Showing papers in "Frontiers in Systems Neuroscience in 2019"

Principles of Neurorehabilitation After Stroke Based on Motor Learning and Brain Plasticity Mechanisms.

Abstract: What are the principles underlying effective neurorehabilitation? The aim of neurorehabilitation is to exploit interventions based on human and animal studies about learning and adaptation, as well as to show that the activation of experience-dependent neuronal plasticity augments functional recovery after stroke. Instead of teaching compensatory strategies that do not reduce impairment but allow the patient to return home as soon as possible, functional recovery might be more sustainable as it ensures a long-term reduction in impairment and an improvement in quality of life. At the same time, neurorehabilitation permits the scientific community to collect valuable data, which allows inferring about the principles of brain organization. Hence neuroscience sheds light on the mechanisms of learning new functions or relearning lost ones. However, current rehabilitation methods lack the exact operationalization of evidence gained from skill learning literature, leading to an urgent need to bridge motor learning theory and present clinical work in order to identify a set of ingredients and practical applications that could guide future interventions. This work aims to unify the neuroscientific literature relevant to the recovery process and rehabilitation practice in order to provide a synthesis of the principles that constitute an effective neurorehabilitation approach. Previous attempts to achieve this goal either focused on a subset of principles or did not link clinical application to the principles of motor learning and recovery. We identified 15 principles of motor learning based on existing literature: massed practice, spaced practice, dosage, task-specific practice, goal-oriented practice, variable practice, increasing difficulty, multisensory stimulation, rhythmic cueing, explicit feedback/knowledge of results, implicit feedback/knowledge of performance, modulate effector selection, action observation/embodied practice, motor imagery, and social interaction. We comment on trials that successfully implemented these principles and report evidence from experiments with healthy individuals as well as clinical work.

Dorsal Striatal Circuits for Habits, Compulsions and Addictions.

Abstract: Here, we review the neural circuit bases of habits, compulsions, and addictions, behaviors which are all characterized by relatively automatic action performance. We discuss relevant studies, primarily from the rodent literature, and describe how major headway has been made in identifying the brain regions and neural cell types whose activity is modulated during the acquisition and performance of these automated behaviors. The dorsal striatum and cortical inputs to this structure have emerged as key players in the wider basal ganglia circuitry encoding behavioral automaticity, and changes in the activity of different neuronal cell-types in these brain regions have been shown to co-occur with the formation of automatic behaviors. We highlight how disordered functioning of these neural circuits can result in neuropsychiatric disorders, such as obsessive-compulsive disorder (OCD) and drug addiction. Finally, we discuss how the next phase of research in the field may benefit from integration of approaches for access to cells based on their genetic makeup, activity, connectivity and precise anatomical location.

The Cortico-Basal Ganglia-Cerebellar Network: Past, Present and Future Perspectives.

Abstract: Much of our present understanding of the function and operation of the basal ganglia rests on models of anatomical connectivity derived from tract-tracing approaches in rodents and primates. However, the last years have been characterized by promising step forwards in the in vivo investigation and comprehension of brain connectivity in humans. The aim of this review is to revise the current knowledge on basal ganglia circuits, highlighting similarities and differences across species, in order to widen the current perspective on the intricate model of the basal ganglia system. This will allow us to explore the implications of additional direct pathways running from cortex to basal ganglia and between basal ganglia and cerebellum recently described in animals and humans.

Coupling the State and Contents of Consciousness

Abstract: One fundamental feature of consciousness is that the contents of consciousness depend on the state of consciousness. Here, we propose an answer to why this is so: both the state and the contents of consciousness depend on the activity of cortical layer 5 pyramidal (L5p) neurons. These neurons affect both cortical and thalamic processing, hence coupling the cortico-cortical and thalamo-cortical loops with each other. Functionally this coupling corresponds to the coupling between the state and the contents of consciousness. Together the cortico-cortical and thalamo-cortical loops form a thalamo-cortical broadcasting system, where the L5p cells are the central elements. This perspective makes one quite specific prediction: cortical processing that does not include L5p neurons will be unconscious. More generally, the present perspective suggests that L5p neurons have a central role in the mechanisms underlying consciousness.

DeepBehavior: A Deep Learning Toolbox for Automated Analysis of Animal and Human Behavior Imaging Data.

Abstract: Detailed behavioral analysis is key to understanding the brain-behavior relationship. Here, we present deep learning-based methods for analysis of behavior imaging data in mice and humans. Specifically, we use three different convolutional neural network architectures and five different behavior tasks in mice and humans and provide detailed instructions for rapid implementation of these methods for the neuroscience community. We provide examples of three dimensional (3D) kinematic analysis in the food pellet reaching task in mice, three-chamber test in mice, social interaction test in freely moving mice with simultaneous miniscope calcium imaging, and 3D kinematic analysis of two upper extremity movements in humans (reaching and alternating pronation/supination). We demonstrate that the transfer learning approach accelerates the training of the network when using images from these types of behavior video recordings. We also provide code for post-processing of the data after initial analysis with deep learning. Our methods expand the repertoire of available tools using deep learning for behavior analysis by providing detailed instructions on implementation, applications in several behavior tests, and post-processing methods and annotated code for detailed behavior analysis. Moreover, our methods in human motor behavior can be used in the clinic to assess motor function during recovery after an injury such as stroke.

The Cortical States of Wakefulness.

Abstract: Cortical neurons process information on a background of spontaneous, ongoing activity with distinct spatiotemporal profiles defining different cortical states. During wakefulness, cortical states alter constantly in relation to behavioral context, attentional level or general motor activity. In this review article, we will discuss our current understanding of cortical states in awake rodents, how they are controlled, their impact on sensory processing, and highlight areas for future research. A common observation in awake rodents is the rapid change in spontaneous cortical activity from high-amplitude, low-frequency (LF) fluctuations, when animals are quiet, to faster and smaller fluctuations when animals are active. This transition is typically thought of as a change in global brain state but recent work has shown variation in cortical states across regions, indicating the presence of a fine spatial scale control system. In sensory areas, the cortical state change is mediated by at least two convergent inputs, one from the thalamus and the other from cholinergic inputs in the basal forebrain. Cortical states have a major impact on the balance of activity between specific subtypes of neurons, on the synchronization between nearby neurons, as well as the functional coupling between distant cortical areas. This reorganization of the activity of cortical networks strongly affects sensory processing. Thus cortical states provide a dynamic control system for the moment-by-moment regulation of cortical processing.

Primed to Sleep: The Dynamics of Synaptic Plasticity Across Brain States.

Abstract: It is commonly accepted that brain plasticity occurs in wakefulness and sleep. However, how these different brain states work in concert to create long-lasting changes in brain circuitry is unclear. Considering that wakefulness and sleep are profoundly different brain states on multiple levels (e.g., cellular, molecular and network activation), it is unlikely that they operate exactly the same way. Rather it is probable that they engage different, but coordinated, mechanisms. In this article we discuss how plasticity may be divided across the sleep-wake cycle, and how synaptic changes in each brain state are linked. Our working model proposes that waking experience triggers short-lived synaptic events that are necessary for transient plastic changes and mark (i.e., 'prime') circuits and synapses for further processing in sleep. During sleep, synaptic protein synthesis at primed synapses leads to structural changes necessary for long-term information storage.

Different Approaches to Modulation of Microglia Phenotypes After Spinal Cord Injury.

Abstract: Microglial cells, which are highly plastic, immediately respond to any change in the microenvironment by becoming activated and shifting the phenotype toward neurotoxicity or neuroprotection. The polarization of microglia/macrophages after spinal cord injury (SCI) seems to be a dynamic process and can change depending on the microenvironment, stage, course, and severity of the posttraumatic process. Effective methods to modulate microglia toward a neuroprotective phenotype in order to stimulate neuroregeneration are actively sought for. In this context, available approaches that can selectively impact the polarization of microglia/macrophages regulate synthesis of trophic factors and cytokines/chemokines in them, and their phagocytic function and effects on the course and outcome of SCI are discussed in this review.

Sleep-Wake Cycle in Young and Older Mice.

Abstract: Sleep plays a key role in multiple cognitive functions and sleep pattern changes with aging. Human studies revealed that aging decreases sleep efficiency and reduces the total sleep time, the time spent in slow-wave sleep (SWS), and the delta power (1-4 Hz) during sleep; however, some studies of sleep and aging in mice reported opposing results. The aim of our work is to estimate how features of sleep-wake state in mice during aging could correspond to age-dependent changes observed in human. In this study, we investigated the sleep/wake cycle in young (3 months old) and older (12 months old) C57BL/6 mice using local-field potentials (LFPs). We found that older adult mice sleep more than young ones but only during the dark phase of sleep-wake cycle. Sleep fragmentation and sleep during the active phase (dark phase of cycle), homologous to naps, were higher in older mice. Older mice show a higher delta power in frontal cortex, which was accompanied with similar trend for age differences in slow wave density. We also investigated regional specificity of sleep-wake electrographic activities and found that globally posterior regions of the cortex show more rapid eye movement (REM) sleep whereas somatosensory cortex displays more often SWS patterns. Our results indicate that the effects of aging on the sleep-wake activities in mice occur mainly during the dark phase and the electrode location strongly influence the state detection. Despite some differences in sleep-wake cycle during aging between human and mice, some features of mice sleep share similarity with human sleep during aging.

General Anesthesia: A Probe to Explore Consciousness.

Abstract: General anesthesia reversibly alters consciousness, without shutting down the brain globally. Depending on the anesthetic agent and dose, it may produce different consciousness states including a complete absence of subjective experience (unconsciousness), a conscious experience without perception of the environment (disconnected consciousness, like during dreaming), or episodes of oriented consciousness with awareness of the environment (connected consciousness). Each consciousness state may potentially be followed by explicit or implicit memories after the procedure. In this respect, anesthesia can be considered as a proxy to explore consciousness. During the recent years, progress in the exploration of brain function has allowed a better understanding of the neural correlates of consciousness, and of their alterations during anesthesia. Several changes in functional and effective between-region brain connectivity, consciousness network topology, and spatio-temporal dynamics of between-region interactions have been evidenced during anesthesia. Despite a set of effects that are common to many anesthetic agents, it is still uneasy to draw a comprehensive picture of the precise cascades during general anesthesia. Several questions remain unsolved, including the exact identification of the neural substrate of consciousness and its components, the detection of specific consciousness states in unresponsive patients and their associated memory processes, the processing of sensory information during anesthesia, the pharmacodynamic interactions between anesthetic agents, the direction-dependent hysteresis phenomenon during the transitions between consciousness states, the mechanisms of cognitive alterations that follow an anesthetic procedure, the identification of an eventual unitary mechanism of anesthesia-induced alteration of consciousness, the relationship between network effects and the biochemical or sleep-wake cycle targets of anesthetic agents, as well as the vast between-studies variations in dose and administration mode, leading to difficulties in between-studies comparisons. In this narrative review, we draw the picture of the current state of knowledge in anesthesia-induced unconsciousness, from insights gathered on propofol, halogenated vapors, ketamine, dexmedetomidine, benzodiazepines and xenon. We also describe how anesthesia can help understanding consciousness, we develop the above-mentioned unresolved questions, and propose tracks for future research.

A Neurocognitive Perspective on the Forms and Functions of Autobiographical Memory Retrieval.

Abstract: Autobiographical memory retrieval involves constructing mental representations of personal past episodes by associating together an array of details related to the retrieved event. This construction process occurs flexibly so that the event details can be associated together in different ways during retrieval. Here, we propose that differences in how this association occurs support a division in autobiographical remembering. We first review theories of autobiographical memory organization that suggest that episodic details of an experience are processed along a gradient of abstraction. This organization allows for the same autobiographical event to be recalled as either a conceptualized or perceptually-based episodic memory. We then use neuroimaging evidence to show how this division within episodic autobiographical memory is also present in the brain, both at a network level and within the hippocampus. Specifically, we suggest that the anterior and posterior hippocampus are obligatorily tuned towards constructing conceptual versus perceptual episodic representations of autobiographical memories. Finally, we discuss the directive purpose of this proposed division of episodic remembering by reviewing decision scenarios that benefit from recalling the past as a conceptual versus a perceptual episode. Conceptual remembering is useful to guide ambiguous decisions that have yet to be encountered whereas perceptual remembering is useful to guide decisions for well-structured tasks that have been previously experienced. We emphasize that the ability to shift between conceptual and perceptual forms of remembering, by virtue of hippocampal specialization, during decision-making and other memory-guided actions is the key to adaptive behaviour.

A Naturalistic Approach to the Hard Problem of Consciousness.

Abstract: Following a brief review of current efforts to identify the neuronal correlates of conscious processing (NCCP) an attempt is made to bridge the gap between the material neuronal processes and the immaterial dimensions of subjective experience. It is argued that this "hard problem" of consciousness research cannot be solved by only considering the neuronal underpinnings of cognition. The proposal is that the hard problem can be treated within a naturalistic framework if one considers not only the biological but also the socio-cultural dimensions of evolution. The argument is based on the following premises: perceptions are the result of a constructivist process that depends on priors. This applies both for perceptions of the outer world and the perception of oneself. Social interactions between agents endowed with the cognitive abilities of humans generated immaterial realities, addressed as social or cultural realities. This novel class of realities assumed the role of priors for the perception of oneself and the embedding world. A natural consequence of these extended perceptions is a dualist classification of observables into material and immaterial phenomena nurturing the concept of ontological substance dualism. It is argued that perceptions shaped by socio-cultural priors lead to the construction of a self-model that has both a material and an immaterial dimension. As priors are implicit and not amenable to conscious recollection the perceived immaterial dimension is experienced as veridical and not derivable from material processes-which is the hallmark of the hard problem. These considerations let the hard problem appear as the result of cognitive constructs that are amenable to naturalistic explanations in an evolutionary framework.

Whisker-Mediated Touch System in Rodents: From Neuron to Behavior.

Abstract: A key question in systems neuroscience is to identify how sensory stimuli are represented in neuronal activity, and how the activity of sensory neurons in turn is ``read out'' by downstream neurons and give rise to behavior. The choice of proper model system to adress these questions, hence, is a crucial step. Over the past decade, the increasingly powerful array of experimental approaches that has become available in non-primate models (e.g. optogenetics and two-photon imaging) has spurred a renewed interest for the use of rodent models in systems neuroscience research. Here we introduce the rodent whisker-mediated touch system as a structurally well-established and well-organized model system which despite its simplicity gives rises to complex behaviors. This system serves as a behaviorally efficient model system; known as nocturnal animals, along with their olfaction, rodents rely on their whisker-mediated touch system to collect information about their surrounding environment. Moreover, this system represents a well-studied circuitry with a somatotopic organization: at every stage of processing, one can identify anatomical and functional topographic maps of whiskers: ``barrelettes'' in the brainstem nuclei, ``barreloids'' in the sensory thalamus, and ``barrels'' in the cortex. This article provides a brief review to the basic anatomy and function of the whisker system in rodents.

Abnormal Cortico-Cerebellar Functional Connectivity in Autism Spectrum Disorder

Abstract: The cerebral cortex and the cerebellum are spatially remote areas that are connected by complex circuits that link both primary and associative areas. Previous studies have revealed abnormalities in autism spectrum disorder (ASD); however, it is not clear whether cortico-cerebellar connectivity is differentially manifested in the disorder. To explore this issue, we investigated differences in intrinsic cortico-cerebellar functional connectivity between individuals with typical development (TD) and those with ASD. To this end, we used functional magnetic resonance imaging (fMRI) of 708 subjects under a resting state protocol provided by the ABIDE I Consortium. We found that people with ASD had diminished functional connectivity between the cerebellum and the following cortical regions: (i) right fusiform gyrus, (ii) right postcentral gyrus, (iii) right superior temporal gyrus, (iv) right middle temporal gyrus, and (v) left middle temporal gyrus. All of these regions are involved in many cognitive systems that contribute to commonly affected functions in ASD. For right fusiform gyrus, right superior temporal gyrus, and left middle temporal gyrus, we reproduced the results in an independent cohort composed of 585 subjects of the ABIDE II Consortium. Our results points toward a consistent atypical cortico-cerebellar connectivity in ASD.

3D Organotypic Spinal Cultures: Exploring Neuron and Neuroglia Responses Upon Prolonged Exposure to Graphene Oxide

Abstract: Graphene-based nanomaterials are increasingly engineered as components of biosensors, interfaces or drug delivery platforms in neuro-repair strategies. In these developments, the mostly used derivative of graphene is graphene oxide (GO). To tailor the safe development of GO nanosheets, we need to model in vitro tissue responses, and in particular the reactivity of microglia, a sub-population of neuroglia that acts as the first active immune response, when challenged by GO. Here, we investigated central nervous system (CNS) tissue reactivity upon long-term exposure to GO nanosheets in 3D culture models. We used the mouse organotypic spinal cord cultures, ideally suited for studying long-term interference with cues delivered at controlled times and concentrations. In cultured spinal segments, the normal presence, distribution and maturation of anatomically distinct classes of neurons and resident neuroglial cells are preserved. Organotypic explants were developed for 2 weeks embedded in fibrin glue alone or presenting GO nanosheets at 10, 25 and 50 μg/mL. We addressed the impact of such treatments on premotor synaptic activity monitored by patch clamp recordings of ventral interneurons. We investigated by immunofluorescence and confocal microscopy the accompanying glial responses to GO exposure, focusing on resident microglia, tested in organotypic spinal slices and in isolated neuroglia cultures. Our results suggest that microglia reactivity to accumulation of GO flakes, maybe due to active phagocytosis, may trim down synaptic activity, although in the absence of an effective activation of inflammatory response and in the absence of neuronal cell death.

An Integrative Model of Effortful Control.

Abstract: This article presents an integrative model of effortful control, a resource-limited top-down control mechanism involved in mental tasks and physical exercises. Based on recent findings in the fields of neuroscience, social psychology and cognitive psychology, this model posits the intrinsic costs related to a weakening of the connectivity of neural networks underpinning effortful control as the main cause of mental fatigue in long and high-demanding tasks. In this framework, effort reflects three different inter-related aspects of the same construct. First, effort is a mechanism comprising a limited number of interconnected processing units that integrate information regarding the task constraints and subject's state. Second, effort is the main output of this mechanism, namely, the effort signal that modulates neuronal activity in brain regions involved in the current task to select pertinent information. Third, effort is a feeling that emerges in awareness during effortful tasks and reflects the costs associated with goal-directed behavior. Finally, the model opens new avenues for research investigating effortful control at the behavioral and neurophysiological levels.

Indicators and Criteria of Consciousness in Animals and Intelligent Machines : An Inside-Out Approach

Abstract: In today's society, it becomes increasingly important to assess which non-human and non-verbal beings possess consciousness. This review article aims to delineate criteria for consciousness especially in animals, while also taking into account intelligent artifacts. First, we circumscribe what we mean with "consciousness" and describe key features of subjective experience: qualitative richness, situatedness, intentionality and interpretation, integration and the combination of dynamic and stabilizing properties. We argue that consciousness has a biological function, which is to present the subject with a multimodal, situational survey of the surrounding world and body, subserving complex decision-making and goal-directed behavior. This survey reflects the brain's capacity for internal modeling of external events underlying changes in sensory state. Next, we follow an inside-out approach: how can the features of conscious experience, correlating to mechanisms inside the brain, be logically coupled to externally observable ("outside") properties? Instead of proposing criteria that would each define a "hard" threshold for consciousness, we outline six indicators: (i) goal-directed behavior and model-based learning; (ii) anatomic and physiological substrates for generating integrative multimodal representations; (iii) psychometrics and meta-cognition; (iv) episodic memory; (v) susceptibility to illusions and multistable perception; and (vi) specific visuospatial behaviors. Rather than emphasizing a particular indicator as being decisive, we propose that the consistency amongst these indicators can serve to assess consciousness in particular species. The integration of scores on the various indicators yields an overall, graded criterion for consciousness, somewhat comparable to the Glasgow Coma Scale for unresponsive patients. When considering theoretically derived measures of consciousness, it is argued that their validity should not be assessed on the basis of a single quantifiable measure, but requires cross-examination across multiple pieces of evidence, including the indicators proposed here. Current intelligent machines, including deep learning neural networks (DLNNs) and agile robots, are not indicated to be conscious yet. Instead of assessing machine consciousness by a brief Turing-type of test, evidence for it may gradually accumulate when we study machines ethologically and across time, considering multiple behaviors that require flexibility, improvisation, spontaneous problem-solving and the situational conspectus typically associated with conscious experience.

Bridging Single Neuron Dynamics to Global Brain States.

Abstract: Biological neural networks produce information backgrounds of multi-scale spontaneous activity that become more complex in brain states displaying higher capacities for cognition, for instance, attentive awake versus asleep or anesthetized states. Here, we review brain state-dependent mechanisms spanning ion channel currents (microscale) to the dynamics of brain-wide, distributed, transient functional assemblies (macroscale). Not unlike how microscopic interactions between molecules underlie structures formed in macroscopic states of matter, using statistical physics, the dynamics of microscopic neural phenomena can be linked to macroscopic brain dynamics through mesoscopic scales. Beyond spontaneous dynamics, it is observed that stimuli evoke collapses of complexity, most remarkable over high dimensional, asynchronous, irregular background dynamics during consciousness. In contrast, complexity may not be further collapsed beyond synchrony and regularity characteristic of unconscious spontaneous activity. We propose that increased dimensionality of spontaneous dynamics during conscious states supports responsiveness, enhancing neural networks' emergent capacity to robustly encode information over multiple scales.

Neuroradiological Changes Following Single or Repetitive Mild TBI.

Abstract: Objectives: To test the hypothesis that there are differences in neuroradiological measures between single and repeated mild TBI using multimodal MRI. Methods: A closed-head momentum exchange model was used to produce one or three mild head injuries in young adult male rats as compared to non-injured, age and weight-matched controls. Six-seven weeks post-injury, rats were studied for deficits in cognitive and motor function. Seven-eight weeks post-injury changes in brain anatomy and function were evaluated through analysis of high resolution T2 weighted images, resting state BOLD functional connectivity, and diffusion weighted imaging with quantitative anisotropy. Results: Head injuries occurred without skull fracture or signs of intracranial bleeding or contusion. There were no significant differences in cognitive or motors behaviors between experimental groups. With a single mild hit, the affected areas were limited to the caudate/putamen and central amygdala. Rats hit three times showed altered diffusivity in white matter tracts, basal ganglia, central amygdala, brainstem, and cerebellum. Comparing three hits to one hit showed a similar pattern of change underscoring a dose effect of repeated head injury on the brainstem and cerebellum. Disruption of functional connectivity was pronounced with three mild hits. The midbrain dopamine system, hippocampus, and brainstem/cerebellum showed hypoconnectivity. Interestingly, rats exposed to one hit showed enhanced functional connectivity (or hyperconnectivity) across brain sites, particularly between the olfactory system and the cerebellum. Interpretation: Neuroradiological evidence of altered brain structure and function, particularly in striatal and midbrain dopaminergic areas, persists long after mild repetitive head injury. These changes may serve as biomarkers of neurodegeneration and risk for dementia later in life.

Activation of Brainstem Neurons During Mesencephalic Locomotor Region-Evoked Locomotion in the Cat.

Abstract: The distribution of locomotor-activated neurons in the brainstem of the cat was studied by c-Fos immunohistochemistry in combination with antibody-based cellular phenotyping following electrical stimulation of the mesencephalic locomotor region (MLR) – the anatomical constituents of which remain debated today, primarily between the cuneiform (CnF) and the pedunculopontine tegmental nuclei (PPT). Effective MLR sites were co-extensive with the CnF nucleus. Animals subject to the locomotor task showed abundant Fos labeling in the CnF, parabrachial nuclei of the subcuneiform region, periaqueductal grey, locus ceruleus/subceruleus, Kolliker-Fuse, magnocellular and lateral tegmental fields, raphe, and the parapyramidal region. Labeled neurons were more abundant on the side of stimulation. In some animals, Fos labeled cells were also observed in the ventral tegmental area, medial and intermediate vestibular nuclei, dorsal motor nucleus of the vagus, n. tractus solitarii and retrofacial nucleus in the ventrolateral medulla. Many neurons in the reticular formation were innervated by serotonergic fibers. Numerous locomotor-activated neurons in the parabrachial nuclei and locus ceruleus/subceruleus/Kolliker-Fuse were noradrenergic. Few cholinergic neurons within the PPT stained for Fos. In the medulla, serotonergic neurons within the parapyramidal region and the nucleus raphe magnus were positive for Fos. Control animals, not subject to locomotion, showed few Fos labeled neurons in these areas. The current study provides positive evidence for a role for the CnF in the initiation of locomotion while providing little evidence for the participation of the PPT. The results also show that MLR-evoked locomotion involves the parallel activation of reticular and monoaminergic neurons in the pons/medulla, and provides the anatomical and functional basis for spinal monoamine release during evoked locomotion. Lastly, the results indicate that vestibular, cardiovascular and respiratory centers are centrally activated during MLR evoked locomotion. Altogether, the results show a complex pattern of neuromodulatory influences of brainstem neurons by electrical activation of the MLR.

Spectral Imprints of Working Memory for Everyday Associations in the Frontoparietal Network.

Abstract: How does the human brain rapidly process incoming information in working memory? In growing divergence from a single-region focus on the prefrontal cortex (PFC), recent work argues for emphasis on how distributed neural networks are rapidly coordinated in support of this central neurocognitive function. Previously, we showed that working memory for everyday "what," "where," and "when" associations depends on multiplexed oscillatory systems, in which signals of different frequencies simultaneously link the PFC to parieto-occipital and medial temporal regions, pointing to a complex web of sub-second, bidirectional interactions. Here, we used direct brain recordings to delineate the frontoparietal oscillatory correlates of working memory with high spatiotemporal precision. Seven intracranial patients with electrodes simultaneously localized to prefrontal and parietal cortices performed a visuospatial working memory task that operationalizes the types of identity and spatiotemporal information we encounter every day. First, task-induced oscillations in the same delta-theta (2-7 Hz) and alpha-beta (9-24 Hz) frequency ranges previously identified using scalp electroencephalography (EEG) carried information about the contents of working memory. Second, maintenance was linked to directional connectivity from the parietal cortex to the PFC. However, presentation of the test prompt to cue identity, spatial, or temporal information changed delta-theta coordination from a unidirectional, parietal-led system to a bidirectional, frontoparietal system. Third, the processing of spatiotemporal information was more bidirectional in the delta-theta range than was the processing of identity information, where alpha-beta connectivity did not exhibit sensitivity to the contents of working memory. These findings implicate a bidirectional delta-theta mechanism for frontoparietal control over the contents of working memory.

Characterizing the Dynamical Complexity Underlying Meditation.

Abstract: Over the past 2,500 years, contemplative traditions have explored the nature of the mind using meditation More recently, neuroimaging research on meditation has revealed differences in brain function and structure in meditators Nevertheless, the underlying neural mechanisms are still unclear In order to understand how meditation shapes global activity through the brain, we investigated the spatiotemporal dynamics across the whole-brain functional network using the Intrinsic Ignition Framework Recent neuroimaging studies have demonstrated that different states of consciousness differ in their underlying dynamical complexity, ie, how the broadness of communication is elicited and distributed through the brain over time and space In this work, controls and experienced meditators were scanned using functional magnetic resonance imaging (fMRI) during resting-state and meditation (focused attention on breathing) Our results evidenced that the dynamical complexity underlying meditation shows less complexity than during resting-state in the meditator group but not in the control group Furthermore, we report that during resting-state, the brain activity of experienced meditators showed higher metastability (ie, a wider dynamical regime over time) than the one observed in the control group Overall, these results indicate that the meditation state operates in a different dynamical regime compared to the resting-state

A Case Series Clinical Trial of a Novel Approach Using Augmented Reality that Inspires Self-body Cognition in Patients with Stroke: Effects on motor function and resting-state brain functional connectivity

Abstract: Barring a few studies, there are not enough established treatments to improve upper limb motor function in patients with severe impairments due to chronic stroke. This study aimed to clarify the effect of the kinesthetic perceptional illusion induced by visual stimulation (KINVIS) on upper limb motor function and the relationship between motor function and resting-state brain networks. Eleven patients with severe paralysis of upper limb motor function in the chronic phase (seven men and four women; age: 54.7 ± 10.8 years; 44.0 ± 29.0 months post-stroke) participated in the study. Patients underwent an intervention consisting of therapy using KINVIS and conventional therapeutic exercise (TherEX) for 10 days. Our originally developed KiNvis™ system was applied to induce KINVIS while watching the movement of the artificial hand. Clinical outcomes were examined to evaluate motor functions and resting-state brain functional connectivity (rsFC) by analyzing blood-oxygen-level-dependent (BOLD) signals measured using functional magnetic resonance imaging (fMRI). The outcomes of motor function (Fugle-Meyer Assessment, FMA) and spasticity (Modified Ashworth Scale, MAS) significantly improved after the intervention. The improvement in MAS scores for the fingers and the wrist flexors reached a minimum of clinically important differences. Before the intervention, strong and significant negative correlations between the motor functions and rsFC of the inferior parietal lobule (IPL) and premotor cortex (PMd) in the unaffected hemisphere was demonstrated. These strong correlations were disappeared after the intervention. A negative and strong correlation between the motor function and rsFC of the bilateral inferior parietal sulcus (IPS) significantly changed to strong and positive correlation after the intervention. These results may suggest that the combination approach of KINVIS therapy and TherEX improved motor functions and decreased spasticity in the paralyzed upper extremity after stroke in the chronic phase, possibly indicating the contribution of embodied-visual stimulation. The rsFC for the interhemispheric IPS and intrahemispheric IPL and PMd may be a possible regulatory factor for improving motor function and spasticity. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01274117.

Entorhinal Layer II Calbindin-Expressing Neurons Originate Widespread Telencephalic and Intrinsic Projections.

Abstract: In the present study we provide the first systematic and quantitative hodological study of the calbindin-expressing (CB+) principal neurons in layer II of the entorhinal cortex and compared the respective projections of the lateral and medial subdivisions of the entorhinal cortex. Using elaborate quantitative retrograde tracing, complemented by anterograde tracing, we report that the layer II CB+ population comprises neurons with diverse, mainly excitatory projections. At least half of them originate local intrinsic and commissural projections which distribute mainly to layer I and II. We further show that long-range CB+ projections from the two entorhinal subdivisions differ substantially in that MEC projections mainly target field CA1 of the hippocampus, whereas LEC CB+ projections distribute much more widely to a substantial number of known forebrain targets. This connectional difference between the CB+ populations in LEC and MEC is reminiscent of the overall projection pattern of the two entorhinal subdivisions.

The role of top-down modulation in shaping sensory processing across brain states: implications for consciousness

Abstract: Top-down, feedback projections account for a large portion of all connections between neurons in the thalamocortical system, yet their precise role remains the subject of much discussion. A large number of studies has focused on investigating how sensory information is transformed across hierarchically-distributed processing stages in a feedforward fashion, and computational models have shown that purely feedforward artificial neural networks can even outperform humans in pattern classification tasks. What is then the functional role of feedback connections? Several key roles have been identified, ranging from attentional modulation to, crucially, conscious perception. Specifically, most of the major theories on consciousness postulate that feedback connections would play an essential role in enabling sensory information to be consciously perceived. Consequently, it follows that their efficacy in modulating target regions should drastically decrease in nonconscious brain states [non-rapid eye movement (REM) sleep, anesthesia] compared to conscious ones (wakefulness), and also in instances when a given sensory stimulus is not perceived compared to when it is. Until recently, however, this prediction could only be tested with correlative experiments, due to the lack of techniques to selectively manipulate and measure the activity of feedback pathways. In this article, we will review the most recent literature on the functions of feedback connections across brain states and based on the presence or absence of perception. We will focus on experiments studying mismatch negativity, a phenomenon which has been hypothesized to rely on top-down modulation but which persists during nonconscious states. While feedback modulation is generally dampened in nonconscious states and enhanced when perception occurs, there are clear deviations from this rule. As we will discuss, this may pose a challenge to most theories of consciousness, and possibly require a change in how the level of consciousness in supposedly nonconscious states is assessed.

Wave Turbulence and Energy Cascade in the Hippocampus

Abstract: Mesoscale cortical activity can be defined as the organization of activity of large neuron populations into collective action, forming time-dependent patterns such as traveling waves. Although collective action may play an important role in the cross-scale integration of brain activity and in the emergence of cognitive behavior, a comprehensive formulation of the laws governing its dynamics is still lacking. Because collective action processes are macroscopic with respect to neuronal activity, these processes cannot be described directly with methods and models developed for the microscale (individual neurons). To identify the characteristic features of mesoscopic dynamics, and to lay the foundations for a theoretical description of mesoscopic activity in the hippocampus, we conduct a comprehensive examination of observational data of hippocampal local field potential (LFP) recordings. We use the strong correlation between rat running-speed and the LFP power to parameterize the energy input into the hippocampus, and show that both the power and nonlinearity of collective action (e.g., theta and gamma rhythms) increase with increased speed. Our results show that collective-action dynamics are stochastic (the precise state of a single neuron is irrelevant), weakly nonlinear, and weakly dissipative. These are the principles of the theory of weak turbulence. Therefore, we propose weak turbulence a theoretical framework for the description of mesoscopic activity in the hippocampus. The weak turbulence framework provides a complete description of the cross-scale energy exchange (the energy cascade). It uncovers the mechanism governing major features of LFP spectra and bispectra, such as the physical meaning of the exponent \alpha of power-law LFP spectra (e.g., f^{-\alpha}, where f is the frequency), the strengthening of theta-gamma coupling with energy input into the hippocampus, as well as specific phase lags associated with their interaction. Remarkably, the weak turbulence framework is consistent with the theory of self organized criticality, which provides a simple explanation for the existence of the power-law background spectrum. Together with self-organized criticality, weak turbulence could provide a unifying approach to modeling the dynamics of mesoscopic activity.

Climbing Fibers Provide Graded Error Signals in Cerebellar Learning

Abstract: The cerebellum plays a critical role in coordinating and learning complex movements. Although its importance has been well recognized, the mechanisms of learning remain hotly debated. According to the classical cerebellar learning theory, depression of parallel fiber synapses instructed by error signals from climbing fibers, drives cerebellar learning. The uniqueness of long-term depression in cerebellar learning has been challenged by evidence showing multi-site synaptic plasticity. In Purkinje cells, long-term potentiation of parallel fiber synapses is now well established and it can be achieved with or without climbing fiber signals, making the role of climbing fiber input more puzzling. The central question is how individual Purkinje cells extract global errors based on climbing fiber input. Previous data seemed to demonstrate that climbing fibers are inefficient instructors, because they were thought to carry ‘binary’ error signals to individual Purkinje cells, which significantly constrains the efficiency of cerebellar learning in several regards. In recent years, new evidence has challenged the traditional view of ‘binary’ climbing fiber responses, suggesting that climbing fibers can provide graded information to efficiently instruct individual Purkinje cells to learn. Here we review recent experimental and theoretical progress regarding modulated climbing fiber responses in Purkinje cells. Analogue error signals are generated by the interaction of varying climbing fibers inputs with simultaneous other synaptic input and with firing states of targeted Purkinje cells. Accordingly, the calcium signals which trigger synaptic plasticity can be graded in both amplitude and spatial range to affect the learning rate and even learning direction. We briefly discuss how these new findings complement the learning theory and help to further our understanding of how the cerebellum works.

Intraoperative Low Alpha Power in the Electroencephalogram Is Associated With Postoperative Subsyndromal Delirium.

Abstract: Background Postoperative delirium (PD) and subsyndromal delirium (PSSD) are frequent complications in older patients associated with poor long-term outcome. It has been suggested that certain electroencephalogram features may be capable of identifying patients at risk during surgery. Thus, the goal of this study was to characterize intraoperative electroencephalographic markers to identify patients prone to develop PD or PSSD. Methods We conducted an exploratory observational study in older patients scheduled for elective major abdominal surgery. Intraoperative 16 channels electroencephalogram was recorded, and PD/PSSD were diagnosed after surgery with the confusion assessment method (CAM). The total power spectra and relative power of alpha band were calculated. Results PD was diagnosed in 2 patients (6.7%), and 11 patients (36.7%) developed PSSD. All of them (13 patients, PD/PSSD group) were compared with patients without any alterations in CAM (17 patients, control group). There were no detectable power spectrum differences before anesthesia between both groups of patients. However, PD/PSSD group in comparison with control group had a lower intraoperative absolute alpha power during anesthesia (4.4 ± 3.8 dB vs. 9.6 ± 3.2 dB, p = 0.0004) and a lower relative alpha power (0.09 ± 0.06 vs. 0.21 ± 0.08, p < 0.0001). These differences were independent of the anesthetic dose. Finally, relative alpha power had a good ability to identify patients with CAM alterations in the ROC analysis (area under the curve 0.90 (CI 0.78-1), p < 0.001). Discussion In conclusion, a low intraoperative alpha power is a novel electroencephalogram marker to identify patients who will develop alterations in CAM - i.e., with PD or PSSD - after surgery.

Graphene-Based Nanomaterials: From Production to Integration With Modern Tools in Neuroscience.

Abstract: Graphene, a two-dimensional carbon crystal, has emerged as a promising material for sensing and modulating neuronal activity in vitro and in vivo. In this review, we provide a primer for how manufacturing processes to produce graphene and graphene oxide result in materials properties that may be tailored for a variety of applications. We further discuss how graphene may be composited with other bio-compatible materials of interest to make novel hybrid complexes with desired characteristics for bio-interfacing. We then highlight graphene's ever-widen utility and unique properties that may in the future be multiplexed for cross-modal modulation or interrogation of neuronal network. As the biological effects of graphene are still an area of active investigation, we discuss recent development, with special focus on how surface coatings and surface properties of graphene are relevant to its biological effects. We discuss studies conducted in both non-murine and murine systems, and emphasize the preclinical aspect of graphene's potential without undermining its tangible clinical implementation.

Eye Movement Compensation and Spatial Updating in Visual Prosthetics: Mechanisms, Limitations and Future Directions

Abstract: Despite appearing automatic and effortless, perceiving the visual world is a highly complex process that depends on intact visual and oculomotor function. Understanding the mechanisms underlying spatial updating (i.e., gaze contingency) represents an important, yet unresolved issue in the fields of visual perception and cognitive neuroscience. Many questions regarding the processes involved in updating visual information as a function of the movements of the eyes are still open for research. Beyond its importance for basic research, gaze contingency represents a challenge for visual prosthetics as well. While most artificial vision studies acknowledge its importance in providing accurate visual percepts to the blind implanted patients, the majority of the current devices do not compensate for gaze position. To-date, artificial percepts to the blind population have been provided either by intraocular light-sensing circuitry or by using external cameras. While the former commonly accounts for gaze shifts, the latter requires the use of eye-tracking or similar technology in order to deliver percepts based on gaze position. Inspired by the need to overcome the hurdle of gaze contingency in artificial vision, we aim to provide a thorough overview of the research addressing the neural underpinnings of eye compensation, as well as its relevance in visual prosthetics. The present review outlines what is currently known about the mechanisms underlying spatial updating and reviews the attempts of current visual prosthetic devices to overcome the hurdle of gaze contingency. We discuss the limitations of the current devices and highlight the need to use eye-tracking methodology in order to introduce gaze-contingent information to visual prosthetics.