Diss. (sammanfattning) Linköping : Univ. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Rett syndrome (RTT), a severe neurodevelopmental disorder, affects females resulting from loss-of-function mutations in the X-linked transcription factor methyl-CpG-binding protein 2 (MECP2). RTT patients show severe verbal, motor, respiratory, and intellectual impairments. We studied two forms of activity-dependent plasticity in Mecp2 mutant mice to better understand the loss of MECP2 function in neuronal circuit and sensory processing. Sensory deprivation was applied by trimming one whisker to 3 mm to study long-term cortical plasticity in Mecp2-/y mice. Intrinsic optical signaling (IOS) imaging showed the neuronal response to wiggling a non-trimmed was consistent from day 0 to 14 but reduced for the trimmed whisker by 49.0 ± 4.3% in wild type (WT) and 22.7 ± 4.6% (p=0.0135) in RTT mice. Primary hindlimb (HL) somatosensory cortical responses to vibratory stimulation were assessed by IOS and intracortical local field potential (LFP). Responses were assessed before, during and, after 1 hour of repeated HL vibratory stimulation (100Hz,1sec, ISI 6 sec) in symptomatic male (4-6 week), female (10-12 month) and pre-symptomatic young female (4 week) RTT model mice. After 1-hour, cortical responses to test vibrations were reduced by approximately 40% in RTT and WT mice as assessed by both methods. Recovery of the IOS responses (1 sec vibration at 100Hz) and LFP (300µm below pia, 7 stimuli, 100mse ISI) were tested at 15 min intervals for 1 hour after ceasing the repeated stimulation. Reduced responses persisted for at least 60 min in WT but recovered to 90-100% of normal within 15-30 min in RTT. Analysis of the LFP responses within the test train indicated that the reduced cortical sensitivity during and after continuous stimulation resulted primarily from an increase in adaptation during the 7-stimulus test train rather than a reduction in the response to a single vibratory stimulus in all groups. Retention of this increased STA is the primary cause of the persistently reduced tactile response in young WT female mice, while in RTT mice the rapid recovery of tactile sensitivity was due to the return of STA to lower, baseline levels. Male RTT mice exhibited a marked increased excitability to the first stimulus in the test train resulting in hypersensitivity to a single vibration by 45 minutes. Old females exhibited the same pattern of adaptation and recovery but retention of adaptation was less pronounced in both WT and RTT compared to younger animals suggesting an age-dependent reduction in neural plasticity may mask deficits specific to RTT. Recording sciatic nerve sensory afferent activity did not reveal any STA, persistent adaptation or sensitization of peripheral afferent endings in any groups. I propose persistent sensory adaptation mediated by increased short-term adaptation may reflect enhanced feedback by inhibitory elements of circuits within the sensory pathway. The rapid recovery of responsiveness in young female RTT mice may therefore reflect a deficit in the capacity for activity dependent plasticity to consolidate and thus could provide a platform to understand the causes of learning and cognitive deficits in RTT patients. / Graduate

No description available.

As animals explore and interact with their surroundings, information about their environment is constantly processed from sensory stimuli into perception. This information informs their behavior, decision-making, and understanding of their world. Information processing and perception have long been thought to be modulated by the behavior state of the animal (Cano et al. 2006; Niell and Stryker 2010; Polack et al. 2013; Poulet & Petersen, 2008; Briggs 2013, Schölvinck et al. 2015). Previous research has shown that behavior state strongly correlates with perceptual performance in a sensory discrimination task in rodents (McGinley et al. 2015, Schriver et al., 2018). However, the neural correlates behind this modulation of perception, information processing, and behavioral performance are not yet fully understood. The first part of this work investigates the relationship between cell-type specific spontaneous cortical activity and behavior state as defined by pupil-linked arousal. Spontaneous activity is essential in understanding the link between behavior state and information processing as it serves as the baseline state of activity prior to processing any stimuli information. Within the sensory cortices, excitatory and inhibitory neurons work in unison to dictate network activity. Three main classes of cortical inhibitory neurons are somatostatin-expressing neurons (SST), vasointestinal peptide-expressing neurons (VIP), and parvalbumin-expressing neurons (PV). These four cell types comprise the VIP disinhibitory circuit, in which VIP neurons disinhibit excitatory neurons by inhibiting PV and SST neurons. PV and SST neurons directly inhibit excitatory cells, so by suppressing their activity VIP neurons indirectly disinhibit excitatory cells. This circuit is a vitally important system used to modify excitatory activity in all cortical regions. The spontaneous activity of excitatory neurons and three classes of inhibitory neurons (somatostatin-expressing neurons (SST), vasointestinal peptide-expressing neurons (VIP), and parvalbumin-expressing neurons (PV)) was individually examined in this study. To visualize in-vivo spontaneous cortical activity, a genetically encoded calcium indicator (GCaMP) was expressed in the somatosensory cortex, and the population-level neural activity was imaged using fiber photometry. Despite the relationship between these neurons as defined by the VIP disinhibitory circuit, the spontaneous activity of excitatory, VIP, PV, and SST neurons was found to positively correlate with pupil size for all of these neuron types. This supports the theory that VIP and other interneuron types may be active in various functions, not just the disinhibition of excitatory cells. Pupil-evoked activity, or spontaneous activity during highly aroused states, was also found to positively correlate with pupil size for all cell types and had the strongest correlation for all correlation types. Therefore, pupil-linked arousal level relates to the increased activity of both excitatory and inhibitory cortical cells. While the first chapter focuses on spontaneous activity, the second focuses on stimulus-evoked activity. Stimulus-evoked activity in the somatosensory pathway can be caused by both internally generated stimuli and external stimuli. In the first step of sensory processing, the sensory receptors cannot distinguish between these two types of stimuli. However, the differentiation between the two is necessary in order to distinguish self from non-self. The motor-related timing signals that influence sensory processing and enable distinction between internally generated and external stimuli is termed corollary discharge. Where and how the mechanism of corollary discharge occurs in the somatosensory system is not well understood. To investigate corollary discharge in the somatosensory system, the neural activity in the somatosensory cortex was analyzed during internally generated stimuli and during delivery of external stimuli. More specifically, the activity in the vibrissa somatosensory cortex of rodents during self-induced whisking and during delivery of an air puff to the whiskers was examined. In the primary and secondary somatosensory cortex, excitatory activity was inhibited just prior to whisking and suppressed to a lower level during whisking in comparison to the activity level during air puff delivery. The three main classes of inhibitory neurons were studied to explore the possibility of local inhibition causing this suppression of the excitatory signal during whisking. VIP, PV and SST neurons all exhibited a similar pre-whisking inhibition and suppression of activity during whisking, eliminating the possibility of their role in pre-whisking inhibition and whisking activity suppression. Other regions involved in the somatosensory pathway and sensorimotor processing, such as the thalamus and motor cortex, were also found to not contribute to pre-whisking inhibition or whisking activity suppression as they were also found to exhibit the same phenomenon. After ruling out cortical inhibitory neurons and somatosensory regions in the involvement of corollary discharge, external higher-order regions were investigated. Previous studies on the sources of corollary discharge in the cerebellum have shown corollary discharge signals originate from coordination of several different higher-order brain regions (Person A., 2019). To determine these potential regions for somatosensory corollary discharge, viral tracing vectors were used to locate regions with long-range inhibitory projections to the somatosensory cortex. The globus pallidus (GP) was first investigated due to its role in voluntary movement and projections to the frontal cortex (Saunders et al. 2015). However, no inhibitory projections from the GP to the somatosensory cortex were found. The striatum, which is mainly GABAergic (and therefore inhibitory), also seemed to be a likely candidate. Preliminary tracing results suggest the striatum does have inhibitory projections to the somatosensory cortex. Further studies of both retrograde and anterograde tracing must be performed to confirm this finding. Nonetheless, the evidence of corollary discharge as seen through pre-whisking inhibition and the suppression of activity during whisking in S1, S2, thalamus, and motor cortex is a novel finding and opens up many avenues for further research.

Primary somatosensory cortex (SI) is an important cortical structure involved in receiving and relaying sensory inputs to condition primary motor cortex (M1). The functional interaction between SI and M1 is important for motor control by providing surround inhibition, which is the inhibition of muscles not involved in the movement and in learning new motor skills. This interconnection is known as short-latency afferent inhibition (SAI) and may be probed using Transcranial magnetic stimulation and peripheral nerve stimulation. SAI is dependent on the afferent volley as increasing the nerve stimulation intensity increases the depth of SAI. Individuals with spinal cord injury show reductions in SAI evoked in lower limb and this may be a contributing factor to the impairments in motor control seen within this population. SAI has yet to be investigated in the upper limb in individuals with chronic cervical SCI and this thesis examines these alterations. Two experiments were performed examining M1 excitability (motor evoked potentials), SI excitability (somatosensory evoked potentials) and the interconnection between SI and M1 (SAI). The first Experiment investigated alterations in these measures in individuals with SCI while the second Experiment investigated these measures as a function of the afferent volley. The collective results from Experiment 1 indicate that motor evoked potentials and SAI are reduced but somatosensory evoked potentials are similar to controls. Further data from Experiment 2 indicate that SAI and SEPs increase as a function of the afferent volley and indicate that alterations seen in individuals with SCI may be due to cortical plasticity in the synapses from SI to M1 or within M1. The novel findings of this thesis have indicated aberrant cortical circuits in individuals with SCI and have indicated potential synapses that may be targets for TMS plasticity protocols to alter and restore function to these circuits. / Thesis / Master of Science (MSc)

Comprised of six distinct layers, the neocortex is a key brain structure for many of our advanced cognitive abilities, ranging from sensation to decision making to movement. Each layer contains distinct cell types differing in their genes, biophysical properties, and connectivity with other parts of the brain. Yet how these diverse cortical layers and cell types contribute to any given behavior remains unresolved. Because sensory cortical areas have stereotyped anatomies and the six cortical layer organization is highly conserved across all mammals, understanding computations in one cortical area, such as the mouse barrel cortex within the primary somatosensory cortex, may inform us of computations being performed by similar microcircuits across the neocortex. This thesis is an investigation of cortical circuit function as it pertains to (1) distinct functional role of cortical layers in sensory discrimination, (2) increased cortical connectivity enhancing sensation, (3) a cautionary tale of selecting appropriate transgenic mouse lines for in vivo manipulations, (4) and the role of proprioception in the establishment of long-term visuospatial memory. Investigating layer-specific function first requires a cortex-dependent task. Yet, despite our extensive understanding of cortical anatomy and physiology, the contributions of different cortical layers to behaviors remain unknown. We developed a two-alternative forced choice paradigm in which head-fixed mice use a single whisker to either discriminate textures of parametrically varied roughness or detect the same textured surfaces. Lesioning barrel cortex revealed that texture discrimination, but not detection, was cortex-dependent. Paralyzing the whisker pad demonstrated that passive can rival active perception and cortical dependence is not movement-related. Transgenic Cre lines were used to target inhibitory opsins to excitatory cortical neurons of specific layers for selective perturbations. Discrimination required all layers, but deep layers (layers 5/6) were critical for accumulation of sensory evidence whereas superficial layers (layers 2-4) appeared to provide top-down motor input. This thesis shows that superficial layers contextually interpret sensory evidence to modify the deep layer output in behaviorally appropriate ways. Having identified distinct functional roles of deep and superficial layers through perturbation experiments, we next sought to enhance texture task performance by selectively activating texture-encoding neurons. However, given that all layers are involved in the task and the technical difficulties of targeting stimulus-selective cells, we turned to humanized mouse model (SRGAP2C) that exhibits increased local and long-range cortico-cortical connections and increased response selectivity to whisker stimulations in layer 2/3 pyramidal neurons in the barrel cortex. This thesis demonstrates that the increased cortico-cortical connectivity not only improved sensory coding accuracy in SRGAP2C mice, but the humanized animals trained on the texture discrimination task displayed increased learning rate and were more likely to learn the task compared to control. Next, we provide a cautionary tale of selecting appropriate mouse lines for in vivo experiments. Advances in optogenetics and transgenic Cre mouse lines enable us to probe the function of genetically defined neuronal populations, but transgene expression can adversely affect cell health and cause neural and behavioral abnormalities. We discovered learning impairments specific to cortex-dependent sensory discrimination behaviors in Emx1-Cre animals that express inhibitory opsins in excitatory cortical neurons. We suggest Nex1-Cre line as a more reliable and robust alternative to Emx1-Cre animals. The thesis highlights the importance of characterizing and selecting appropriate transgenic lines for in vivo optogenetic experiments.  In addition to touch, the primary somatosensory cortex processes other tactile information including temperature, pain, and proprioception. Creating a spatially accurate representation of the visual world requires transforming spatially inaccurate visual information coming from a constantly moving retina into a representation that can be used for accurate perception and action. This thesis shows that the dysgranular zone, the proprioceptive region of the primary somatosensory cortex, is required to establish long-term visuospatial memory.

<p>The control of unimanual and bimanual tasks is a highly orchestrated process in which primary motor cortex (M1) and primary somatosensory cortex (SI) play key roles. While somatic cortices are known to aid in the control of hand movements, the neural mechanisms by which they act remain largely unknown. One mechanism which is thought to mediate the control of hand movements between bilateral M1s is called interhemispheric inhibition (IHI), a neurophysiological mechanism by which one M1 is able to inhibit the contralateral M1, reducing the occurrence of unwanted movements, or enabling the performance of two differing tasks. Previous research suggests that IHI may be one mechanism by which SI aids in the control of hand movements and this thesis further examined this relationship. Two experiments were performed to investigate the influence of SI on IHI. Experiment 1 investigated the effects of direct modulation of SI cortical excitability on IHI. Experiment 2 investigated the effects of peripheral somatosensory inputs on IHI. The collective results of Experiments 1 and 2 suggest that SI can indeed modulate IHI from either the cortical or peripheral level, with increases in IHI seen following either intervention. Further, it was found that SI selectively modulates only the short latency phase of IHI (SIHI) as well as that mixed afferent inputs were most effective in altering SIHI. The novel findings of this thesis suggest that SI is indeed capable of aiding in the control of motor outputs and thus may be a possible target in future rehabilitative strategies.</p> / Master of Science in Kinesiology

Les deux fonctions principales de la main sont la manipulation d’objet et l’exploration tactile. La détection du glissement, rapportée par les mécanorécepteurs de la peau glabre, est essentielle pour l’exécution de ces deux fonctions. Durant la manipulation d’objet, la détection rapide du micro-glissement (incipient slip) amène la main à augmenter la force de pince pour éviter que l’objet ne tombe. À l’opposé, le glissement est un aspect essentiel à l’exploration tactile puisqu’il favorise une plus grande acuité tactile. Pour ces deux actions, les forces normale et tangentielle exercées sur la peau permettent de décrire le glissement mais également ce qui arrive juste avant qu’il y ait glissement. Toutefois, on ignore comment ces forces contrôlées par le sujet pourraient être encodées au niveau cortical. C’est pourquoi nous avons enregistré l’activité unitaire des neurones du cortex somatosensoriel primaire (S1) durant l’exécution de deux tâches haptiques chez les primates. Dans la première tâche, deux singes devaient saisir une pastille de métal fixe et y exercer des forces de cisaillement sans glissement dans une de quatre directions orthogonales. Des 144 neurones enregistrés, 111 (77%) étaient modulés à la direction de la force de cisaillement. L’ensemble de ces vecteurs préférés s’étendait dans toutes les directions avec un arc variant de 50° à 170°. Plus de 21 de ces neurones (19%) étaient également modulés à l’intensité de la force de cisaillement. Bien que 66 neurones (59%) montraient clairement une réponse à adaptation lente et 45 autres (41%) une réponse à adaptation rapide, cette classification ne semblait pas expliquer la modulation à l’intensité et à la direction de la force de cisaillement. Ces résultats montrent que les neurones de S1 encodent simultanément la direction et l’intensité des forces même en l’absence de glissement. Dans la seconde tâche, deux singes ont parcouru différentes surfaces avec le bout des doigts à la recherche d’une cible tactile, sans feedback visuel. Durant l’exploration, les singes, comme les humains, contrôlaient les forces et la vitesse de leurs doigts dans une plage de valeurs réduite. Les surfaces à haut coefficient de friction offraient une plus grande résistance tangentielle à la peau et amenaient les singes à alléger la force de contact, normale à la peau. Par conséquent, la somme scalaire des composantes normale et tangentielle demeurait constante entre les surfaces. Ces observations démontrent que les singes contrôlent les forces normale et tangentielle qu’ils appliquent durant l’exploration tactile. Celles-ci sont également ajustées selon les propriétés de surfaces telles que la texture et la friction. Des 230 neurones enregistrés durant la tâche d’exploration tactile, 96 (42%) ont montré une fréquence de décharge instantanée reliée aux forces exercées par les doigts sur la surface. De ces neurones, 52 (54%) étaient modulés avec la force normale ou la force tangentielle bien que l’autre composante orthogonale avait peu ou pas d’influence sur la fréquence de décharge. Une autre sous-population de 44 (46%) neurones répondait au ratio entre la force normale et la force tangentielle indépendamment de l’intensité. Plus précisément, 29 (30%) neurones augmentaient et 15 (16%) autres diminuaient leur fréquence de décharge en relation avec ce ratio. Par ailleurs, environ la moitié de tous les neurones (112) étaient significativement modulés à la direction de la force tangentielle. De ces neurones, 59 (53%) répondaient à la fois à la direction et à l’intensité des forces. L’exploration de trois ou quatre différentes surfaces a permis d’évaluer l’impact du coefficient de friction sur la modulation de 102 neurones de S1. En fait, 17 (17%) neurones ont montré une augmentation de leur fréquence de décharge avec l’augmentation du coefficient de friction alors que 8 (8%) autres ont montré le comportement inverse. Par contre, 37 (36%) neurones présentaient une décharge maximale sur une surface en particulier, sans relation linéaire avec le coefficient de friction des surfaces. La classification d’adaptation rapide ou lente des neurones de S1 n’a pu être mise en relation avec la modulation aux forces et à la friction. Ces résultats montrent que la fréquence de décharge des neurones de S1 encode l’intensité des forces normale et tangentielle, le ratio entre les deux composantes et la direction du mouvement. Ces résultats montrent que le comportement d’une importante sous-population des neurones de S1 est déterminé par les forces normale et tangentielle sur la peau. La modulation aux forces présentée ici fait le pont entre les travaux évaluant les propriétés de surfaces telles que la rugosité et les études touchant à la manipulation d’objets. Ce système de référence s’applique en présence ou en absence de glissement entre la peau et la surface. Nos résultats quant à la modulation des neurones à adaptation rapide ou lente nous amènent à suggérer que cette classification découle de la manière que la peau est stimulée. Nous discuterons aussi de la possibilité que l’activité des neurones de S1 puisse inclure une composante motrice durant ces tâches sensorimotrices. Finalement, un nouveau cadre de référence tridimensionnel sera proposé pour décrire et rassembler, dans un même continuum, les différentes modulations aux forces normale et tangentielle observées dans S1 durant l’exploration tactile. / The two most important functions of the hand are object manipulation and tactile exploration. The detection of slip provided by specialized mechanoreceptors in the glabrous skin is essential for the execution of both these functions. During object manipulation, the early detection of incipient slip leads to a grip force increase in order to prevent dropping an object. Slip is also an important aspect of tactile exploration because it greatly increases the acuity of touch perception. In both actions, normal and tangential forces on the skin can describe slip itself but also what occurs just before slip. However, little is known about how these self-generated forces are encoded at the cortical level. To better understand this encoding, we recorded from single neurons in primary somatosensory cortex (S1) as monkeys executed two haptic tasks. In the first task, two monkeys grasped a stationary metal tab with a key grip and exerted shear forces, without slip, in one of four orthogonal directions. Of 144 recorded neurons, 111 (77%) had activity modulated with shear force directions. These preferred shear force vectors were distributed in every direction with tuning arcs varying from 50° to 170°. Also, more than 21 (19%) of these neurons had a firing rate correlated with shear force magnitude. Even if 66 (59%) modulated neurons showed clear slowly adapting response and 45 (41%) other neurons a rapidly adapting response, this classification failed to explain the modulation to force direction and magnitude. These results show that S1 neurons encode force direction and magnitude simultaneously even in the absence of slip. In the second task, two monkeys scanned different surfaces with the fingertips in search of a tactile target without visual feedback. During the exploration, the monkeys, like humans, carefully controlled the finger forces and speeds. High friction surfaces offered greater tangential shear force resistance to the skin that was associated with decrease of the normal contact forces. Furthermore, the scalar sum of the normal and tangential forces remained constant. These observations demonstrate that monkeys control the applied normal and tangential finger forces within a narrow range which is adjusted according to surface properties such as texture and friction. Of the 230 recorded neurons during tactile exploration, 96 (42%) showed instantaneous frequency changes in relation to finger forces. Of these, 52 (54%) were correlated with either the normal or tangential force magnitude with little or no influence from the other orthogonal force component. Another subset of 44 neurons (46%) responded to the ratio between normal and tangential forces regardless of magnitude. Namely, 29 neurons (30%) increased and 15 (16%) others decreased their discharge frequency related to this ratio, which corresponds to the coefficient of friction. Tangential force direction significantly modulated about half the recorded neurons (112). Of these, 59 (53%) responded to both direction and force magnitude. Of the 102 neurons recorded during exploration of three or more surfaces, 17 (17%) showed increased firing rate with increased surface friction and 8 (8%) presented the opposite behavior. However, 37 (36%) neurons seemed to discharge optimally for one of the surfaces without any linear relation to the surfaces’ coefficient of friction. The classification of rapidly and slowly adaptation for neuronal responses in S1 could not be associated with the modulation to forces or direction. These results show that the firing rates of S1 neurons reflect the tangential and normal force magnitude, the ratio of the two forces and the direction of finger movement. These results show that the activity of a significant subpopulation of S1 neurons is represented by normal and tangential forces on the skin. This force modulation uses a frame of reference that can be applied with or without slip. This aspect provides a link between investigations of the cortical representation of surface properties and studies on object manipulation. Our results regarding the distinction between rapidly and slowly adapting neurons leads us to suggest that this difference is a consequence of the manner in which the skin was stimulated. A potential motor component in the modulation of S1 neurons during these sensorimotor tasks is also discussed. Finally, a novel three-dimensional reference frame is proposed to describe, as a single continuum, the different modulations to forces observed in S1 during tactile exploration.

La douleur est une expérience perceptive comportant de nombreuses dimensions. Ces dimensions de douleur sont inter-reliées et recrutent des réseaux neuronaux qui traitent les informations correspondantes. L’élucidation de l'architecture fonctionnelle qui supporte les différents aspects perceptifs de l'expérience est donc une étape fondamentale pour notre compréhension du rôle fonctionnel des différentes régions de la matrice cérébrale de la douleur dans les circuits corticaux qui sous tendent l'expérience subjective de la douleur. Parmi les diverses régions du cerveau impliquées dans le traitement de l'information nociceptive, le cortex somatosensoriel primaire et secondaire (S1 et S2) sont les principales régions généralement associées au traitement de l'aspect sensori-discriminatif de la douleur. Toutefois, l'organisation fonctionnelle dans ces régions somato-sensorielles n’est pas complètement claire et relativement peu d'études ont examiné directement l'intégration de l'information entre les régions somatiques sensorielles. Ainsi, plusieurs questions demeurent concernant la relation hiérarchique entre S1 et S2, ainsi que le rôle fonctionnel des connexions inter-hémisphériques des régions somatiques sensorielles homologues. De même, le traitement en série ou en parallèle au sein du système somatosensoriel constitue un autre élément de questionnement qui nécessite un examen plus approfondi. Le but de la présente étude était de tester un certain nombre d'hypothèses sur la causalité dans les interactions fonctionnelle entre S1 et S2, alors que les sujets recevaient des chocs électriques douloureux. Nous avons mis en place une méthode de modélisation de la connectivité, qui utilise une description de causalité de la dynamique du système, afin d'étudier les interactions entre les sites d'activation définie par un ensemble de données provenant d'une étude d'imagerie fonctionnelle. Notre paradigme est constitué de 3 session expérimentales en utilisant des chocs électriques à trois différents niveaux d’intensité, soit modérément douloureux (niveau 3), soit légèrement douloureux (niveau 2), soit complètement non douloureux (niveau 1). Par conséquent, notre paradigme nous a permis d'étudier comment l'intensité du stimulus est codé dans notre réseau d'intérêt, et comment la connectivité des différentes régions est modulée dans les conditions de stimulation différentes. Nos résultats sont en faveur du mode sériel de traitement de l’information somatosensorielle nociceptive avec un apport prédominant de la voie thalamocorticale vers S1 controlatérale au site de stimulation. Nos résultats impliquent que l'information se propage de S1 controlatéral à travers notre réseau d'intérêt composé des cortex S1 bilatéraux et S2. Notre analyse indique que la connexion S1→S2 est renforcée par la douleur, ce qui suggère que S2 est plus élevé dans la hiérarchie du traitement de la douleur que S1, conformément aux conclusions précédentes neurophysiologiques et de magnétoencéphalographie. Enfin, notre analyse fournit des preuves de l'entrée de l'information somatosensorielle dans l'hémisphère controlatéral au côté de stimulation, avec des connexions inter-hémisphériques responsable du transfert de l'information à l'hémisphère ipsilatéral. / Pain is a perceptual experience comprising many dimensions. These pain dimensions interrelate with each other and recruit neuronal networks that process the corresponding information. Elucidating the functional architecture that supports different perceptual aspects of the experience is thus, a fundamental step to our understanding of the functional role of different regions in the cerebral pain matrix that are involved in the cortical circuitry underlying the subjective experience of pain. Among various brain regions involved in the processing of nociceptive information, primary and secondary somatosensory cortices (S1 and S2) are the main areas generally associated with the processing of sensory-discriminative aspect of pain. However the functional organization in these somatosensory areas is not completely clear and relatively few studies have directly examined the integration of information among somatic sensory regions. Thus, several questions remain regarding the hierarchical relationship between S1 and S2, as well as the functional role of the inter-hemispheric connections of the homologous somatic sensory areas. Likewise, the question of serial or parallel processing within the somatosensory system is another questionable issue that requires further investigation. The purpose of the present study was to test a number of causal hypotheses regarding the functional interactions between S1 and S2, while subjects were receiving painful electric shocks. We implemented a connectivity modeling approach, which utilizes a causal description of system dynamics, in order to study the interactions among activation sites defined by a data set derived from a functional imaging study. Our paradigm consists of 3 experimental scans using electric shock stimuli, with the stimulus intensity changing from moderately painful (level 3), to slightly painful (level 2), and to completely non-painful (level 1) during the final scan. Therefore our paradigm allowed us to investigate how stimulus intensity is encoded within our network of interest, and how the connectivity of the different regions is modulated across the different stimulus conditions. Our result is in favor of serial mode of somatosensory processing with thalamocortical input to S1 contralateral to stimulation site. Thus our results implicates that pain information is propogated from S1 contralateral through our network of interest comprising of bilateral S1 and S2. Our analysis indicates that S1→S2 connection is modulated by pain, which suggests that S2 is higher on the hierarchy of pain processing than S1, in accordance with previous neurophysiological and MEG findings. Lastly, our analysis provides evidence for the entrance of somatosensory information into the hemisphere contralateral to the stimulation side, with inter-hemispheric connections responsible for the transfer of information to the ipsilateral hemisphere.