Novel analytical tools reveal that local synchronization of cilia coincides with tissue-scale metachronal waves in zebrafish multiciliated epithelia.

Motile cilia are hair-like cell extensions that beat periodically to generate fluid flow along various epithelial tissues within the body. In dense multiciliated carpets, cilia were shown to exhibit a remarkable coordination of their beat in the form of traveling metachronal waves, a phenomenon which supposedly enhances fluid transport. Yet, how cilia coordinate their regular beat in multiciliated epithelia to move fluids remains insufficiently understood, particularly due to lack of rigorous quantification. We combine experiments, novel analysis tools, and theory to address this knowledge gap. To investigate collective dynamics of cilia, we studied zebrafish multiciliated epithelia in the nose and the brain. We focused mainly on the zebrafish nose, due to its conserved properties with other ciliated tissues and its superior accessibility for non-invasive imaging. We revealed that cilia are synchronized only locally and that the size of local synchronization domains increases with the viscosity of the surrounding medium. Even though synchronization is local only, we observed global patterns of traveling metachronal waves across the zebrafish multiciliated epithelium. Intriguingly, these global wave direction patterns are conserved across individual fish, but different for left and right noses, unveiling a chiral asymmetry of metachronal coordination. To understand the implications of synchronization for fluid pumping, we used a computational model of a regular array of cilia. We found that local metachronal synchronization prevents steric collisions, i.e., cilia colliding with each other, and improves fluid pumping in dense cilia carpets, but hardly affects the direction of fluid flow. In conclusion, we show that local synchronization together with tissue-scale cilia alignment coincide and generate metachronal wave patterns in multiciliated epithelia, which enhance their physiological function of fluid pumping.

RBDtector: an open-source software to detect REM sleep without atonia according to visual scoring criteria.

REM sleep without atonia (RSWA) is a key feature for the diagnosis of rapid eye movement (REM) sleep behaviour disorder (RBD). We introduce RBDtector, a novel open-source software to score RSWA according to established SINBAR visual scoring criteria. We assessed muscle activity of the mentalis, flexor digitorum superficialis (FDS), and anterior tibialis (AT) muscles. RSWA was scored manually as tonic, phasic, and any activity by human scorers as well as using RBDtector in 20 subjects. Subsequently, 174 subjects (72 without RBD and 102 with RBD) were analysed with RBDtector to show the algorithm's applicability. We additionally compared RBDtector estimates to a previously published dataset. RBDtector showed robust conformity with human scorings. The highest congruency was achieved for phasic and any activity of the FDS. Combining mentalis any and FDS any, RBDtector identified RBD subjects with 100% specificity and 96% sensitivity applying a cut-off of 20.6%. Comparable performance was obtained without manual artefact removal. RBD subjects also showed muscle bouts of higher amplitude and longer duration. RBDtector provides estimates of tonic, phasic, and any activity comparable to human scorings. RBDtector, which is freely available, can help identify RBD subjects and provides reliable RSWA metrics.

[Sleep spindles-Function, detection and use as biomarker for diagnostics in psychiatry]. / Schlafspindeln ­ Funktion, Detektion und Nutzung als Biomarker für die psychiatrische Diagnostik.

BACKGROUND: The sleep spindle is a graphoelement of an electroencephalogram (EEG), which can be observed in light and deep sleep. Alterations in spindle activity have been described for a range of psychiatric disorders. Due to their relatively constant properties, sleep spindles may therefore be potential biomarkers in psychiatric diagnostics. METHOD: This article presents an overview of the state of the science on the characteristics and functions of the sleep spindle as well as known alterations of spindle activity in psychiatric disorders. Various methodological approaches and developments of spindle detection are explained with respect to their potential for application in psychiatric diagnostics. RESULTS AND CONCLUSION: Although alterations in spindle activity in psychiatric disorders are known and have been described in detail, their exact potential for psychiatric diagnostics has yet to be fully determined. In this respect, the acquisition of knowledge in research is currently constrained by manual and automated methods for spindle detection, which require high levels of resources and are error prone. Newer approaches to spindle detection based on deep-learning procedures could overcome the difficulties of previous detection methods, and thus open up new possibilities for the practical application of sleep spindles as biomarkers in the psychiatric practice.

Advanced sleep spindle identification with neural networks.

Sleep spindles are neurophysiological phenomena that appear to be linked to memory formation and other functions of the central nervous system, and that can be observed in electroencephalographic recordings (EEG) during sleep. Manually identified spindle annotations in EEG recordings suffer from substantial intra- and inter-rater variability, even if raters have been highly trained, which reduces the reliability of spindle measures as a research and diagnostic tool. The Massive Online Data Annotation (MODA) project has recently addressed this problem by forming a consensus from multiple such rating experts, thus providing a corpus of spindle annotations of enhanced quality. Based on this dataset, we present a U-Net-type deep neural network model to automatically detect sleep spindles. Our model's performance exceeds that of the state-of-the-art detector and of most experts in the MODA dataset. We observed improved detection accuracy in subjects of all ages, including older individuals whose spindles are particularly challenging to detect reliably. Our results underline the potential of automated methods to do repetitive cumbersome tasks with super-human performance.

Automated scoring of pre-REM sleep in mice with deep learning.

Reliable automation of the labor-intensive manual task of scoring animal sleep can facilitate the analysis of long-term sleep studies. In recent years, deep-learning-based systems, which learn optimal features from the data, increased scoring accuracies for the classical sleep stages of Wake, REM, and Non-REM. Meanwhile, it has been recognized that the statistics of transitional stages such as pre-REM, found between Non-REM and REM, may hold additional insight into the physiology of sleep and are now under vivid investigation. We propose a classification system based on a simple neural network architecture that scores the classical stages as well as pre-REM sleep in mice. When restricted to the classical stages, the optimized network showed state-of-the-art classification performance with an out-of-sample F1 score of 0.95 in male C57BL/6J mice. When unrestricted, the network showed lower F1 scores on pre-REM (0.5) compared to the classical stages. The result is comparable to previous attempts to score transitional stages in other species such as transition sleep in rats or N1 sleep in humans. Nevertheless, we observed that the sequence of predictions including pre-REM typically transitioned from Non-REM to REM reflecting sleep dynamics observed by human scorers. Our findings provide further evidence for the difficulty of scoring transitional sleep stages, likely because such stages of sleep are under-represented in typical data sets or show large inter-scorer variability. We further provide our source code and an online platform to run predictions with our trained network.

Early warning signal for interior crises in excitable systems.

The ability to reliably predict critical transitions in dynamical systems is a long-standing goal of diverse scientific communities. Previous work focused on early warning signals related to local bifurcations (critical slowing down) and nonbifurcation-type transitions. We extend this toolbox and report on a characteristic scaling behavior (critical attractor growth) which is indicative of an impending global bifurcation, an interior crisis in excitable systems. We demonstrate our early warning signal in a conceptual climate model as well as in a model of coupled neurons known to exhibit extreme events. We observed critical attractor growth prior to interior crises of chaotic as well as strange-nonchaotic attractors. These observations promise to extend the classes of transitions that can be predicted via early warning signals.

Data-driven prediction and prevention of extreme events in a spatially extended excitable system.

Extreme events occur in many spatially extended dynamical systems, often devastatingly affecting human life, which makes their reliable prediction and efficient prevention highly desirable. We study the prediction and prevention of extreme events in a spatially extended system, a system of coupled FitzHugh-Nagumo units, in which extreme events occur in a spatially and temporally irregular way. Mimicking typical constraints faced in field studies, we assume not to know the governing equations of motion and to be able to observe only a subset of all phase-space variables for a limited period of time. Based on reconstructing the local dynamics from data and despite being challenged by the rareness of events, we are able to predict extreme events remarkably well. With small, rare, and spatiotemporally localized perturbations which are guided by our predictions, we are able to completely suppress extreme events in this system.

Time-dependent degree-degree correlations in epileptic brain networks: from assortative to dissortative mixing.

We investigate the long-term evolution of degree-degree correlations (assortativity) in functional brain networks from epilepsy patients. Functional networks are derived from continuous multi-day, multi-channel electroencephalographic data, which capture a wide range of physiological and pathophysiological activities. In contrast to previous studies which all reported functional brain networks to be assortative on average, even in case of various neurological and neurodegenerative disorders, we observe large fluctuations in time-resolved degree-degree correlations ranging from assortative to dissortative mixing. Moreover, in some patients these fluctuations exhibit some periodic temporal structure which can be attributed, to a large extent, to daily rhythms. Relevant aspects of the epileptic process, particularly possible pre-seizure alterations, contribute marginally to the observed long-term fluctuations. Our findings suggest that physiological and pathophysiological activity may modify functional brain networks in a different and process-specific way. We evaluate factors that possibly influence the long-term evolution of degree-degree correlations.

Extreme events due to localization of energy.

We study a one-dimensional chain of harmonically coupled units in an asymmetric anharmonic soft potential. Due to nonlinear localization of energy, this system exhibits extreme events in the sense that individual elements of the chain show very large excitations. A detailed statistical analysis of extremes in this system reveals some unexpected properties, e.g., a pronounced pattern in the interevent interval statistics. We relate these statistical properties to underlying system dynamics and notice that often when extreme events occur the system dynamics adopts (at least locally) an oscillatory behavior, resulting in, for example, a quick succession of such events. The model therefore might serve as a paradigmatic model for the study of the interplay of nonlinearity, energy transport, and extreme events.

How important is the seizure onset zone for seizure dynamics?

PURPOSE: Research into epileptic networks has recently allowed deeper insights into the epileptic process. Here we investigated the importance of individual network nodes for seizure dynamics. METHODS: We analysed intracranial electroencephalographic recordings of 86 focal seizures with different anatomical onset locations. With time-resolved correlation analyses, we derived a sequence of weighted epileptic networks spanning the pre-ictal, ictal, and post-ictal period, and each recording site represents a network node. We assessed node importance with commonly used centrality indices that take into account different network properties. RESULTS: A high variability of temporal evolution of node importance was observed, both intra- and interindividually. Nevertheless, nodes near and far off the seizure onset zone (SOZ) were rated as most important for seizure dynamics more often (65% of cases) than nodes from within the SOZ (35% of cases). CONCLUSION: Our findings underline the high relevance of brain outside of the SOZ but within the large-scale epileptic network for seizure dynamics. Knowledge about these network constituents may elucidate targets for individualised therapeutic interventions that aim at preventing seizure generation and spread.

Incidental and intentional learning of verbal episodic material differentially modifies functional brain networks.

Learning- and memory-related processes are thought to result from dynamic interactions in large-scale brain networks that include lateral and mesial structures of the temporal lobes. We investigate the impact of incidental and intentional learning of verbal episodic material on functional brain networks that we derive from scalp-EEG recorded continuously from 33 subjects during a neuropsychological test schedule. Analyzing the networks' global statistical properties we observe that intentional but not incidental learning leads to a significantly increased clustering coefficient, and the average shortest path length remains unaffected. Moreover, network modifications correlate with subsequent recall performance: the more pronounced the modifications of the clustering coefficient, the higher the recall performance. Our findings provide novel insights into the relationship between topological aspects of functional brain networks and higher cognitive functions.

Assortative mixing in functional brain networks during epileptic seizures.

We investigate assortativity of functional brain networks before, during, and after one-hundred epileptic seizures with different anatomical onset locations. We construct binary functional networks from multi-channel electroencephalographic data recorded from 60 epilepsy patients; and from time-resolved estimates of the assortativity coefficient, we conclude that positive degree-degree correlations are inherent to seizure dynamics. While seizures evolve, an increasing assortativity indicates a segregation of the underlying functional network into groups of brain regions that are only sparsely interconnected, if at all. Interestingly, assortativity decreases already prior to seizure end. Together with previous observations of characteristic temporal evolutions of global statistical properties and synchronizability of epileptic brain networks, our findings may help to gain deeper insights into the complicated dynamics underlying generation, propagation, and termination of seizures.

Unraveling spurious properties of interaction networks with tailored random networks.

We investigate interaction networks that we derive from multivariate time series with methods frequently employed in diverse scientific fields such as biology, quantitative finance, physics, earth and climate sciences, and the neurosciences. Mimicking experimental situations, we generate time series with finite length and varying frequency content but from independent stochastic processes. Using the correlation coefficient and the maximum cross-correlation, we estimate interdependencies between these time series. With clustering coefficient and average shortest path length, we observe unweighted interaction networks, derived via thresholding the values of interdependence, to possess non-trivial topologies as compared to Erdös-Rényi networks, which would indicate small-world characteristics. These topologies reflect the mostly unavoidable finiteness of the data, which limits the reliability of typically used estimators of signal interdependence. We propose random networks that are tailored to the way interaction networks are derived from empirical data. Through an exemplary investigation of multichannel electroencephalographic recordings of epileptic seizures--known for their complex spatial and temporal dynamics--we show that such random networks help to distinguish network properties of interdependence structures related to seizure dynamics from those spuriously induced by the applied methods of analysis.

From brain to earth and climate systems: small-world interaction networks or not?

We consider recent reports on small-world topologies of interaction networks derived from the dynamics of spatially extended systems that are investigated in diverse scientific fields such as neurosciences, geophysics, or meteorology. With numerical simulations that mimic typical experimental situations, we have identified an important constraint when characterizing such networks: indications of a small-world topology can be expected solely due to the spatial sampling of the system along with the commonly used time series analysis based approaches to network characterization.

State dependent properties of epileptic brain networks: comparative graph-theoretical analyses of simultaneously recorded EEG and MEG.

OBJECTIVE: To investigate whether functional brain networks of epilepsy patients treated with antiepileptic medication differ from networks of healthy controls even during the seizure-free interval. METHODS: We applied different rules to construct binary and weighted networks from EEG and MEG data recorded under a resting-state eyes-open and eyes-closed condition from 21 epilepsy patients and 23 healthy controls. The average shortest path length and the clustering coefficient served as global statistical network characteristics. RESULTS: Independent on the behavioral condition, epileptic brains exhibited a more regular functional network structure. Similarly, the eyes-closed condition was characterized by a more regular functional network structure in both groups. The amount of network reorganization due to behavioral state changes was similar in both groups. Consistent findings could be achieved for networks derived from EEG but hardly from MEG recordings, and network construction rules had a rather strong impact on our findings. CONCLUSIONS: Despite the locality of the investigated processes epileptic brain networks differ in their global characteristics from non-epileptic brain networks. Further methodological developments are necessary to improve the characterization of disturbed and normal functional networks. SIGNIFICANCE: An increased regularity and a diminished modulation capability appear characteristic of epileptic brain networks.

Synchronization phenomena in human epileptic brain networks.

Epilepsy is a malfunction of the brain that affects over 50 million people worldwide. Epileptic seizures are usually characterized by an abnormal synchronized firing of neurons involved in the epileptic process. In human epilepsy the exact mechanisms underlying seizure generation are still uncertain as are mechanisms underlying seizure spreading and termination. There is now growing evidence that an improved understanding of the epileptic process can be achieved through the analysis of properties of epileptic brain networks and through the analysis of interactions in such networks. In this overview, we summarize recent methodological developments to assess synchronization phenomena in human epileptic brain networks and present findings obtained from analyses of brain electromagnetic signals recorded in epilepsy patients.

Evolving functional network properties and synchronizability during human epileptic seizures.

We assess electrical brain dynamics before, during, and after 100 human epileptic seizures with different anatomical onset locations by statistical and spectral properties of functionally defined networks. We observe a concave-like temporal evolution of characteristic path length and cluster coefficient indicative of a movement from a more random toward a more regular and then back toward a more random functional topology. Surprisingly, synchronizability was significantly decreased during the seizure state but increased already prior to seizure end. Our findings underline the high relevance of studying complex systems from the viewpoint of complex networks, which may help to gain deeper insights into the complicated dynamics underlying epileptic seizures.

State-of-the-art of seizure prediction.

SUMMARY: Although there are numerous studies exploring basic neuronal mechanisms that are likely to be associated with seizures, to date no definite information is available as to how, when, or why a seizure occurs in humans. The fact that seizures occur without warning in the majority of cases is one of the most disabling aspects of epilepsy. If it were possible to identify preictal precursors from the EEG of epilepsy patients, therapeutic possibilities and quality of life could improve dramatically. The last three decades have witnessed a rapid increase in the development of new EEG analysis techniques that appear to be capable of defining seizure precursors. Since the 1970s, studies on seizure prediction have advanced from preliminary descriptions of preictal phenomena and proof of principle studies via controlled studies to studies on continuous multiday recordings. At present, it is unclear whether prospective algorithms can predict seizures. If prediction algorithms are to be used in invasive seizure intervention techniques in humans, they must be proven to perform considerably better than a random predictor. The authors present an overview of the field of seizure prediction, its history, accomplishments, recent controversies, and potential for future development.

Detecting synchronization clusters in multivariate time series via coarse-graining of Markov chains.

Synchronization cluster analysis is an approach to the detection of underlying structures in data sets of multivariate time series, starting from a matrix R of bivariate synchronization indices. A previous method utilized the eigenvectors of R for cluster identification, analogous to several recent attempts at group identification using eigenvectors of the correlation matrix. All of these approaches assumed a one-to-one correspondence of dominant eigenvectors and clusters, which has however been shown to be wrong in important cases. We clarify the usefulness of eigenvalue decomposition for synchronization cluster analysis by translating the problem into the language of stochastic processes, and derive an enhanced clustering method harnessing recent insights from the coarse-graining of finite-state Markov processes. We illustrate the operation of our method using a simulated system of coupled Lorenz oscillators, and we demonstrate its superior performance over the previous approach. Finally we investigate the question of robustness of the algorithm against small sample size, which is important with regard to field applications.

Identifying phase synchronization clusters in spatially extended dynamical systems.

We investigate two recently proposed multivariate time series analysis techniques that aim at detecting phase synchronization clusters in spatially extended, nonstationary systems with regard to field applications. The starting point of both techniques is a matrix whose entries are the mean phase coherence values measured between pairs of time series. The first method is a mean-field approach which allows one to define the strength of participation of a subsystem in a single synchronization cluster. The second method is based on an eigenvalue decomposition from which a participation index is derived that characterizes the degree of involvement of a subsystem within multiple synchronization clusters. Simulating multiple clusters within a lattice of coupled Lorenz oscillators we explore the limitations and pitfalls of both methods and demonstrate (a) that the mean-field approach is relatively robust even in configurations where the single-cluster assumption is not entirely fulfilled and (b) that the eigenvalue-decomposition approach correctly identifies the simulated clusters even for low coupling strengths. Using the eigenvalue-decomposition approach we studied spatiotemporal synchronization clusters in long-lasting multichannel EEG recordings from epilepsy patients and obtained results that fully confirm findings from well established neurophysiological examination techniques. Multivariate time series analysis methods such as synchronization cluster analysis, which account for nonlinearities in the data, are expected to provide complementary information which allows one to gain deeper insights into the collective dynamics of spatially extended complex systems.