Ce travail de thèse a pour objectif de préciser le rôle du cortex operculo-insulaire dans la somesthésie et la douleur chez l'Homme à l'aide d'études réalisées par stimulations électriques intracérébrales et en IRM fonctionnelle (IRMf). Deux secteurs fonctionnels distincts ont été mis en évidence; d'une part l'insula dont 60% des stimulations induisent des réponses somato-sensitives dont 10% sont douloureuses, où il existe une localisation préférentiellement postérieure des sites de stimulation donnant lieu à une réponse douloureuse et un décrément antéro-postérieur du seuil de déclenchement d'une réponse douloureuse, dont les champs récepteurs couvrent de larges surfaces cutanées, et où les réponses douloureuses ont une organisation somatotopique grossière ; d'autre part l'aire SII dont la stimulation induit quasi exclusivement des réponses somato-sensitives dont 10% sont douloureuses, sur des surfaces cutanées plus restreintes. SII et l'insula postérieure sont les deux seules régions corticales dont la stimulation est capable d'induire une sensation douloureuse. Une ségrégation fonctionnelle au sein de SII et de l'insula a été montrée en IRMf, par l'existence de patterns spécifiques d'activation pour chaque modalité sensitive, comprenant des sous- régions dont l'activation semble spécifique de la sensation douloureuse. Ceci confère à ces régions une originalité toute particulière au sein de la matrice douleur, puisqu'il semble qu'elles seules puissent activer le réseau fonctionnel des aires impliquées dans la sensation douloureuse et ainsi permettre 'l'expérience' de la douleur / This work aims at assessing the role of operculo-insular cortex in somesthesia and pain in Humans, using intracerebral electrical stimulations and fMRI. Two distinct functional zones were highlighted; the insular cortex on one hand, in which 60% of stimulations induced somato-sensory responses (10% painful), with a clear antero-posterior gradient in terms of localization and pain stimulation threshold, and where receptive fields were large and pain evoked sensations showed a rough somatotopic organization. The inner part of the parietal operculum (second somatosensory area SII) on the other hand, where electrical stimulation induced almost exclusively somato-sensory sensations, of which 10% were painful, in more restricted cutaneous territories. SII and posterior insula are the only cortical regions where electrical stimulation can elicit painful sensation. Functional segregation in SII and insula was found using fMRI, showing that specific patterns of activation do exist, depending on the type of somato-sensory stimulations, including sub-regions specifically activated during pain stimulation. These characteristics confer to these regions a crucial and special role, which consists in triggering the building of pain 'experience' by the pain matrix

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Following peripheral nerve transection and microsurgical repair (PNIr) most patients retain significant sensorimotor impairments, a proportion of which also develop chronic neuropathic pain. Individual psychological factors may contribute to the development, intensity and duration of chronic pain. Furthermore, a large body of evidence has indentified beneficial and maladaptive cortical plasticity following disease or injury. The general aim of this thesis was to determine the extent of sensory and motor recovery, functional and structural brain changes, and the impact of chronic neuropathic pain on sensorimotor outcomes following upper limb PNIr. Towards this main aim a sensorimotor psychophysical assessment (that included psychological assessments), nerve conduction testing, and an MRI session that examined brain function and structure was performed in patients with peripipheral nerve injury induced neuropathic pain (PNI-P) and those with no neuropathic pain (PNI-NP). Nerve conduction testing demonstrated that all patients had incomplete peripheral nerve regeneration, and that PNI-P patients had worse sensory nerve regeneration. Psychophysical assessment confirmed that all PNIr patients had significant sensorimotor deficits. Additionally, deficits on tests of vibration detection, sensorimotor integration, and fine dexterity were significantly greater in PNI-P patients. Psychological measures clearly distinguished PNI-P from PNI-NP and healthy controls (HC). Vibrotactile stimulation of the deafferented territory in PNI-NP patients results in reduced BOLD activation within the primary and secondary somatosensory cortices. Interestingly, the regions of reduced BOLD corresponded with gray matter thinning which was negatively correlated with behavioural measures of sensory recovery. Structural abnormalities were also identified in the right insula. PNI-P patients had thinning within the right middle insula and a corresponding decrease in white matter pathways projecting into/out of that region. PNI-P patients also had white matter abnormalities in pathways feeding into/out of the contralesional primary somatosensory cortex and thalamus. In conclusion, PNIr is clearly associated with sensorimotor impairments and brain plasticity. Furthermore, neuropathic pain is associated with worse peripheral nerve regeneration, sensorimotor deficits, different psychological profiles, and structural alterations in brain regions involved in pain perception and somatosensation. These results provide insight into peripheral regeneration, the development of chronic pain, brain plasticity and structure-function-behavioural relationships following nerve injury and have important therapeutic implications.

Following peripheral nerve transection and microsurgical repair (PNIr) most patients retain significant sensorimotor impairments, a proportion of which also develop chronic neuropathic pain. Individual psychological factors may contribute to the development, intensity and duration of chronic pain. Furthermore, a large body of evidence has indentified beneficial and maladaptive cortical plasticity following disease or injury. The general aim of this thesis was to determine the extent of sensory and motor recovery, functional and structural brain changes, and the impact of chronic neuropathic pain on sensorimotor outcomes following upper limb PNIr. Towards this main aim a sensorimotor psychophysical assessment (that included psychological assessments), nerve conduction testing, and an MRI session that examined brain function and structure was performed in patients with peripipheral nerve injury induced neuropathic pain (PNI-P) and those with no neuropathic pain (PNI-NP). Nerve conduction testing demonstrated that all patients had incomplete peripheral nerve regeneration, and that PNI-P patients had worse sensory nerve regeneration. Psychophysical assessment confirmed that all PNIr patients had significant sensorimotor deficits. Additionally, deficits on tests of vibration detection, sensorimotor integration, and fine dexterity were significantly greater in PNI-P patients. Psychological measures clearly distinguished PNI-P from PNI-NP and healthy controls (HC). Vibrotactile stimulation of the deafferented territory in PNI-NP patients results in reduced BOLD activation within the primary and secondary somatosensory cortices. Interestingly, the regions of reduced BOLD corresponded with gray matter thinning which was negatively correlated with behavioural measures of sensory recovery. Structural abnormalities were also identified in the right insula. PNI-P patients had thinning within the right middle insula and a corresponding decrease in white matter pathways projecting into/out of that region. PNI-P patients also had white matter abnormalities in pathways feeding into/out of the contralesional primary somatosensory cortex and thalamus. In conclusion, PNIr is clearly associated with sensorimotor impairments and brain plasticity. Furthermore, neuropathic pain is associated with worse peripheral nerve regeneration, sensorimotor deficits, different psychological profiles, and structural alterations in brain regions involved in pain perception and somatosensation. These results provide insight into peripheral regeneration, the development of chronic pain, brain plasticity and structure-function-behavioural relationships following nerve injury and have important therapeutic implications.

Functional Magnetic Resonance Imaging (fMRI) is a noninvasive imaging method that reflects local changes in brain activity. FMRI group studies involves the analysis of the functional images acquired for each of a group of subjects under the same experimental conditions. We propose a spatial marked point-process model for the activation patterns of the subjects in a group study. Each pattern is described as the sum of individual centres of activation. The marked point-process that we propose allows the researcher to enforce repulsion between all pairs of centres of an individual subject that are within a specified minimum distance of each other. It also allows the researcher to enforce attraction between similarly-located centres from different subjects. This attraction helps to compensate for the misalignment of corresponding functional areas across subjects and is a novel method of addressing the problem of imperfect inter-subject registration of functional images. We use a Bayesian framework and choose prior distributions according to current understanding of brain activity. Simulation studies and exploratory studies of our reference dataset are used to fine-tune the prior distributions. We perform inference via Markov chain Monte Carlo. The fitted model gives a summary of the activation in terms of its location, height and size. We use this summary both to identify brain regions that were activated in response to the stimuli under study and to quantify the discrepancies between the activation maps of subjects. Applied to our reference dataset, our measure is successful in separating out those subjects with activation patterns that do not agree with the overall group pattern. In addition, our measure is sensitive to subjects with a large number of activation centres relative to the other subjects in the group. The activation summary given by our model makes it possible to pursue a range of inferential questions that cannot be addressed with ease by current model-based approaches.

Dans ce mémoire, nous décrivons le travail effectué pour étendre nos connaissances sur les sources d’instabilité instrumentales en imagerie de résonance magnétique, en particulier dans le domaine anatomique par une étude où cinq adultes ont été scannés quatre fois dans la même plate-forme IRM, deux fois avant et deux fois après une mise à niveau importante d’un scanner 3T de Siemens. Les volumes de l’hippocampe droit et gauche de chaque sujet ont été mesurés avec une segmentation manuelle. Nous avons analysé la fiabilité test-retest avant et après la mise à niveau du système d’IRM. Dans le domaine fonctionnel, cinq adultes ont été scannés quatre fois dans la même plate forme IRM deux fois avant et deux fois après la même mise à niveau du scanneur. Les acquisitions du signal BOLD sont faites dans deux différentes résolutions spatiales (2x2x2mm et 4x4x4mm) pour évaluer la sensibilité du signal BOLD sous conditions de haute et basse SNR. Une dernière étude fonctionnelle sur fantôme avait pour but d’étudier la stabilité de la machine pour les images fonctionnelles et détecter les sources de bruit de type machine. La séquence EPI (Echo Planar Imaging) d’écho de gradient à deux dimensions a été utilisée. Des analyses comme le pourcentage des fluctuations et l’analyse de Fourier des résidus ont également été réalisées. Nous résultats indiquent que les différences dans le matériel provenant d’une importante mise à niveau ne peuvent pas compromettre la validité des études structurelles et fonctionnelles faites à travers la mise à niveau du scanneur. Les acquisitions quotidiennes ont permis de suivre l’évolution de la stabilité et de détecter toute source de bruit qui peut détériorer la détection des activations dans les images fonctionnelles. / In this thesis, we describe work we carried out to extend our knowledge on instrumental sources of MRI variability, in both anatomical and functional imaging. The anatomical study involved five adults scanned four times in the same platform MRI twice before and twice after a major update of a 3T Siemens scanner. The volumes of left and right hippocampus of each subject were measured with a manual segmentation. We then analyzed the test-retest reliability before and after updating the MRI system. In the functional study, five adults were scanned four times on the same MRI system twice before and twice after a major hardware update. Blood oxygenation level- dependent (BOLD) acquisitions were made at two different spatial resolutions (2x2x2mm and 4x4x4mm) to assess the reproducibility of BOLD measurements under conditions of high and low SNR. A final functional study using a gel phantom was used to study the stability of the machine for functional images and isolate the sources of noise arising from hardware. Two-dimensional gradient-echo EPI (Echo Planar Imaging) signals were analyzed to assess the percentage variability and Fourier analysis of residual error performed. Our results indicate that the differences in hardware from a major upgrade do not significantly affect the reliability of structural and functional studies spanning a major hardware upgrade. Daily quality assurance acquisitions on phantoms can be used to monitor the stability of the machine, which may aid in the early detection of hardware faults.

Dans le but de mieux comprendre le rôle et le fonctionnement des régions cérébrales impliquées dans le traitement et la modulation de la perception douloureuse, la première partie de cette thèse s’intéresse à l’évaluation en IRMf des modifications de la réponse cérébrale à la douleur grâce à deux modulations de la perception douloureuse. La première s’intéresse à l’effet d’un contexte émotionnel négatif sur la perception douloureuse afin de dissocier des aires cérébrales répondant à la douleur, les réponses liées à la composante émotionnelle. La deuxième s’intéresse à l’effet d’une manipulation de l’appréciation de la durée d’une stimulation douloureuse sur la perception de la douleur. L’utilisation d’une illusion permet, pour une intensité de stimulation thermique donnée, de modifier la perception douloureuse et d’évaluer les zones cérébrales impliquées dans ce type de modulation. Nous avons modulé la douleur perçue et pu observer que l’émotion met en jeu la partie prégénuale du cortex cingulaire antérieur, tandis que l’illusion d’une durée raccourcie met en jeu un réseau occipito-pariétal attentionnel. La seconde partie de cette thèse s’intéresse à la caractérisation du décours temporel de la réponse hémodynamique dans deux régions importantes pour le traitement de l’information douloureuse qui sont l’insula et le cortex cingulaire. La douleur est caractérisée par une latence de la réponse plus courte, par rapport à une stimulation non-douloureuse, dans l’insula antérieure et le cortex cingulaire moyen, tandis qu’il est possible de différencier une stimulation douloureuse d’une stimulation non-douloureuse grâce à l’amplitude de la réponse dans l’insula postérieure. / Pain is a complex and multidimensional experience that can be modulated by many factors. In order to better understand the respective role and function of the brain regions involved in the processing and the modulation of pain perception, the first part of this thesis focuses on the evaluation with functional magnetic resonance imaging (fMRI) of changes in the brain response to pain through two modulations of pain perception. The first study examines the effect of a negative emotional context on pain perception in order to dissociate the brain areas responding to pain from that related to the emotional context. The second study focuses on the effect of the manipulation of perceived duration of a painful stimulation on the perception of pain. The use of this illusion allows us to change the perceived intensity of pain and to assess the brain areas involved in this type of modulation at given intensity of thermal stimulation. We succeeded to increase or decrease perceived pain intensity and we observed that emotion involves pregenual part of the anterior cingulate cortex, while the illusion of a shortened duration involves an occipito-parietal attentional network. The second part of this thesis focuses on characterizing the time course of the hemodynamic response recorded with fMRI in two important areas processing pain that are the insula and the cingulate cortex. Painful sensation is characterized by a shortened latency of hemodynamic response compared to a non-painful sensation in the anterior insula and the midcingulate cortex, while it is possible to differentiate painful and non-painful sensation by the amplitude of the hemodynamic response in the posterior insula.