Simulating human sleep spindle MEG and EEG from ion channel and circuit level dynamics

Although they form a unitary phenomenon, the relationship between extracranial M/EEG and transmembrane ion flows is understood only as a general principle rather than as a well-articulated and quantified causal chain.We present an integrated multiscale model, consisting of a neural simulation of thalamus and cortex during stage N2 sleep and a biophysical model projecting cortical current densities to M/EEG fields. Sleep spindles were generated through the interactions of local and distant network connections and intrinsic currents within thalamocortical circuits. 32,652 cortical neurons were mapped onto the cortical surface reconstructed from subjects' MRI, interconnected based on geodesic distances, and scaled-up to current dipole densities based on laminar recordings in humans. MRIs were used to generate a quasi-static electromagnetic model enabling simulated cortical activity to be projected to the M/EEG sensors.The simulated M/EEG spindles were similar in amplitude and topography to empirical examples in the same subjects. Simulated spindles with more core-dominant activity were more MEG weighted.Previous models lacked either spindle-generating thalamic neural dynamics or whole head biophysical modeling; the framework presented here is the first to simultaneously capture these disparate scales.This multiscale model provides a platform for the principled quantitative integration of existing information relevant to the generation of sleep spindles, and allows the implications of future findings to be explored. It provides a proof of principle for a methodological framework allowing large-scale integrative brain oscillations to be understood in terms of their underlying channels and synapses

Sleep spindles in primates: modelling the effects of distinct laminar thalamocortical connectivity in core, matrix, and reticular thalamic circuits

Sleep spindles are associated with the beginning of deep sleep and memory consolidation and are disrupted in schizophrenia and autism. In primates, distinct core and matrix thalamocortical (TC) circuits regulate sleep-spindle activity, through communications that are filtered by the inhibitory thalamic reticular nucleus (TRN) however, little is known about typical TC network interactions and the mechanisms that are disrupted in brain disorders. We developed a primate-specific, circuit-based TC computational model with distinct core and matrix loops that can simulate sleep spindles. We implemented novel multilevel cortical and thalamic mixing, and included local thalamic inhibitory interneurons, and direct layer 5 projections of variable density to TRN and thalamus to investigate the functional consequences of different ratios of core and matrix node connectivity contribution to spindle dynamics. Our simulations showed that spindle power in primates can be modulated based on the level of cortical feedback, thalamic inhibition, and engagement of model core vs. matrix, with the latter having a greater role in spindle dynamics. The study of the distinct spatial and temporal dynamics of core-, matrix-, and mix-generated sleep spindles establishes a framework to study disruption of TC circuit balance underlying deficits in sleep and attentional gating seen in autism and schizophrenia.5R01MH118500-05 REVISED - NIH/National Institute of Mental HealthFirst author draf

Characterization Of Somatosensation In The Brainstem And The Development Of A Sensory Neuroprosthesis

Innovations in neuroprosthetics have restored sensorimotor function to paralysis patients and amputees. However, to date there is a lack of solutions available to adequately address the needs of spinal cord injury patients (SCI). In this dissertation we develop a novel sensor-brain interface (SBI) that delivers electric microstimulation to the cuneate nucleus (CN) to restore somatosensory feedback in patients with intact limbs. In Chapter II, we develop a fully passive liquid metal antenna using gallium-indium (GaIn) alloy injected in polydimethylsiloxane (PDM) channels to measure forces within the physiological sensitivity of a human fingertip. In Chapter III, we present the first chronic neural interface with the CN in primates to provide access to long-term unit recordings and stimulation. In Chapter IV, we demonstrate that microstimulation to the CN is detectable in a Three Alternative Force Choice Oddity task in awake behaving primates. In Chapter V, we explore the downstream effects of CN stimulation on primary somatosensory cortex, in the context of spontaneous and evoked spindles under sedation. In summary, these findings constitute a proof-of-concept for the sensory half of a bidirectional sensorimotor prosthesis in the CN

A model for cerebral cortical neuron group electric activity and its implications for cerebral function

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2002.Includes bibliographical references (p. 245-265).The electroencephalogram, or EEG, is a recording of the field potential generated by the electric activity of neuronal populations of the brain. Its utility has long been recognized as a monitor which reflects the vigilance states of the brain, such as arousal, drowsiness, and sleep stages. Moreover, it is used to detect pathological conditions such as seizures, to calibrate drug action during anesthesia, and to understand cognitive task signatures in healthy and abnormal subjects. Being an aggregate measure of neural activity, understanding the neural origins of EEG oscillations has been limited. With the advent of recording techniques, however, and as an influx of experimental evidence on cellular and network properties of the neocortex has become available, a closer look into the neuronal mechanisms for EEG generation is warranted. Accordingly, we introduce an effective neuronal skeleton circuit at a neuronal group level which could reproduce basic EEG-observable slow ( 3mm). The effective circuit makes use of the dynamic properties of the layer 5 network to explain intra-cortically generated augmenting responses, restful alpha, slow wave (< 1Hz) oscillations, and disinhibition-induced seizures. Based on recent cellular evidence, we propose a hierarchical binding mechanism in tufted layer 5 cells which acts as a controlled gate between local cortical activity and inputs arriving from distant cortical areas. This gate is manifested by the switch in output firing patterns in tufted(cont.) layer 5 cells between burst firing and regular spiking, with specific implications on local functional connectivity. This hypothesized mechanism provides an explanation of different alpha band (10Hz) oscillations observed recently under cognitive states. In particular, evoked alpha rhythms, which occur transiently after an input stimulus, could account for initial reogranization of local neural activity based on (mis)match between driving inputs and modulatory feedback of higher order cortical structures, or internal expectations. Emitted alpha rhythms, on the other hand, is an example of extreme attention where dominance of higher order control inputs could drive reorganization of local cortical activity. Finally, the model makes predictions on the role of burst firing patterns in tufted layer 5 cells in redefining local cortical dynamics, based on internal representations, as a prelude to high frequency oscillations observed in various sensory systems during cognition.by Fadi Nabih Karameh.Ph.D

Laminar analysis of the slow wave activity in the somatosensory cortex of anesthetized rats.

Rhythmic slow waves characterize brain electrical activity during natural deep sleep and under anesthesia, reflecting the synchronous membrane potential fluctuations of neurons in the thalamocortical network. Strong evidence indicates that the neocortex plays an important role in the generation of slow wave activity (SWA), however, contributions of individual cortical layers to the SWA generation are still unclear. The anatomically correct laminar profiles of SWA were revealed under ketamine/xylazine anesthesia, with combined local field potential recordings, multiple-unit activity (MUA), current source density (CSD) and time-frequency analyses precisely co-registered with histology. The up-state related negative field potential wave showed the largest amplitude in layer IV, the CSD was largest in layers I and III, while MUA was maximal in layer V, suggesting spatially dissociated firing and synaptic/transmembrane processes in the rat somatosensory cortex. Up-state related firing could start in virtually any layers (III-VI) of the cortex, but were most frequently initiated in layer V. However, in a subset of experiments, layer IV was considerably active in initiating up-state related MUA even in the absence of somatosensory stimulation. Somatosensory stimulation further strengthened up-state initiation in layer IV. Our results confirm that cortical layer V firing may have a major contribution to the up-state generation of ketamine/xylazine-induced SWA, however, thalamic influence through the thalamorecipient layer IV can also play an initiating role, even in the absence of sensory stimulation. This article is protected by copyright. All rights reserved

Slow-wave sleep : generation and propagation of slow waves, role in long-term plasticity and gating

Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2012-2013.Le sommeil est connu pour réguler plusieurs fonctions importantes pour le cerveau et parmi celles-ci, il y a le blocage de l’information sensorielle par le thalamus et l’amélioration de la consolidation de la mémoire. Le sommeil à ondes lentes, en particulier, est considéré être critique pour ces deux processus. Cependant, leurs mécanismes physiologiques sont inconnus. Aussi, la marque électrophysiologique distinctive du sommeil à ondes lentes est la présence d’ondes lentes de grande amplitude dans le potentiel de champ cortical et l’alternance entre des périodes d’activités synaptiques intenses pendant lesquelles les neurones corticaux sont dépolarisés et déchargent plusieurs potentiels d’action et des périodes silencieuses pendant lesquelles aucune décharge ne survient, les neurones corticaux sont hyperpolarisés et très peu d’activités synaptiques sont observées. Tout d'abord, afin de mieux comprendre les études présentées dans ce manuscrit, une introduction générale couvrant l'architecture du système thalamocortical et ses fonctions est présentée. Celle-ci comprend une description des états de vigilance, suivie d'une description des rythmes présents dans le système thalamocortical au cours du sommeil à ondes lentes, puis par une description des différents mécanismes de plasticité synaptique, et enfin, deux hypothèses sur la façon dont le sommeil peut affecter la consolidation de la mémoire sont présentées. Puis, trois études sont présentées et ont été conçues pour caractériser les propriétés de l'oscillation lente du sommeil à ondes lentes. Dans la première étude (chapitre II), nous avons montré que les périodes d'activité (et de silence) se produisent de façon presque synchrone dans des neurones qui ont jusqu'à 12 mm de distance. Nous avons montré que l'activité était initiée en un point focal et se propageait rapidement à des sites corticaux voisins. Étonnamment, le déclenchement des états silencieux était encore plus synchronisé que le déclenchement des états actifs. L'hypothèse de travail pour la deuxième étude (chapitre III) était que les états actifs sont générés par une sommation de relâches spontanées de médiateurs. Utilisant différents enregistrements à la fois chez des animaux anesthésiés et chez d’autres non-anesthésiés, nous avons montré qu’aucune décharge neuronale ne se produit dans le néocortex pendant les états silencieux du sommeil à ondes lentes, mais certaines activités synaptiques peuvent ii être observées avant le début des états actifs, ce qui était en accord avec notre hypothèse. Nous avons également montré que les neurones de la couche V étaient les premiers à entrer dans l’état actif pour la majorité des cycles, mais ce serait ainsi uniquement pour des raisons probabilistes; ces cellules étant équipées du plus grand nombre de contacts synaptiques parmi les neurones corticaux. Nous avons également montré que le sommeil à ondes lentes et l’anesthésie à la kétamine-xylazine présentent de nombreuses similitudes. Ayant utilisé une combinaison d'enregistrements chez des animaux anesthésiés à la kétamine-xylazine et chez des animaux non-anesthésiés, et parce que l'anesthésie à la kétamine-xylazine est largement utilisée comme un modèle de sommeil à ondes lentes, nous avons effectué des mesures quantitatives des différences entre les deux groupes d'enregistrements (chapitre IV). Nous avons trouvé que l'oscillation lente était beaucoup plus rythmique sous anesthésie et elle était aussi plus cohérente entre des sites d’enregistrements distants en comparaison aux enregistrements de sommeil naturel. Sous anesthésie, les ondes lentes avaient également une amplitude plus grande et une durée plus longue par rapport au sommeil à ondes lentes. Toutefois, les ondes fuseaux (spindles) et gamma étaient également affectées par l'anesthésie. Dans l'étude suivante (Chapitre V), nous avons investigué le rôle du sommeil à ondes lentes dans la formation de la plasticité à long terme dans le système thalamocortical. À l’aide de stimulations pré-thalamiques de la voie somatosensorielle ascendante (fibres du lemnisque médial) chez des animaux non-anesthésiés, nous avons montré que le potentiel évoqué enregistré dans le cortex somatosensoriel était augmenté dans une période d’éveil suivant un épisode de sommeil à ondes lentes par rapport à l’épisode d’éveil précédent et cette augmentation était de longue durée. Nous avons également montré que le sommeil paradoxal ne jouait pas un rôle important dans cette augmentation d'amplitude des réponses évoquées. À l’aide d'enregistrements in vitro en mode cellule-entière, nous avons caractérisé le mécanisme derrière cette augmentation et ce mécanisme est compatible avec la forme classique de potentiation à long terme, car il nécessitait une activation à la fois les récepteurs NMDA et des récepteurs AMPA, ainsi que la présence de calcium dans le neurone post-synaptique. iii La dernière étude incluse dans cette thèse (chapitre VI) a été conçue pour caractériser un possible mécanisme physiologique de blocage sensoriel thalamique survenant pendant le sommeil. Les ondes fuseaux sont caractérisées par la présence de potentiels d’action calcique à seuil bas et le calcium joue un rôle essentiel dans la transmission synaptique. En utilisant plusieurs techniques expérimentales, nous avons vérifié l'hypothèse que ces potentiels d’action calciques pourraient causer un appauvrissement local de calcium dans l'espace extracellulaire ce qui affecterait la transmission synaptique. Nous avons montré que les canaux calciques responsables des potentiels d’action calciques étaient localisés aux synapses et que, de fait, une diminution locale de la concentration extracellulaire de calcium se produit au cours d’un potentiel d’action calcique à seuil bas spontané ou provoqué, ce qui était suffisant pour nuire à la transmission synaptique. Nous concluons que l'oscillation lente est initiée en un point focal et se propage ensuite aux aires corticales voisines de façon presque synchrone, même pour des cellules séparées par jusqu'à 12 mm de distance. Les états actifs de cette oscillation proviennent d’une sommation de relâches spontanées de neuromédiateurs (indépendantes des potentiels d’action) et cette sommation peut survenir dans tous neurones corticaux. Cependant, l’état actif est généré plus souvent dans les neurones pyramidaux de couche V simplement pour des raisons probabilistes. Les deux types d’expériences (kétamine-xylazine et sommeil à ondes lentes) ont montré plusieurs propriétés similaires, mais aussi quelques différences quantitatives. Nous concluons également que l'oscillation lente joue un rôle essentiel dans l'induction de plasticité à long terme qui contribue très probablement à la consolidation de la mémoire. Les ondes fuseaux, un autre type d’ondes présentes pendant le sommeil à ondes lentes, contribuent au blocage thalamique de l'information sensorielle.Sleep is known to mediate several major functions in the brain and among them are the gating of sensory information during sleep and the sleep-related improvement in memory consolidation. Slow-wave sleep in particular is thought to be critical for both of these processes. However, their physiological mechanisms are unknown. Also, the electrophysiological hallmark of slow-wave sleep is the presence of large amplitude slow waves in the cortical local field potential and the alternation of periods of intense synaptic activity in which cortical neurons are depolarized and fire action potentials and periods of silence in which no firing occurs, cortical neurons are hyperpolarized, and very little synaptic activities are observed. First, in order to better understand the studies presented in this manuscript, a general introduction covering the thalamocortical system architecture and function is presented, which includes a description of the states of vigilance, followed by a description of the rhythms present in the thalamocortical system during slow-wave sleep, then by a description of the mechanisms of synaptic plasticity, and finally two hypotheses about how sleep might affect the consolidation of memory are presented. Then, three studies are presented and were designed to characterize the properties of the sleep slow oscillation. In the first study (Chapter II), we showed that periods of activity (and silence) occur almost synchronously in neurons that are separated by up to 12 mm. The activity was initiated in a focal point and rapidly propagated to neighboring sites. Surprisingly, the onsets of silent states were even more synchronous than onsets of active states. The working hypothesis for the second study (Chapter III) was that active states are generated by a summation of spontaneous mediator releases. Using different recordings in both anesthetized and non-anesthetized animals, we showed that no neuronal firing occurs in the neocortex during silent states of slow-wave sleep but some synaptic activities might be observed prior to the onset of active states, which was in agreement with our hypothesis. We also showed that layer V neurons were leading the onset of active states in most of the cycles but this would be due to probabilistic reasons; these cells being equipped with the most numerous synaptic contacts among cortical neurons. We also showed that slow-wave sleep and ketamine-xylazine shares many similarities. v Having used a combination of recordings in ketamine-xylazine anesthetized and non-anesthetized animals, and because ketamine-xylazine anesthesia is extensively used as a model of slow-wave sleep, we made quantitative measurements of the differences between the two groups of recordings (Chapter IV). We found that the slow oscillation was much more rhythmic under anesthesia and it was also more coherent between distant sites as compared to recordings during slow-wave sleep. Under anesthesia, slow waves were also of larger amplitude and had a longer duration as compared to slow-wave sleep. However, spindles and gamma were also affected by the anesthesia. In the following study (Chapter V), we investigated the role of slow-wave sleep in the formation of long-term plasticity in the thalamocortical system. Using pre-thalamic stimulations of the ascending somatosensory pathway (medial lemniscus fibers) in non-anesthetized animals, we showed that evoked potential recorded in the somatosensory cortex were enhanced in a wake period following a slow-wave sleep episode as compared to the previous wake episode and this enhancement was long-lasting. We also showed that rapid eye movement sleep did not play a significant role in this enhancement of response amplitude. Using whole-cell recordings in vitro, we characterized the mechanism behind this enhancement and it was compatible with the classical form of long-term potentiation, because it required an activation of both NMDA and AMPA receptors as well as the presence of calcium in the postsynaptic neuron. The last study included in this thesis (Chapter VI) was designed to characterise a possible physiological mechanism of thalamic sensory gating occurring during sleep. Spindles are characterized by the presence of low-threshold calcium spikes and calcium plays a critical role in the synaptic transmission. Using several experimental techniques, we verified the hypothesis that these calcium spikes would cause a local depletion of calcium in the extracellular space which would impair synaptic transmission. We showed that calcium channels responsible for calcium spikes were co-localized with synapses and that indeed, local extracellular calcium depletion occurred during spontaneous or induced low-threshold calcium spike, which was sufficient to impair synaptic transmission. We conclude that slow oscillation originate at a focal point and then propagate to neighboring cortical areas being almost synchronous even in cells located up to 12 mm vi apart. Active states of this oscillation originate from a summation of spike-independent mediator releases that might occur in any cortical neurons, but happens more often in layer V pyramidal neurons simply due to probabilistic reasons. Both experiments in ketamine-xylazine anesthesia and non-anesthetized animals showed several similar properties, but also some quantitative differences. We also conclude that slow oscillation plays a critical role in the induction of long-term plasticity, which very likely contributes to memory consolidation. Spindles, another oscillation present in slow-wave sleep, contribute to the thalamic gating of information

Cognitive Consilience: Primate Non-Primary Neuroanatomical Circuits Underlying Cognition

Interactions between the cerebral cortex, thalamus, and basal ganglia form the basis of cognitive information processing in the mammalian brain. Understanding the principles of neuroanatomical organization in these structures is critical to understanding the functions they perform and ultimately how the human brain works. We have manually distilled and synthesized hundreds of primate neuroanatomy facts into a single interactive visualization. The resulting picture represents the fundamental neuroanatomical blueprint upon which cognitive functions must be implemented. Within this framework we hypothesize and detail 7 functional circuits corresponding to psychological perspectives on the brain: consolidated long-term declarative memory, short-term declarative memory, working memory/information processing, behavioral memory selection, behavioral memory output, cognitive control, and cortical information flow regulation. Each circuit is described in terms of distinguishable neuronal groups including the cerebral isocortex (9 pyramidal neuronal groups), parahippocampal gyrus and hippocampus, thalamus (4 neuronal groups), basal ganglia (7 neuronal groups), metencephalon, basal forebrain, and other subcortical nuclei. We focus on neuroanatomy related to primate non-primary cortical systems to elucidate the basis underlying the distinct homotypical cognitive architecture. To display the breadth of this review, we introduce a novel method of integrating and presenting data in multiple independent visualizations: an interactive website (http://www.frontiersin.org/files/cognitiveconsilience/index.html) and standalone iPhone and iPad applications. With these tools we present a unique, annotated view of neuroanatomical consilience (integration of knowledge)

The thalamic low-threshold Ca2+ potential: a key determinant of the local and global dynamics of the slow (<1 Hz) sleep oscillation in thalamocortical networks

During non-rapid eye movement sleep and certain types of anaesthesia, neurons in the neocortex and thalamus exhibit a distinctive slow (<1 Hz) oscillation that consists of alternating UP and DOWN membrane potential states and which correlates with a pronounced slow (<1 Hz) rhythm in the electroencephalogram. While several studies have claimed that the slow oscillation is generated exclusively in neocortical networks and then transmitted to other brain areas, substantial evidence exists to suggest that the full expression of the slow oscillation in an intact thalamocortical (TC) network requires the balanced interaction of oscillator systems in both the neocortex and thalamus. Within such a scenario, we have previously argued that the powerful low-threshold Ca2+ potential (LTCP)-mediated burst of action potentials that initiates the UP states in individual TC neurons may be a vital signal for instigating UP states in related cortical areas. To investigate these issues we constructed a computational model of the TC network which encompasses the important known aspects of the slow oscillation that have been garnered from earlier in vivo and in vitro experiments. Using this model we confirm that the overall expression of the slow oscillation is intricately reliant on intact connections between the thalamus and the cortex. In particular, we demonstrate that UP state-related LTCP-mediated bursts in TC neurons are proficient in triggering synchronous UP states in cortical networks, thereby bringing about a synchronous slow oscillation in the whole network. The importance of LTCP-mediated action potential bursts in the slow oscillation is also underlined by the observation that their associated dendritic Ca2+ signals are the only ones that inform corticothalamic synapses of the TC neuron output, since they, but not those elicited by tonic action potential firing, reach the distal dendritic sites where these synapses are located

PHOSPHENE IMAGES OF THALAMIC SLEEP RHYTHMS INDUCED BY SELF-HYPNOSIS

A medical writer describes internally-generated light sensations (phosphenes) induced by a technique of self-hypnosis that combines relaxation, convergent eye movement, and attentive fixation. The phosphene images include: (1) a threshold sequence of receding annuli, (2) amorphous phosphene mists or clouds, and (3) phosphene clouds with two levels of brightness and color saturation. These images share some similarities with visions of light reported by religious mystics. Based on an analysis of the distinctive spatiotemporal characteristics exhibited by the phosphenes. the author proposes the hypothesis that they are generated by thalamic sleep rhythms oscillating in the lateral geniculate nucleus (LGN). Since humans usually lose consciousness at the onset of non-rapid-eye-movement sleep (NREMS), the author also proposes the hypothesis that his technique of phosphene induction preserves consciousness, despite the operation of thalamic sleep rhythms, because eye movements and attentive fixation send excitatory feedback to the visual pathways. This selective facilitation of visual neurons appears to preserve their signal-processing capacity even though synchronous sleep rhythms may be installed in the non-visual thalamus. The author speculates that this selective disruption of sleep rhythm activity in the visual pathways may be the mechanism that produces the cutaneous analgesia (hypnoanalgesia) he experiences when he induces phosphenes