220 research outputs found

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

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    AbstractSleep 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 versus 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

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

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    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

    Pathophysiology of Spinal Cord Injury (SCI)

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    Spinal cord injury (SCI) leads to paralysis, sensory, and autonomic nervous system dysfunctions. However, the pathophysiology of SCI is complex, and not limited to the nervous system. Indeed, several other organs and tissue are also affected by the injury, directly or not, acutely or chronically, which induces numerous health complications. Although a lot of research has been performed to repair motor and sensory functions, SCI-induced health issues are less studied, although they represent a major concern among patients. There is a gap of knowledge in pre-clinical models studying these SCI-induced health complications that limits translational applications in humans. This reprint describes several aspects of the pathophysiology of spinal cord injuries. This includes, but is not limited to, the impact of SCI on cardiovascular and respiratory functions, bladder and bowel function, autonomic dysreflexia, liver pathology, metabolic syndrome, bones and muscles loss, and cognitive functions

    Advancing Medical Technology for Motor Impairment Rehabilitation: Tools, Protocols, and Devices

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    Excellent motor control skills are necessary to live a high-quality life. Activities such as walking, getting dressed, and feeding yourself may seem mundane, but injuries to the neuromuscular system can render these tasks difficult or even impossible to accomplish without assistance. Statistics indicate that well over 100 million people are affected by diseases or injuries, such as stroke, Parkinson’s Disease, Multiple Sclerosis, Cerebral Palsy, peripheral nerve injury, spinal cord injury, and amputation, that negatively impact their motor abilities. This wide array of injuries presents a challenge to the medical field as optimal treatment paradigms are often difficult to implement due to a lack of availability of appropriate assessment tools, the inability for people to access the appropriate medical centers for treatment, or altogether gaps in technology for treating the underlying impairments causing the disability. Addressing each of these challenges will improve the treatment of movement impairments, provide more customized and continuous treatment to a larger number of patients, and advance rehabilitative and assistive device technology. In my research, the key approach was to develop tools to assess and treat upper extremity movement impairment. In Chapter 2.1, I challenged a common biomechanical[GV1] modeling technique of the forearm. Comparing joint torque values through inverse dynamics simulation between two modeling platforms, I discovered that representing the forearm as a single cylindrical body was unable to capture the inertial parameters of a physiological forearm which is made up of two segments, the radius and ulna. I split the forearm segment into a proximal and distal segment, with the rationale being that the inertial parameters of the proximal segment could be tuned to those of the ulna and the inertial parameters of the distal segment could be tuned to those of the radius. Results showed a marked increase in joint torque calculation accuracy for those degrees of freedom that are affected by the inertial parameters of the radius and ulna. In Chapter 2.2, an inverse kinematic upper extremity model was developed for joint angle calculations from experimental motion capture data, with the rationale being that this would create an easy-to-use tool for clinicians and researchers to process their data. The results show accurate angle calculations when compared to algebraic solutions. Together, these chapters provide easy-to-use models and tools for processing movement assessment data. In Chapter 3.1, I developed a protocol to collect high-quality movement data in a virtual reality task that is used to assess hand function as part of a Box and Block Test. The goal of this chapter is to suggest a method to not only collect quality data in a research setting but can also be adapted for telehealth and at home movement assessment and rehabilitation. Results indicate that the data collected in this protocol are good and the virtual nature of this approach can make it a useful tool for continuous, data driven care in clinic or at home. In Chapter 3.2 I developed a high-density electromyography device for collecting motor unit action potentials of the arm. Traditional surface electromyography is limited by its ability to obtain signals from deep muscles and can also be time consuming to selectively place over appropriate muscles. With this high-density approach, muscle coverage is increased, placement time is decreased, and deep muscle activity can potentially be collected due to the high-density nature of the device[GV2] . Furthermore, the high-density electromyography device is built as a precursor to a high-density electromyography-electrical stimulation device for functional electrical stimulation. The customizable nature of the prototype in Chapter 3.2 allows for the implementation both recording and stimulating electrodes. Furthermore, signal results show that the electromyography data obtained from the device are of high quality and are correlated with gold standard surface electromyography sensors. One key factor in a device that can record and then stimulate based on the information from the recorded signals is an accurate movement intent decoder. High-quality movement decoders have been designed by closed-loop device controllers in the past, but they still struggle when the user interacts with objects of varying weight due to underlying alterations in muscle signals. In Chapter 4, I investigate this phenomenon by administering an experiment where participants perform a Box and Block Task with objects of 3 different weights, 0 kg, 0.02 kg, and 0.1 kg. Electromyography signals of the participants right arm were collected and co-contraction levels between antagonistic muscles were analyzed to uncover alterations in muscle forces and joint dynamics. Results indicated contraction differences between the conditions and also between movement stages (contraction levels before grabbing the block vs after touching the block) for each condition. This work builds a foundation for incorporating object weight estimates into closed-loop electromyography device movement decoders. Overall, we believe the chapters in this thesis provide a basis for increasing availability to movement assessment tools, increasing access to effective movement assessment and rehabilitation, and advance the medical device and technology field

    A parahippocampal-sensory Bayesian vicious circle generates pain or tinnitus: a source-localized EEG study

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    Pain and tinnitus share common pathophysiological mechanisms, clinical features, and treatment approaches. A source-localized resting-state EEG study was conducted in 150 participants: 50 healthy controls, 50 pain, and 50 tinnitus patients. Resting-state activity as well as functional and effective connectivity was computed in source space. Pain and tinnitus were characterized by increased theta activity in the pregenual anterior cingulate cortex, extending to the lateral prefrontal cortex and medial anterior temporal lobe. Gamma-band activity was increased in both auditory and somatosensory cortex, irrespective of the pathology, and extended to the dorsal anterior cingulate cortex and parahippocampus. Functional and effective connectivity were largely similar in pain and tinnitus, except for a parahippocampal-sensory loop that distinguished pain from tinnitus. In tinnitus, the effective connectivity between parahippocampus and auditory cortex is bidirectional, whereas the effective connectivity between parahippocampus and somatosensory cortex is unidirectional. In pain, the parahippocampal-somatosensory cortex is bidirectional, but parahippocampal auditory cortex unidirectional. These modality-specific loops exhibited theta-gamma nesting. Applying a Bayesian brain model of brain functioning, these findings suggest that the phenomenological difference between auditory and somatosensory phantom percepts result from a vicious circle of belief updating in the context of missing sensory information. This finding may further our understanding of multisensory integration and speaks to a universal treatment for pain and tinnitus-by selectively disrupting parahippocampal-somatosensory and parahippocampal-auditory theta-gamma activity and connectivity

    Modelling emergent rhythmic activity in the cerebal cortex

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    A la portada consta: IDIBAPS Institut d'Investigacions Biomèdiques August Pi i SunyerThe brain, a natural adaptive system, can generate a rich dynamic repertoire of spontaneous activity even in the absence of stimulation. The spatiotemporal pattern of this spontaneous activity is determined by the brain state, which can range from highly synchronized to desynchronized states. During slow wave sleep, for example, the cortex operates in synchrony, defined by low-frequency fluctuations, known as slow oscillations (<1Hz). Conversely, during wakefulness, the cortex is characterized mainly by desynchronized activity, where low-frequency fluctuations are suppressed. Thus, an inherent property of the cerebral cortex is to transit between different states characterized by distinct spatiotemporal complexity patterns, varying in a large spectrum between synchronized and desynchronized activity. All these complex emergent patterns are the product of the interaction between tens of billions of neurons endowed with diverse ionic channels with complex biophysical properties. Nevertheless, what are the mechanisms behind these transitions? In this thesis, we sought to understand the mechanisms and properties behind slow oscillations, their modulation and their transitions towards wakefulness by employing experimental data analysis and computational models. We reveal the relevance of specific ionic channels and synaptic properties to maintaining the cortical state and also get out of it, and its spatiotemporal dynamics. Using a mean-field model, we also propose bridging neuronal spiking dynamics to a population description.El cerebro, un sistema adaptativo natural, es capaz de generar un amplio repertorio dinámico de actividad espontánea, incluso en ausencia de estímulos. La patrón espacio-temporal de esta actividad espontánea viene determinada por el estado cerebral, el cual puede variar de estados altamente sincronizados hasta estados muy desincronizados. Cuando en el sueño se entra en la fase de ondas lentas, por ejemplo, la corteza opera en sincronía, cuya actividad es definida por fluctuaciones de baja frecuencia, conocidas como oscilaciones lentas (<1Hz). En cambio, durante la vigilia, el córtex se caracteriza principalmente por tener una actividad desincronizada, donde las fluctuaciones de baja frecuencia desaparecen. Por lo tanto, una propiedad inherente de la corteza cerebral es transitar entre diferentes estados caracterizados por distintos patrones de complejidad espacio-temporal, los cuales se sitúan dentro del amplio espectro marcado por la actividad sincronizada y la desincronizada. Estos patrones emergentes son el producto de la interacción entre decenas de miles de millones de neuronas dotadas de múltiples y distintos canales iónicos con complejas propiedades biofísicas. Sin embargo, ¿cuáles son los mecanismos que regulan estas transiciones? En esta tesis tratamos de entender los mecanismos, propiedades y sus transiciones hacia la vigilia, que están detrás de las oscilaciones lentas a través del uso y análisis de datos experimentales y modelos computacionales. En ella describimos la importancia de los canales iónicos específicos y sus propiedades sinápticas tanto para mantener el estado cortical como para salir de él, estudiando así su dinámica espacio-temporal. Además, mediante el uso de un modelo de campo medio, proponemos establecer un puente que pueda describir la dinámica de disparos neuronales con una descripción general de la población neuronal.Postprint (published version

    The impact of ischemic injury on behavioral outcomes and cortical interactions in rats

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    L’accident vasculaire cérébral (AVC) est une maladie débilitante qui a rendu des centaines de milliers de personnes handicapées. Les lésions du cortex moteur entraînent des déficiences motrices dont certaines sont permanentes. Le rat est le modèle animal le plus populaire dans la recherche sur les AVC. Il est capable de mouvements adroits d'atteinte et de préhension malgré un système moteur cortical beaucoup plus simple qui se compose de deux régions motrices des membres antérieurs, une plus grande région, l’aire caudale de la patte antérieure (CFA), considérée comme un équivalent du M1; et une plus petite, l’aire rostrale de la patte antérieure (RFA), considérée comme prémoteur. Leur contribution exacte à la production de mouvement, et leurs effets modulateurs sur le cortex moteur controlatéral ne sont pas clairs. L'effet des AVC sur les différentes modalités de mouvement et sur la réorganisation ipsi- et contralésionnelle n'a pas non plus été quantifié chez le rat. L'ensemble actuel d'expériences vise à établir l'impact de l'AVC ischémique sur les résultats comportementaux et les interactions corticales chez le rat. Dans le chapitre 1, le contexte scientifique et les connaissances actuelles de l’AVC comme trouble moteur du système nerveux central sont revus. Dans le chapitre 2, une relation entre les accidents vasculaires cérébraux de différentes tailles et les troubles du comportement et la récupération sur différentes modalités comportementales a été établie. Dans le chapitre 3, nous avons caractérisé les différences de retour moteur de deux régions corticales du membre antérieur et quantifié les effets modulateurs du cortex moteur du membre antérieur controlatéral sur ledit retour moteur. Enfin, nous avons quantifié la réorganisation du retour moteur et la modulation controlatérale suite à un accident vasculaire cérébral dans le cortex moteur des membres antérieurs au chapitre 4. Le chapitre 5 conclue la thèse avec une discussion générale et des orientations futures pour la recherche. Les résultats présentés ici établissent un lien clair entre les dommages aux sous-régions corticales et l'altération de domaines moteurs spécifiques. La caractérisation des différences dans les retours moteurs du CFA et du RFA ainsi que leurs interactions interhémisphériques ont confirmé leurs rôles distincts dans le contrôle moteur et établit une base pour des comparaisons avec les primates. Enfin, des preuves nouvelles et surprenantes de réorganisation bilatérale après un AVC ont été définies et caractérisées.Stroke is a debilitating condition that has left hundreds of thousands of people disabled. Injury to the motor cortex leads to motor impairments, some of which are permanent. The rat is the most popular animal model in stroke research. It is capable of dexterous reach and grasp movements, despite having a much simpler cortical motor system, which consists of two forelimb motor regions; the larger area is the caudal forelimb area (CFA), thought to be an M1 equivalent, and the smaller one is rostral forelimb area (RFA), considered to be premotor. Neither their exact contribution to movement production nor modulatory effects on the contralateral motor cortex are clear. The effect of strokes on different movement modalities and the ipsi- and contralesional reorganization has not been quantified in the rat either. The current set of experiments set out to establish the impact of ischemic stroke on behavioral outcomes and cortical interactions in the rat. Chapter 1 introduces the scientific background and the present understanding of stroke as a motor disorder of the central nervous system. In Chapter 2, a relationship between strokes of various sizes and behavioral impairment and recovery on different behavioral modalities was established. In Chapter 3, we characterized the differences in motor outputs from two cortical forelimb regions and quantified the modulatory effects of the contralateral forelimb motor cortex on said motor outputs. Lastly, we quantified the reorganization of motor outputs and contralateral modulation following a stroke in the forelimb motor cortex in Chapter 4. Chapter 5 concludes the thesis with the general discussion and future directions. The results presented here establish a clear link between damage to cortical subregions and impairment to specific motor domains. Characterization of differences in motor outputs of the CFA and RFA as well as their interhemispheric interactions confirmed their distinct roles in motor control and lay the groundwork for comparisons to primates. Lastly, novel and surprising evidence of bilateral reorganization after stroke was defined and characterized

    The functional anatomy of white matter pathways for visual configuration learning

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    The role of the medial temporal lobes (MTL) in visuo-spatial learning has been extensively studied and documented in the neuroscientific literature. Numerous animal and human studies have demonstrated that the parahippocampal place area (PPA), which sits at the confluence of the parahippocampal and lingual gyri, is particularly important for learning the spatial configuration of objects in visually presented scenes. In current visuo-spatial processing models, the PPA sits downstream from the parietal lobes which are involved in multiple facets of spatial processing. Yet, direct input to the PPA from early visual cortex (EVC) is rarely discussed and poorly understood. This thesis adopted a multimodal neuroimaging analysis approach to study the functional anatomy of these connections. First, the pattern of structural connectivity between EVC and the MTL was explored by means of surface-based ‘connectomes’ constructed from diffusion MRI tractography in a cohort of 200 healthy young adults from the Human Connectome Project. Through this analysis, the PPA emerged as a primary recipient of EVC connections within the MTL. Second, a data-driven clustering analysis of the PPA’s connectivity to an extended cortical region (including EVC, retrosplenial cortex, and other areas) revealed multiple clusters with different connectivity profiles within the PPA. The two main clusters were located in the posterior and anterior portions of the PPA, with the posterior cluster preferentially connected to EVC. Motivated by this result, virtual tractography dissections were used to delineate the medial occipital longitudinal tract (MOLT), the white matter bundle connecting the PPA with EVC. The properties of this bundle and its relation to visual configuration learning were verified in a different, cross-sectional adult cohort of 90 subjects. Finally, the role of the MOLT in the visuo-spatial learning domain was further confirmed in the case of a stroke patient who, after bilateral occipital injury, exhibited deficits confined to this domain. The results presented in this work suggest that the MOLT should be included in current visuo-spatial processing models as it offers additional insight into how the MTL acquires and processes information for spatial learning

    Enhancing memory-related sleep spindles through learning and electrical brain stimulation

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    Sleep has been strongly implicated in mediating memory consolidation through hippocampal-neocortical communication. Evidence suggests offline processing of encoded information in the brain during slow wave sleep (SWS), specifically during slow oscillations and spindles. In this work, we used active exploration and learning tasks to study post-experience sleep spindle density changes in rats. Experiences lead to subsequent changes in sleep spindles, but the strength and timing of the effect was task-dependent. Brain stimulation in humans and rats have been shown to enhance memory consolidation. However, the exact stimulation parameters which lead to the strongest memory enhancement have not been fully explored. We tested the efficacy of both cortical sinusoidal direct current stimulation and intracortical pulse stimulation to enhance slow oscillations and spindle density. Pulse stimulation reliably evoked state-dependent slow oscillations and spindles during SWS with increased hippocampal ripple-spindle coupling, demonstrating potential in memory enhancement

    Disuse-Driven Plasticity in the Human Brain

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    Brain circuits are shaped and maintained by active use. We blocked use of motor circuits in three adult participants by constraining the dominant upper extremity in a cast for two weeks, causing loss of strength and fine motor function. Daily resting-state functional magnetic resonance imaging (rs-fMRI) collected for 42-64 days before, during and after casting revealed two sets of changes in brain function. First, large, spontaneous pulses of activity occurred in the disused motor circuits. Pulses showed a consistent pattern of propagation through the disused circuits— occurring earliest in the dorsal anterior cingulate cortex (dACC) and supplementary motor area (SMA), then propagating to the primary motor cortex, and finally occurring in motor regions of the cerebellum. Second, participants exhibited anatomically focal changes in functional connectivity (FC), i.e., synchrony of spontaneous activity. The disused motor cortex lost typical FC with the remainder of the somatomotor system. Additionally, disused regions of the primary motor cortex and cerebellum became more connected to an executive control system known as the cingulo-opercular network (CON). Spontaneous activity pulses, which occurred in disused motor regions and the CON, accounted for observed increases in FC. Loss of FC between the disused motor circuits and the somatomotor network was not explained by pulses and may have resulted from decreased co-use of the affected circuits with the remainder of the somatomotor system, which is typically thought to maintain FC in a Hebbian-like manner. Together, these two forms of plasticity, Hebbian disconnection from the somatomotor system and pulse-mediated connection to the CON, may form a protective “standby mode” that isolates disused circuits and prevents premature functional degradation
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