’exprime par un carré symptomatique incluant un syndrome de répétition, d’évitement, une hyperactivation neurovégétative ainsi qu’une altération négative des cognitions et de l’humeur. Un des traitements les plus efficaces dans cette pathologie est une psychothérapie nommée EMDR pour Eye Movement Desensitization and Reprocessing. Bien que cette thérapie ne soit plus à faire la preuve de son efficacité, les mécanismes d’actions de celle-ci demeurent encore aujourd’hui à l’état d’hypothèse. L’objectif de notre travail de thèse fut d’explorer le mécanisme d’action de la thérapie EMDR à travers différents paradigmes en EEG, TEP-scanner et IRMf, en comparant l’activité cérébrale avant et après traitement ou pendant les stimulations bilatérales alternées. Nous avons pu démontrer que la thérapie EMDR modifiait l’activité cérébrale d’un réseau cérébral impliqué dans le traitement émotionnel et la mémoire et d’une structure en particulier, le précuneus. Les stimulations bilatérales alternées qui sous-tendent l’action de l’EMDR activent elles aussi une partie de ce réseau expliquant l’impact de l’EMDR sur la mémoire traumatique. Pour la première fois, nous avons également montré que l’activité du précuneus avant traitement est capable de prédire l’intensité de la diminution des symptômes de TSPT. La durée du sommeil paradoxal avant traitement permet quant à elle de prédire le nombre de séances nécessaires pour obtenir la rémission. / Post-Traumatic Stress Disorder (PTSD) is a common condition affecting nearly 8% of the general population. This psychiatric pathology is expressed by a symptomatic square including a syndrome of repetition, avoidance, neurovegetative hyperactivation and a negative alteration of cognitions and mood. One of the most effective treatments in this pathology is a psychotherapy called EMDR for Eye Movement Desensitization and Reprocessing. Although this therapy no longer needs to prove its effectiveness, its mechanisms of action are still at the hypothesis stage today. The objective of our thesis work was to explore the mechanism of action of EMDR therapy through different paradigms in EEG, PET-scanner and fMRI, comparing brain activity before and after treatment or during bilateral alternating stimuli. We were able to demonstrate that EMDR therapy altered the brain activity of a brain network involved in emotional treatment and memory and of a particular structure, the precuneus. The alternating bilateral stimuli underlying the action of EMDR also activate part of this network explaining the impact of EMDR on traumatic memory. For the first time, we also have shown that the activity of the precuneus before treatment is able to predict the magnitude of the decrease in PTSD symptoms. The length of REM sleep before treatment can predict the number of sessions needed to reach remission.

L'étude de la conscience est un sujet d'investigation fascinant avec un large champ d'applications et d'implications. Les processus de la conscience peuvent être divisés en deux composantes indépendantes quoiqu'intimement liées : l'état conscient et le contenu conscient. L'état conscient correspond aux processus de variation de la vigilance, tandis que le contenu conscient fait référence aux expériences sensorielles perçues et manipulées dans un espace conscient. Bien que la conscience soit un élément essentiel de la cognition humaine, qui conditionne ce que les gens vivent et peuvent se remémorer, la légitimité et le bien-fondé de l'analyse scientifique et rigoureuse des corrélats neuronaux de la conscience soulèvent encore des débats houleux. Dans la première partie de cette thèse, j'utilise un célèbre paradigme de conflit sensorimoteur pour identifier des corrélats neuronaux de l'émergence de la conscience. Les travaux initiés par Torstein Nielsen (Nielsen 1963) ont démontré que la majorité des traitements sensorimoteurs s'effectuent sans nécessiter une analyse consciente. L'émergence de phénomènes conscients apparaissant à partir d'un seuil subjectif de conflit sensori-moteur appelé point d'égalité subjective. A partir d'enregistrements électroencéphalographiques, effectués chez une population de sujets adultes, il est possible d'identifier des sources d'activités corticales indépendantes des intensités des stimulations sensorielles expérimentées et spécifiques de l'émergence d'une sensation perçue consciemment. Ainsi, j'ai pu démontrer que le précuneus était une structure centrale dans les processus qui transforment un conflit sensorimoteur en une expérience consciente. J'ai également étudié ce phénomène d'un point de vue développemental en examinant les performances comportementales et des enregistrements EEG recueillies chez l'enfant. Bien que le moment de la correction du mouvement et la qualité du tracé de la trajectoire étaient similaires aux données mesurées chez les sujets adultes, le seuil de conscience motrice s'est montré plus élevé et l'activité du cortex pariétal n'a pas été retrouvée. En revanche, l'aire motrice supplémentaire a été identiée comme un corrélat important de l'émergence d'une sensation consciente d'un conflit sensorimoteur chez l'enfant. Dans une seconde partie, mes travaux ont été consacrés à l'hypothèse audacieuse qu'une stimulation électrique du nerf vague pourrait modifier l'état de conscience d'un patient se trouvant dans un état végétatif depuis 15 ans. Nous rapportons les effets bénéfiques observés après cette thérapeutique expérimentale au niveau comportemental, clinique et neurophysiologiques. Les enregistrements EEG et les méthodes de mesure de connectivité fonctionnelle m'ont permis d'observer chez ce patient une augmentation du partage d'informations corticales particulièrement importante dans les régions pariétales. L'effet de la stimulation a été également confirmé par d'autres méthodes. L'imagerie métabolique a montré une augmentation généralisée de l'activité corticale et sous-corticale et les évaluations cliniques par la CRS-R ont montré une amélioration de l'état de conscience corrélée aux observations électroencéphalographiques. Ces changements induits par la stimulation du nerf vague sont prometteurs car les modifications cérébrales observées sont caractéristiques de l'amélioration des états de conscience chez les patients gravement cérébrolésés. L'ensemble de ces résultats suggèrent que le lobe pariétal constitue à la fois un corrélat important de l'état de conscience et du contenu conscient, faisant de cette région une composante essentielle de l'émergence de la conscience. De plus, nos résultats préliminaires suggèrent que la conscience peut être, au moins partiellement, restaurée. Cette découverte ouvre de toutes nouvelles perspectives pour le futur des recherches en neurosciences où, l'hypothèse d'une modulation de la plasticité cérébrale avait été oubliée / The study of consciousness is a fascinating topic of investigation with a wide field of applications and implications. Consciousness processes can be divided into two orthogonal though intimately linked components: the conscious state, that is the state of vigilance or arousal, and the conscious content which refers to the external inputs perceived and manipulated in a conscious space. Although consciousness represents the most important human dimension where people's personal events are continuously experienced and remembered, it is somewhat surprising that its underlying neural processes still sparks lot of debates. In the first part of this PhD thesis, I took advantage from a well-known sensorimotor conflict paradigm, the Nielsen task, to investigate the neural correlates of the emergence of consciousness. Starting from the principle that much of motor processing occurs outside of awareness, I adapted the Nielsen paradigm to neurally investigate how the perception of a motor conflict in healthy subjects smoothly shifted along the unaware/aware state (i.e. point of subjective equality). Using EEG recordings, I then identify the brain sources which I consider the neural fingerprint of awareness. I found that the precuneus was critical for bringing the sensorimotor conflict into awareness. I also investigated this issue from a developmental perspective by examining the performance of healthy children. Although the timing of movement correction and the quality of movement trajectory in children was similar to adult subjects, motor awareness was shifted towards higher perception thresholds while parietal cortex activity was not found. Rather, children's response to conflict awareness was linked to SMA. After having addressed the topic of awareness in this first part, I will focus more on the second component, wakefulness. Usually these two components evolve together, however there are some pathological states in which they can be dissociated. It is the case for vegetative state patients who experience a state of wakefulness without awareness. In the second part of the thesis, I investigated the challenging hypothesis of a potential return to a conscious state, in a patient lying in a vegetative state for 15 years, after vagus nerve stimulation (VNS). We report beneficial effects of VNS including improved behavioural responsiveness and reinforced brain connectivity patterns as key signs of increased consciousness. The results showed an increase of information sharing a measure of functional connectivity particularly prominent across centro-posterior regions. Converging findings, coming from different methods, showed that VNS promoted the spread of cortical signals and metabolism which we found correlated with behavioural improvement as measured with the CRS-R scale. The VNS-induced changes are promising since they seem to follow an already known connectivity pattern characterizing state of consciousness improvements. Taken together, these findings indicate that the parietal lobe constitutes the neural correlate of both state and content-specific consciousness and suggest that this region is a "hot zone" for its emergence. Moreover, our first findings in a vegetative state patient also suggest that consciousness can be potentially repaired, thus opening the way to a new avenue of research in a domain where brain plasticity was underestimated

Deficits in interval timing have been described in focal brain lesions and in various neuropsychiatric disorders including Parkinson's disease (PD). The aim of this study was to explore brain areas responsible for human time perception and for the timing deficit in PD. We used a time reproduction task (TRT) which consisted of an encoding phase (during which visual stimuli of durations from 5 to 16.6 sec were presented) and a reproduction phase (during which interval durations were reproduced by a button pressing). In our first fMRI study, we used a parametric modulated analysis searching for brain areas with activity, expressed as Blood Oxygenation Level Dependent (BOLD) signal, correlated with the duration of time interval. During the encoding phase, there was a gradual deactivation of the left prefrontal cortex (PFC) and cingulate gyrus. During the reproduction phase, there was a gradual deactivation in precuneus and an accumulation of activity in the left PFC, primary motor area, right caudate and supplementary motor area (SMA). The second study aimed at supporting the role of two of these areas, SMA and precuneus in interval timing by repetitive transcranial magnetic stimulation (rTMS). Accuracy and variability of time estimates were compared before and after rTMS. Accuracy of estimates was not...

Deficits in interval timing have been described in focal brain lesions and in various neuropsychiatric disorders including Parkinson's disease (PD). The aim of this study was to explore brain areas responsible for human time perception and for the timing deficit in PD. We used a time reproduction task (TRT) which consisted of an encoding phase (during which visual stimuli of durations from 5 to 16.6 sec were presented) and a reproduction phase (during which interval durations were reproduced by a button pressing). In our first fMRI study, we used a parametric modulated analysis searching for brain areas with activity, expressed as Blood Oxygenation Level Dependent (BOLD) signal, correlated with the duration of time interval. During the encoding phase, there was a gradual deactivation of the left prefrontal cortex (PFC) and cingulate gyrus. During the reproduction phase, there was a gradual deactivation in precuneus and an accumulation of activity in the left PFC, primary motor area, right caudate and supplementary motor area (SMA). The second study aimed at supporting the role of two of these areas, SMA and precuneus in interval timing by repetitive transcranial magnetic stimulation (rTMS). Accuracy and variability of time estimates were compared before and after rTMS. Accuracy of estimates was not...