Large scale functional brain networks, defined by synchronized spontaneous oscillations between spatially distinct anatomical regions, are essential to brain function and have been implicated in disease states, cognitive capacity, and many sensing and motor processes. In this work, we sever the corpus callosum in the rodent model to determine if structural connectivity (specifically the primary interhemispheric pathway) organizes and influences bilateral functional connectivity and brain-wide spatiotemporal dynamic activity patterns. Prior to the callosotomy work, resting state brain networks were evaluated using blood oxygen level dependent (BOLD) and cerebral blood volume (CBV) magnetic resonance imaging contrast mechanisms, and revealed that BOLD and CBV provide highly similar spatial maps of functional connectivity; however, the amplitude of BOLD connectivity was generally stronger. The effects of extended anesthetic durations on functional connectivity were also evaluated revealing extended isoflurane anesthetic periods prior to the switch to dexmedetomidine attenuates functional activity for a longer duration as compared to a shorter isoflurane paradigm. We also observed a secondary significant evolution of functional metrics occurring during long durations of dexmedetomidine use under the currently accepted and refined dexmedetomidine sedation paradigm. Taking these previous findings into account, we moved forward with the callosotomy study. Functional network integrity was evaluated in sham and full callosotomy groups using BOLD and electrophysiology. Functional connectivity analysis indicated a similar significant reduction in bilateral connectivity in the full callosotomy group as compared to the sham group across both recording modalities. Spatiotemporal dynamic analysis revealed bilaterally symmetric propagating waves of activity in the sham data, but none were present in the full callosotomy data; however, the emergence of unilateral spatiotemporal patterns became prominent following the callosotomy. This finding suggests that the corpus callosum could be largely responsible for maintaining bilateral network integrity, but non-bilaterally symmetric propagating waves occur in the absence of the corpus callosum, suggesting a possible subcortical driver of the dynamic cascading event. This work represents a robust finding indicating the corpus callosum's influence on maintaining integrity in bilateral functional networks.

The brain processes information sensed from the environment and guides behaviour. A fundamental component in this process is the storage and retrieval of past experiences as memories, which relies on the hippocampal formation. Although there has been a great progress in understanding the underlying neural code by which neurons communicate information, there are still open questions. Neural activity can be measured extracellularly as either spikes or field potentials. Isolated spikes and bursts of high-frequency spikes followed by silent periods can transmit messages to distant networks. The local field potential (LFP) reflects synaptic activity within a local network. The interplay between the two has been linked to cognitive functions, such as memory, attention and decision making. However, the code by which this neural communication is achieved is not well understood. We investigated a mechanism by which local network information contained in LFP rhythms can be transmitted to distant networks in the formof spike patterns fired by bursting neurons. Since rhythms within different frequency bands are prevalent during behavioural states, we studied this encoding during different states within the hippocampal formation. In the first paper, using a computational model we show that bursts of different size preferentially lock to the phase of the dominant rhythm within the LFP.We also present examples showing that bursting activity in the subiculum of an anaesthetised rat was phase-locked to delta or theta rhythms as predicted by the model. In the second paper, we explored possible neural codes by which bursting neurons can encode features of the LFP.We used the computational model reported in the first paper and analysed recordings from the subiculum of anaesthetised rats and the medial entorhinal cortex of an awake behaving rat. We show that bursting neurons encoded information about the instantaneous voltage, phase, slope and/or amplitude of the dominant LFP rhythm (delta or theta) in their firing rate. In addition, some neurons encoded about 10-15% of this information in intra-burst spike counts. We subsequently studied how the interactions between delta or theta rhythms can transfer information between different areas within the hippocampal formation. In the third paper, we show that delta and theta rhythms can act as separate routes for simultaneously transferring segregate information between the hippocampus and the subiculum of anaesthetised mice. We found that the phase of the rhythms conveyed more information than amplitude. We next investigated whether neurodegenerative pathology affects this information exchange. We compared information transfer within the hippocampal formation of young transgenic mice exhibiting Alzheimer’s disease-like pathology and healthy aged-matched control mice and show that at early stages of the disease the information transmission by LFP rhythm interactions appears to be intact but with some differences. The outcome of this project supports a burst code for relaying information about local network activity to downstream neurons and underscores the importance of LFP phase, which provides a reference time frame for coordinating neural activity, in information exchange between neural networks.

Pour un mouvement de saisie, le système moteur doit contrôler un certain nombre de paramètres pour produire une commande motrice adaptée aux propriétés de l'objet. La compréhension des mécanismes mis en jeu dans l’élaboration de cette commande motrice repose ainsi sur plusieurs questions. Quelle est la nature des paramètres traités par le système nerveux ? Quelles sont les structures corticales impliquées ? Quand et comment ces paramètres sont-ils traités ? Durant l’exécution du mouvement ou durant la phase de préparation qui précède son initiation ? Ces questions sont autant de problématiques abordées dans ce travail de thèse dont l'objectif général est d'apporter une meilleure compréhension, d'une part, de l'organisation fonctionnelle des processus mentaux qui lient la perception à l'action, et d'autre part, de la façon dont ces processus se traduisent au niveau neurophysiologique. Nos recherches reposent notamment sur la comparaison entre l'homme et le singe étudiés dans un contexte expérimental similaire et réalisant une tâche de saisie manuelle identique. L'ensemble de nos travaux ont orienté notre réflexion vers 3 axes principaux. Premièrement, ils nous ont permis de préciser les principes fonctionnels qui régissent la préparation des mouvements de saisie manuelle. Deuxièmement, ils nous ont conduits à identifier plusieurs composantes qui caractérisent les modulations du rythme bêta (13 -35 Hz) et à dégager les principaux facteurs régissant leur présence ou leur absence. En ce sens, nous avons proposé une hypothèse qui permet d’interpréter dans un cadre théorique unifié la majorité des études proposant des interprétations souvent contradictoires du rythme bêta. / For grasping, the motor system has to control several movement parameters to produce a motor command adapted to the object properties. The understanding of the mechanisms involved in the development of this motor command relies on several questions. What kinds of parameters are processed by the nervous systems? What are the cortical structures involved? When and how these parameters are processed? During the execution or during the preparation phase preceding movement initiation? All these questions are addressed in this thesis which general objective is to provide a better understanding of the mental processes linking perception to action and to clarify how the functional organization of these processes is reflected in the neurophysiological activity. Our research is based in particular on the comparison between humans and monkeys studied in a similar experimental setting and performing an identical reach-to-grasp task. The results of this work led us to focus our discussion on three main axes. First, they allowed to specify the functional principles underlying the preparation of grasping movements. Second, we identified several components that characterize the modulations of the beta rhythm (15-35 Hz) and pinpointed the main factors governing their presence or absence. In this sense, we propose a hypothesis for interpreting in a unified theoretical framework a large number of studies that often provide conflicting interpretations of this sensorimotor rhythm.

京都大学 / 新制・課程博士 / 博士(理学) / 甲第22981号 / 理博第4658号 / 新制||理||1669(附属図書館) / 京都大学大学院理学研究科数学・数理解析専攻 / (主査)教授 玉川 安騎男, 教授 小野 薫, 教授 望月 新一 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Le temps est une dimension essentielle de la vie. Il est nécessaire, entre autres, pour réaliser des mouvements coordonnés, pour communiquer, mais aussi dans la prise de décisions. L’objectif principal de cette thèse était de caractériser le rôle d’un réseau amygdalo-préfronto-dorsostriatal dans la mémorisation et l’encodage du temps chez le rat. Dans un premier temps, nous avons décrit le comportement temporel du rat lors d’une tâche de suppression conditionnée (i.e. la suppression d’une réponse instrumentale d’appui sur levier par la présentation d’un son associé à un stimulus aversif), démontrant ainsi un contrôle temporel fin du comportement dans une situation Pavlovienne aversive. Dans un deuxième temps, nous avons analysé les potentiels de champs locaux (analyse fréquentielle des activités oscillatoires) de notre réseau d’intérêt au début d’un apprentissage associatif et après surentraînement dans la tâche de suppression conditionnée. En effet, le comportement temporel moteur nécessite un grand nombre de séances d’apprentissage pour devenir optimal, alors que l’apprentissage temporel est, lui, très rapide. Cette étude nous a permis de caractériser des corrélats neuronaux temporels au sein de ce réseau, que ce soit au niveau des structures individuelles ou au niveau de l’interaction entre ces structures. De plus, ces corrélats neuronaux sont modifiés selon le niveau d’entraînement des animaux. Enfin, dans une troisième étude, nous avons démontré que des ratons juvéniles (pré-sevrage), qui présentent un cortex préfrontal ainsi qu’un striatum dorsal immatures, peuvent mémoriser et différencier des intervalles de temps, ouvrant donc la question sur le rôle de ce réseau dans l’apprentissage temporel au cours du développement. / Time is an essential dimension of life. It is necessary for coordinating movement, for communication, but also for decision-making. The principal goal of this work was to characterize the role of an amygdalo-prefronto-dorsostriatal network in the memorization and encoding of time in a rat model. Firstly, we described temporal behavior in a conditioned suppression task (i.e. the suppression of an instrumental lever-pressing response for food by the presentation of a cue associated with an aversive event), therefore showing a precise temporal control in Pavlovian aversive conditioning. Secondly, we measured local field potentials in our network of interest at the beginning of associative learning and after overtraining in the conditioned suppression task. In effect, motor temporal behavior requires a large number of training sessions to become optimum, but temporal learning happens very early in training. This study allowed us to characterize, using frequency analysis of oscillatory activities, neuronal correlates of time in this network both at the level of individual structures, but also in their interactions. Interestingly, these neural correlates were modified by the level of training. Finally, we demonstrated that juvenile rats (pre-weaning), with an immature prefrontal cortex and dorsal striatum, can memorize and discriminate temporal intervals, raising questions on the role of this amygdalo-prefronto-dorsostriatal network in temporal learning during development.

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No description available.

A growing interest for Cannabidiol (CBD), a component of Cannabis Sativa, has occurred over the past years. The medical potential of the component is yet to be better characterized, as its effects on sleep, and in particular memory, are to date not well understood or consistently characterized. This master thesis project focuses on analysing the effect of CBD on an anaesthesia-induced sleep-like state in rats, and its effects on the hippocampal sharp-wave-ripples, which have been shown to be associated with memory replay during sleep, and hence system consolidation. The hippocampus and prefrontal cortex, the two structures involved in memory consolidation, were recorded in 19 rats, split in two groups (CBD and vehicle). From these recordings, an automated sleep scorer using principal component analysis was developed to obtain the animals’ hypnograms, which were analysed to study sleep-like structure. From the recordings of the hippocampal pyramidal layer, and an additionnal layer deeper under it, respectively ripples and sharp waves were detected in all animals, and characterized for each group. We observed and demonstrated that CBD changes the sleep-like structure by shortening both REM and NREM bouts, resulting in an increase in transitions between both states. Additionally, we observed that, although ripples are not significantly different between both groups, sharp waves tend to be smaller among CBD animals. Lastly we noticed that both sharp wave and ripple activity, after increasing upon transition to NREM, decreases as the bout last. This finding suggests that vehicle animals, who have longer bouts and less transitions, would display less sharp wave and ripple activity, although we found no significant difference in the amount of both brain events. This paradox suggests that there is still more to characterize in order to understand if CBD enhances or not memory consolidation. In sum, CBD changes anaesthesia-induced sleep by shortening the duration of both NREM and REM bouts, resulting in an increase in transitions between both state. As for sleep events, sharp waves appeared shorter among CBD animals, although the same difference was not observed for ripples. Finally, sharp wave and ripple activity appear to peak upon transition from REM to NREM sleep, and decreases as the NREM bout lasts longer, however, no effect of CBD on this observation was highlighted.

Visual attention improves sensory processing, as well as perceptual readout and behavior. Over the last decades, many proposals have been put forth to explain how attention affects visual neural processing. These include the modulation of neural firing rates and synchrony, neural tuning properties, and rhythmic, subthreshold activity. Despite the wealth of knowledge provided by previous studies, the way attention shapes interactions between cortical layers within and between visual sensory areas is only just emerging. To investigate this, we studied neural signals from macaque V1 and V4 visual areas, while monkeys performed a covert, feature-based spatial attention task. The data were simultaneously recorded from laminar electrodes disposed normal to cortical surface in both areas (16 contacts, 150 μm inter-contact spacing). Stimuli presentation was based on the overlap of the receptive fields (RFs) of V1 and V4. Channel depths alignment was referenced to laminar layer IV, based on spatial current source density and temporal latency analyses. Our analyses mainly focused on the study of Local Field Potential (LFP) signals, for which we applied local (bipolar) re-referencing offline. We investigated the effects of attention on LFP spectral power and laminar interactions between LFP signals at different depths, both at the local level within V1 and V4, and at the inter-areal level across V1 and V4. Inspired by current progress from literature, we were interested in the characterization of frequency-specific laminar interactions, which we investigated both in terms of rhythmic synchronization by computing spectral coherence, and in terms of directed causal influence, by computing Granger causalities (GCs). The spectral power of LFPs in different frequency bands showed relatively small differences along cortical depths both in V1 and in V4. However, we found attentional effects on LFP spectral power consistent with previous literature. For V1 LFPs, attention to stimuli in RF location mainly resulted in a shift of the low-gamma (∼30-50 Hz) spectral power peak towards (∼3-4 Hz) higher frequencies and increases in power for frequency bands above low-gamma peak frequencies, as well as decreases in power below these frequencies. For V4 LFPs, attention towards stimuli in RF locations caused a decrease in power for frequencies < 20 Hz and a broad band increase for frequencies > 20 Hz. Attention affected spectral coherence within V1 and within V4 layers in similar way as the spectral power modulation described above. Spectral coherence between V1 and V4 channel pairs was increased by attention mainly in the beta band (∼ 15-30 Hz) and the low-gamma range (∼ 30-50 Hz). Attention affected GC interactions in a layer and frequency dependent manner in complex ways, not always compliant with predictions made by the canonical models of laminar feed-forward and feed-back interactions. Within V1, attention increased feed-forward efficacy across almost all low-frequency bands (∼ 2-50 Hz). Within V4, attention mostly increased GCs in the low and high gamma frequency in a 'downwards' direction within the column, i.e. from supragranular to granular and to infragranular layers. Increases were also evident in an ‘upwards’ direction from granular to supragranular layers. For inter-areal GCs, the dominant changes were an increase in the gamma frequency range from V1 granular and infragranular layers to V4 supragranular and granular layers, as well as an increase from V4 supragranular layers to all V1 layers.

Deep brain stimulation (DBS) is a neurosurgical intervention now established for the treatment of movement disorders. For the treatment of chronic pain refractory to medical therapies, several prospective case series have been reported, but few centres worldwide have published findings from patients treated during the last decade using current standards of technology. This thesis seeks to survey the current clinical status of DBS for pain, investigate its mechanisms and their interactions with autonomic function, its clinical limitations and ablative alternatives. Presented first is a review of the current status of analgesic DBS including contemporary clinical studies. The historical background, scientific rationale, patient selection and assessment methods, surgical techniques and results are described. The clinical outcomes of DBS of the sensory thalamus and periventricular / periaqueductal grey (PAVG) matter in two centres are presented including results from several pain and quality of life measures. A series of translational investigations in human subjects receiving DBS for pain elucidating mechanisms of analgesic DBS and its effects upon autonomic function are then presented. Single photon emission tomography comparing PAVG, VP thalamus and dual target stimulation is described. Somatosensory and local field potential (LFP) recordings suggesting PAVG somatotopy are shown. ABPM results demonstrating changes with PAVG DBS are given and Portapres studies into heart rate variability changes with ventral PAVG DBS are detailed. Investigations using naloxone are then shown to hypothesise separate dorsal opioidergic and ventral parasympathetic analgesic streams in the PAVG. Finally, cingulotomy in lung cancer to relieve pain and dyspnoea results are discussed in the context of altering pain and autonomic function by functional neurosurgery. Pain and autonomic interactions and mechanisms in deep brain surgery for pain are then discussed alongside its limitations with proposals made for optimising treatment and improving outcomes.