Sensory neocortex contains a significant number of inhibitory neurons that use gamma-aminobutyric acid (GABA) as their neurotransmitter. Functional roles for these neurons have been identified in physiological studies. For example, in primary somatosensory cortex (SI), blockade of GABAa receptors with bicuculline leads to expansion of receptive fields (RFs). The magnitude of RF enlargement varies between SIpopulations of GABAergic neurons were identified by labeling specific calcium binding proteins.

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<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

<p>Temporal order judgment (TOJ) refers to one’s ability to successively report the temporal order of two tactile stimuli delivered to independent skin sites. The brain regions involved in processing TOJ remain unclear. Research has shown that TOJ performance can be impaired with a conditioning background stimuli and this phenomenon, known as TOJ synchronization (TOJ-S), is suggested to be mediated by inhibitory neural mechanisms within the primary somatosensory cortex (SI) that create perceptual binding across the two skin sites. Continuous theta-burst stimulation (cTBS) over SI impairs tactile spatial and temporal acuity. This dissertation examines the effects of cTBS on TOJ and TOJ-S performance on the hand. In Experiment 1, TOJ and TOJ-S were measured from the right hand before and for up to 34 minutes following 50 Hz cTBS over SI. In Experiment 2, same measurements were obtained bilaterally for up to 42 minutes following 30 Hz cTBS over SI. Compared to pre-cTBS values, TOJ was impaired for up to 42 minutes on the right hand following 30 Hz cTBS. TOJ-S performance was improved for up to 18 minutes on the right hand following 50 Hz cTBS. These experiments reveal two major findings. First, cTBS act upon different inhibitory circuits that are suggested to mediate TOJ and TOJ-S. Second, cTBS parameters may dictate cTBS effects over SI excitability. The findings of this work not only emphasize the significant contributions of SI on tactile temporal perception, it provides novel insight of the underlying neural mechanisms of cTBS effects on SI cortical excitability.</p> / Master of Science in Kinesiology

Zahlreiche Untersuchungen belegen, dass räumlich selektive Aufmerksamkeit visuelle und auditive Reizverarbeitung beeinflusst. Bestehende Modellvorstellungen sind, aufgrund der geringen Kenntnisse vergleichbarer somatosensorischer Effekte, schwer zu einem allgemeinen Mechanismus generalisieren. Mittels zeitlich-räumlich hoch aufgelöster Messmethoden wurde in dieser Dissertation Effekte räumlich selektiver Aufmerksamkeit auf die bewusste Wahr-nehmung und kortikale Verarbeitung somatosensorischer Reize untersucht. Im Einzelnen wurde gezeigt, dass die räumlich selektive Aufmerksamkeit die Maskierung eines überschwelli-gen Reizes an einer Hand durch einen starken Reiz an der anderen Hand moduliert. Mittels Elektroenzephalografie (EEG) wurde nachgewiesen, dass nach der Stimulation die Verarbei-tung in einem fronto-parietalen Netzwerk den Zugang ins Bewusstsein signalisiert. Der Be-fund einer der bewussten Wahrnehmung zeitlich vorausgehenden neuronalen Desynchronisa-tion im frontalen Kortex und in S1 erlaubt eine Erweiterung bestehender Modellvorstellun-gen. In einer simultanen EEG-funktionelle Magnetresonanztomografie (fMRT) -Studie wurde gezeigt, dass räumlich selektive Aufmerksamkeit die Signalverarbeitung während einer frühen sensorischen Phase der Reizverarbeitung beeinflusst (50 ms). Dieser Effekt korrelierte mit den Blutflußveränderungen in S1. Zusammenfassend zeigen die Studien, dass räumlich selektive Aufmerksamkeit zwar frühe somatosensorische Aktivität in S1 sowie die Wahrnehmung so-matosensorischer Reize moduliert, dies jedoch keine hinreichende Bedingung für die bewusste Wahrnehmung ist. Hingegen ist die attentional kontrollierte Desynchronisation somatosenso-rischer Rhythmen vor der Stimulation, die eine verstärkte fronto-parietale Reizverarbeitung nach sich zieht, hierfür entscheidend. / Numerous studies have shown that selective orientation of attention to a stimulus location modulates visual and auditory stimulus processing. Due to the relatively little knowledge about comparable effects of attention in the somatosensory system, existing models can barely be assigned to general cortical mechanisms. The studies conducted in this dissertation should therefore contribute to this knowledge. Effects of spatial selective attention on conscious per-ception and cortical processing of somatosensory stimuli have been investigated by applying recording methods with high temporal and spatial resolutions. Specifically, it was shown that spatial selective attention modulates masking of supra-threshold stimulus on one hand by a strong stimulus applied to the other hand. Using electroencephalography (EEG), it was dem-onstrated that processing in a fronto-parietal network but not early S1-activation signals the entry into conscious perception. The finding of neuronal desynchronisation in the frontal cor-tex and S1 preceding conscious stimulus perception permits the extension of the existing models. With the aim of localizing the temporal effects of spatial selective attention, a simul-taneous EEG-functional magnetic resonance imaging (fMRI)-study was conducted. In con-trast to findings of visual attention, it was shown that orientation of attention enhances soma-tosensory processing at an early stage of stimulus processing (50 ms). This effect correlated with the changes of cortical blood flow in S1. Together, these studies show that spatial-selective attention modulates early activity in S1 as well as conscious perception of somatosen-sory stimuli. Nevertheless, this is not sufficient for an entrance into conscious perception. Instead, attentionally controlled pre-stimulus desynchronisation of somatosensory rhythmic activity, followed by an increased fronto-parietal stimulus processing are necessary prerequi-sites for conscious perception.

Performance of efficient and precise motor output requires proper planning of movement parameters as well as integration of sensory feedback. Peripheral sensory information is projected not only to parietal somatosensory areas but also to cortical motor areas, particularly the supplementary motor area (SMA). These afferent sensory pathways to the frontal cortices are likely involved in the integration of sensory information for assistance in motor program planning and execution. It is not well understood how and where sensory information from the limb contralateral to motor output is modulated, but the SMA is a potential cortical source as it is active both before and during motor output and is particularly involved in movements that require coordination and bilateral upper-limb selection and use. A promising physiological index of sensory inflow to the SMA is the frontal N30 component of the median nerve (MN) somatosensory-evoked potential (SEP), which is generated in the SMA. The SMA has strong connections with ipsilateral areas 2, 5 and secondary somatosensory cortex (S2) as well as ipsilateral primary motor cortex (M1). As such, the SMA proves a fruitful candidate to assess how sensory information is modulated across the upper-limbs during the various stages of motor output. This thesis inquires into how somatosensory information is modulated in both the SMA and primary somatosensory cortical areas (S1) during the planning and execution of a motor output contralateral to sensory input across the upper-limbs, and further, how and what effect ipsilateral primary motor cortex (iM1) has upon modulation of sensory inputs to the SMA.

Performance of efficient and precise motor output requires proper planning of movement parameters as well as integration of sensory feedback. Peripheral sensory information is projected not only to parietal somatosensory areas but also to cortical motor areas, particularly the supplementary motor area (SMA). These afferent sensory pathways to the frontal cortices are likely involved in the integration of sensory information for assistance in motor program planning and execution. It is not well understood how and where sensory information from the limb contralateral to motor output is modulated, but the SMA is a potential cortical source as it is active both before and during motor output and is particularly involved in movements that require coordination and bilateral upper-limb selection and use. A promising physiological index of sensory inflow to the SMA is the frontal N30 component of the median nerve (MN) somatosensory-evoked potential (SEP), which is generated in the SMA. The SMA has strong connections with ipsilateral areas 2, 5 and secondary somatosensory cortex (S2) as well as ipsilateral primary motor cortex (M1). As such, the SMA proves a fruitful candidate to assess how sensory information is modulated across the upper-limbs during the various stages of motor output. This thesis inquires into how somatosensory information is modulated in both the SMA and primary somatosensory cortical areas (S1) during the planning and execution of a motor output contralateral to sensory input across the upper-limbs, and further, how and what effect ipsilateral primary motor cortex (iM1) has upon modulation of sensory inputs to the SMA.

One of the most common risk factors for stroke is diabetes. Diabetics are 2 to 4 times more likely to have a stroke and are also significantly more likely to show poor functional recovery. In order to determine why diabetes is associated with poor stroke recovery, we tested the hypotheses that diabetes either exacerbates initial stroke damage, or inhibits neuronal circuit plasticity in surviving brain regions that is crucial for successful recovery. Type 1 diabetes was chemically induced in mice four weeks before receiving a targeted photothrombotic stroke in the right forelimb somatosensory cortex to model a chronic diabetic condition. Following stroke, a subset of diabetic mice were treated with insulin to determine if controlling blood glucose levels could improve stroke recovery. Consistent with previous studies, one behavioural test revealed a progressive improvement in sensory function of the forepaw in non-diabetic mice after stroke. By contrast, diabetic mice treated with and without insulin showed persistent deficits in sensori-motor forepaw function. To determine whether these different patterns of stroke recovery correlated with changes in functional brain activation, forepaw evoked responses in the somatosensory cortex were imaged using voltage sensitive dyes at 1 and 14 weeks after stroke. In both diabetic and non-diabetic mice that did not have a stroke, brief mechanical stimulation of the forepaw evoked a robust and near simultaneous depolarization in the primary (FLS1) and secondary somatosensory (FLS2) cortex. One week after stroke, forepaw-evoked responses had not been remapped in the peri-infarct cortex in both diabetic and non-diabetic mice. Fourteen weeks after stroke, forepaw evoked responses in non-diabetic mice re-emerged in the peri-infarct cortex whereas diabetic mice showed very little activation, reminiscent of the 1 week recovery group. Moreover, controlling hyperglycemia using insulin therapy failed to restore sensory evoked responses in the peri-infarct cortex. In addition to these differences in peri-infarct responsiveness, we discovered that stroke was associated with increased responsiveness in FLS2 of non-diabetic, but not diabetic or insulin treated mice. To determine the importance of FLS2 in stroke recovery, we silenced the FLS2 cortex and found that it re-instated behavioural impairments in stroke recovered mice, significantly more so than naïve mice that still had a functioning FLS1. Collectively, these results indicate that both diabetes and the secondary somatosensory cortex play an important role in determining the extent of functional recovery after ischemic cortical stroke. Furthermore, the fact that insulin therapy after stroke did not normalize functional recovery, suggests that prolonged hyperglycemia (before stroke) may induce pathological changes in the brain’s circulation or nervous system that cannot be easily reversed. / Graduate

Plusieurs illusions tactiles suggèrent que la temporalité des stimulations cutanées dans une séquence modifie leur perception spatiale. S’ils sont assez proches dans l’espace, plus l’intervalle temporel entre deux stimuli est court, plus la distance perçue entre eux est courte. Lorsque les deux stimuli sont présentés simultanément, on observe une perception fusionnée, unique et centrée entre les positions réelles. Ainsi, le système de perception tactile semble utiliser le temps entre les stimuli pour estimer l’espace qui les sépare. Dans l’optique de comprendre comment cette règle perceptive est implémentée dans le système nerveux, nous avons étudié la représentation corticale des stimulations qui induisent ces illusions. Nous avons recherché les distorsions spatiales de la représentation somatotopique dans le cortex somesthésique primaire, à la suite de l’application séquentielle ou simultanée d’une paire de stimuli cutanés sur l’extrémité des phalanges distales de la patte antérieure chez le rat anesthésié. Avec des enregistrements électrophysiologiques et d’imagerie optique extrinsèque, nous avons mis en évidence un phénomène de fusion corticale des entrées sensorielles simultanées, avec un patron spatial d’activation unimodal, centré entre les représentations individuelles des doigts adjacents costimulés. Dans le cas de stimuli successifs, nous avons observé des modifications des réponses au deuxième stimulus dépendantes de l’intervalle inter stimuli. Cette intégration spatiotemporelle ne semble pas contribuer directement au raccourcissement des distances perçues, mais pourrait favoriser les erreurs de localisation constatées lors de la perception des illusions. / Several tactile spatiotemporal illusions suggest that the timing of successive cutaneous stimulations modify the perception of their spatial location. If they are close enough in time and space, shorter inter-stimuli time intervals (ISI) lead to shorted perceived distances. To the extreme of this time-space relation, when the stimuli are simultaneous, subjects report the merged perception of a unique and centered point of stimulation. Therefore, the tactile perceptual system seems to use the time separating two stimuli to compute their spatial distance. To understand the implementation of this perceptual rule, one can investigate the neural representation of the stimuli that elicit the illusory percept, looking for spatial distortions and their underlying mechanisms. Studies based on the measure of the hemodynamic responses have shown such distortions of the somatotopic representations in the primary somatosensory cortex, for simultaneous and delayed stimulations. In order to enhance our understanding of the elementary phenomenon that underpins those spatial modifications of the sensory inputs, we investigated the cortical representation of pairs of simultaneous and delayed cutaneous stimuli in the S1 of anesthetized rats. Using electrophysiological recordings and extrinsic optical imaging, we revealed the cortical merging of inputs from simultaneous digits stimulation. When the stimuli were delayed, we observed ISI-dependent modulations of the responses to the second stimulus. This spatiotemporal integration, that didn’t seem to contribute directly to a distance contraction effect, could however favor the mislocalization observed in illusory perception.

Cette étude explore les réponses évoquées, l'activité intrinsèque et spontanée de deux populations neuronales différentes dans la région du cerveau correspondant à la patte arrière des souris. Dans cet article, nous nous sommes concentrés sur un modèle murin du syndrome de l'X fragile (SXF), qui est la forme la plus commune de syndrome de retard mental héréditaire et une cause fréquente de troubles du spectre autistique (TSA). SXF est un trouble à gène unique (Fmr1), qui peut être modélisé de manière fiable par un modèle murin transgénique : la souris Fmr1-/y déficiente pour le gène codant Fmr1. L'hyperexcitabilité des réseaux néocorticaux et l'hypersensibilité aux stimuli sensoriels sont des caractéristiques importantes du SXF et des TSA.Ceci est directement lié à un changement du nombre de synapses locales, de canaux ioniques, de l'excitabilité membranaire et de la connectivité des circuits de cellules individuelles. Précédemment, nous avons identifié un défaut dans les canaux ioniques, comme pouvant contribuer à ces phénotypes. Nous avons testé cette hypothèse comme un mécanisme contribuant aux défauts de traitement sensoriel chez les souris Fmr1-/y. Le cortex somatosensoriel primaire de la souris (S1) traite différentes informations sensorielles et constitue la plus grande zone du néocortex, soulignant l'importance de la modalité sensorielle pour le comportement des rongeurs. Nos connaissances concernant le traitement de l'information dans S1 proviennent d'études du cortex en tonneaux lié aux moustaches, mais le traitement des entrées sensorielles des pattes postérieures est mal compris. Par l’utilisation de la technique d’enregistrement de cellule entière par patch clamp in vivo, nous avons classes les cellules en répondeurs supraliminaires (cellules qui répondaient aux stimulations de la patte arrière avec un potentiel d'action), les répondeurs subliminaires (les cellules qui répondaient sans déclencher un potentiel d'action) et les cellules non répondeuses qui ne présentaient aucune réponse. Puis, nous avons comparé les réponses évoquées sub et supraliminaires, les propriétés intrinsèques et l’activité spontanée des neurones pyramidaux de la couche 2/3 (L2/3) de la region S1 de la patte arrière (S1-HP) d’animaux anesthésiés sauvage (WT) et Fmr1-/y. Nous avons identifié des altérations de réponse spontanée, intrinsèque et évoquée chez les souris Fmr1-/y. L’application d’un ouvreur de canaux ioniques BKCa a restauré certaines de ces propriétés altérées chez les souris Fmr1-/y / This study explores the evoked responses, intrinsic and spontaneous activity of two different neuronal populations in the hind paw region of the primary somatosensory cortex (S1) of mice. Initially, we explored information processing in these neurons under normal physiological conditions, and subsequently in a mouse model of Fragile X Syndrome (FXS). FXS is the most common form of inherited mental retardation syndrome and a frequent cause of autism spectrum disorders (ASD). FXS is a single gene (Fmr1) disorder, which can be reliably modeled by a mutant mouse model, the Fmr1 knockout (Fmr1-/y) mouse. Hyperexcitability of neocortical networks and hypersensibility to sensory stimuli are prominent features of FXS and ASD. We previously established a strong causal link between a channelopathy, hyperexcitability of neurons in the primary sensory region of the neocortex and sensory hypersensitivity in this mouse model. In the current study, we extended these findings, by conducting a detailed exploration of the processing of tactile sensory information (evoked by hind paw stimulation) in the neocortex of these mice.Most of our knowledge regarding information processing in S1 comes from studies of the whisker-related barrel cortex (which processes tactile-related sensory information derived from the whiskers), yet the processing of sensory inputs from the hind-paws is poorly understood. Using in vivo whole-cell patch-clamp recordings, we classified the cells into suprathreshold responders (the cells which responded to the hind-paw stimulations with an action potential), subthreshold responders (the cells responded without eliciting an action potential) and non-responder cells (neurons which did not show any response). We then compared the evoked sub- and supra-threshold responses, intrinsic properties, and spontaneous activity of layer (L) 2/3 pyramidal neurons of the S1 hind-paw (S1-HP) region of anaesthetized wild type (WT) and Fmr1-/y mice. We identified spontaneous, intrinsic and evoked response alterations in Fmr1-/y mice. We probed possible mechanisms contributing to this sensory impairment in Fmr1-/y mice. Finally, we tested the possibility of correcting pathophysiological alterations in these neurons using specific pharmacological agents targeting the ion channel defects described previously by our team.