Multi-modal cryo-EM reveals trimers of protein A10 to form the palisade layer in poxvirus cores.

Poxviruses are among the largest double-stranded DNA viruses, with members such as variola virus, monkeypox virus and the vaccination strain vaccinia virus (VACV). Knowledge about the structural proteins that form the viral core has remained sparse. While major core proteins have been annotated via indirect experimental evidence, their structures have remained elusive and they could not be assigned to individual core features. Hence, which proteins constitute which layers of the core, such as the palisade layer and the inner core wall, has remained enigmatic. Here we show, using a multi-modal cryo-electron microscopy (cryo-EM) approach in combination with AlphaFold molecular modeling, that trimers formed by the cleavage product of VACV protein A10 are the key component of the palisade layer. This allows us to place previously obtained descriptions of protein interactions within the core wall into perspective and to provide a detailed model of poxvirus core architecture. Importantly, we show that interactions within A10 trimers are likely generalizable over members of orthopox- and parapoxviruses.

MOD: A novel machine-learning optimal-filtering method for accurate and efficient detection of subthreshold synaptic events in vivo.

BACKGROUND: To understand information coding in single neurons, it is necessary to analyze subthreshold synaptic events, action potentials (APs), and their interrelation in different behavioral states. However, detecting excitatory postsynaptic potentials (EPSPs) or currents (EPSCs) in behaving animals remains challenging, because of unfavorable signal-to-noise ratio, high frequency, fluctuating amplitude, and variable time course of synaptic events. NEW METHOD: We developed a method for synaptic event detection, termed MOD (Machine-learning Optimal-filtering Detection-procedure), which combines concepts of supervised machine learning and optimal Wiener filtering. Experts were asked to manually score short epochs of data. The algorithm was trained to obtain the optimal filter coefficients of a Wiener filter and the optimal detection threshold. Scored and unscored data were then processed with the optimal filter, and events were detected as peaks above threshold. RESULTS: We challenged MOD with EPSP traces in vivo in mice during spatial navigation and EPSC traces in vitro in slices under conditions of enhanced transmitter release. The area under the curve (AUC) of the receiver operating characteristics (ROC) curve was, on average, 0.894 for in vivo and 0.969 for in vitro data sets, indicating high detection accuracy and efficiency. COMPARISON WITH EXISTING METHODS: When benchmarked using a (1 - AUC)-1 metric, MOD outperformed previous methods (template-fit, deconvolution, and Bayesian methods) by an average factor of 3.13 for in vivo data sets, but showed comparable (template-fit, deconvolution) or higher (Bayesian) computational efficacy. CONCLUSIONS: MOD may become an important new tool for large-scale, real-time analysis of synaptic activity.

How connectivity rules and synaptic properties shape the efficacy of pattern separation in the entorhinal cortex-dentate gyrus-CA3 network.

Pattern separation is a fundamental brain computation that converts small differences in input patterns into large differences in output patterns. Several synaptic mechanisms of pattern separation have been proposed, including code expansion, inhibition and plasticity; however, which of these mechanisms play a role in the entorhinal cortex (EC)-dentate gyrus (DG)-CA3 circuit, a classical pattern separation circuit, remains unclear. Here we show that a biologically realistic, full-scale EC-DG-CA3 circuit model, including granule cells (GCs) and parvalbumin-positive inhibitory interneurons (PV+-INs) in the DG, is an efficient pattern separator. Both external gamma-modulated inhibition and internal lateral inhibition mediated by PV+-INs substantially contributed to pattern separation. Both local connectivity and fast signaling at GC-PV+-IN synapses were important for maximum effectiveness. Similarly, mossy fiber synapses with conditional detonator properties contributed to pattern separation. By contrast, perforant path synapses with Hebbian synaptic plasticity and direct EC-CA3 connection shifted the network towards pattern completion. Our results demonstrate that the specific properties of cells and synapses optimize higher-order computations in biological networks and might be useful to improve the deep learning capabilities of technical networks.

Selective Routing of Spatial Information Flow from Input to Output in Hippocampal Granule Cells.

Dentate gyrus granule cells (GCs) connect the entorhinal cortex to the hippocampal CA3 region, but how they process spatial information remains enigmatic. To examine the role of GCs in spatial coding, we measured excitatory postsynaptic potentials (EPSPs) and action potentials (APs) in head-fixed mice running on a linear belt. Intracellular recording from morphologically identified GCs revealed that most cells were active, but activity level varied over a wide range. Whereas only ∼5% of GCs showed spatially tuned spiking, ∼50% received spatially tuned input. Thus, the GC population broadly encodes spatial information, but only a subset relays this information to the CA3 network. Fourier analysis indicated that GCs received conjunctive place-grid-like synaptic input, suggesting code conversion in single neurons. GC firing was correlated with dendritic complexity and intrinsic excitability, but not extrinsic excitatory input or dendritic cable properties. Thus, functional maturation may control input-output transformation and spatial code conversion.

Biosignals, Standards and FHIR - The Way to Go?

BACKGROUND: Standards have become available to share semantically encoded vital parameters from medical devices, as required for example by personal healthcare records. Standardised sharing of biosignal data largely remains open. OBJECTIVES: The goal of this work is to explore available biosignal file format and data exchange standards and profiles, and to conceptualise end-to-end solutions. METHODS: The authors reviewed and discussed available biosignal file format standards with other members of international standards development organisations (SDOs). RESULTS: A raw concept for standards based acquisition, storage, archiving and sharing of biosignals was developed. The GDF format may serve for storing biosignals. Signals can then be shared using FHIR resources and may be stored on FHIR servers or in DICOM archives, with DICOM waveforms as one possible format. CONCLUSION: Currently a group of international SDOs (e.g. HL7, IHE, DICOM, IEEE) is engaged in intensive discussions. This discussion extends existing work that already was adopted by large implementer communities. The concept presented here only reports the current status of the discussion in Austria. The discussion will continue internationally, with results to be expected over the coming years.

Synaptic mechanisms of pattern completion in the hippocampal CA3 network.

The hippocampal CA3 region plays a key role in learning and memory. Recurrent CA3-CA3 synapses are thought to be the subcellular substrate of pattern completion. However, the synaptic mechanisms of this network computation remain enigmatic. To investigate these mechanisms, we combined functional connectivity analysis with network modeling. Simultaneous recording from up to eight CA3 pyramidal neurons revealed that connectivity was sparse, spatially uniform, and highly enriched in disynaptic motifs (reciprocal, convergence, divergence, and chain motifs). Unitary connections were composed of one or two synaptic contacts, suggesting efficient use of postsynaptic space. Real-size modeling indicated that CA3 networks with sparse connectivity, disynaptic motifs, and single-contact connections robustly generated pattern completion. Thus, macro- and microconnectivity contribute to efficient memory storage and retrieval in hippocampal networks.

Stimfit: quantifying electrophysiological data with Python.

Intracellular electrophysiological recordings provide crucial insights into elementary neuronal signals such as action potentials and synaptic currents. Analyzing and interpreting these signals is essential for a quantitative understanding of neuronal information processing, and requires both fast data visualization and ready access to complex analysis routines. To achieve this goal, we have developed Stimfit, a free software package for cellular neurophysiology with a Python scripting interface and a built-in Python shell. The program supports most standard file formats for cellular neurophysiology and other biomedical signals through the Biosig library. To quantify and interpret the activity of single neurons and communication between neurons, the program includes algorithms to characterize the kinetics of presynaptic action potentials and postsynaptic currents, estimate latencies between pre- and postsynaptic events, and detect spontaneously occurring events. We validate and benchmark these algorithms, give estimation errors, and provide sample use cases, showing that Stimfit represents an efficient, accessible and extensible way to accurately analyze and interpret neuronal signals.

Sequential effects in continued visual search: using fixation-related potentials to compare distractor processing before and after target detection.

To search for a target in a complex environment is an everyday behavior that ends with finding the target. When we search for two identical targets, however, we must continue the search after finding the first target and memorize its location. We used fixation-related potentials to investigate the neural correlates of different stages of the search, that is, before and after finding the first target. Having found the first target influenced subsequent distractor processing. Compared to distractor fixations before the first target fixation, a negative shift was observed for three subsequent distractor fixations. These results suggest that processing a target in continued search modulates the brain's response, either transiently by reflecting temporary working memory processes or permanently by reflecting working memory retention.

A deconvolution-based method with high sensitivity and temporal resolution for detection of spontaneous synaptic currents in vitro and in vivo.

Spontaneous postsynaptic currents (PSCs) provide key information about the mechanisms of synaptic transmission and the activity modes of neuronal networks. However, detecting spontaneous PSCs in vitro and in vivo has been challenging, because of the small amplitude, the variable kinetics, and the undefined time of generation of these events. Here, we describe a, to our knowledge, new method for detecting spontaneous synaptic events by deconvolution, using a template that approximates the average time course of spontaneous PSCs. A recorded PSC trace is deconvolved from the template, resulting in a series of delta-like functions. The maxima of these delta-like events are reliably detected, revealing the precise onset times of the spontaneous PSCs. Among all detection methods, the deconvolution-based method has a unique temporal resolution, allowing the detection of individual events in high-frequency bursts. Furthermore, the deconvolution-based method has a high amplitude resolution, because deconvolution can substantially increase the signal/noise ratio. When tested against previously published methods using experimental data, the deconvolution-based method was superior for spontaneous PSCs recorded in vivo. Using the high-resolution deconvolution-based detection algorithm, we show that the frequency of spontaneous excitatory postsynaptic currents in dentate gyrus granule cells is 4.5 times higher in vivo than in vitro.

Review of the BCI Competition IV.

The BCI competition IV stands in the tradition of prior BCI competitions that aim to provide high quality neuroscientific data for open access to the scientific community. As experienced already in prior competitions not only scientists from the narrow field of BCI compete, but scholars with a broad variety of backgrounds and nationalities. They include high specialists as well as students. The goals of all BCI competitions have always been to challenge with respect to novel paradigms and complex data. We report on the following challenges: (1) asynchronous data, (2) synthetic, (3) multi-class continuous data, (4) session-to-session transfer, (5) directionally modulated MEG, (6) finger movements recorded by ECoG. As after past competitions, our hope is that winning entries may enhance the analysis methods of future BCIs.

BioSig: the free and open source software library for biomedical signal processing.

BioSig is an open source software library for biomedical signal processing. The aim of the BioSig project is to foster research in biomedical signal processing by providing free and open source software tools for many different application areas. Some of the areas where BioSig can be employed are neuroinformatics, brain-computer interfaces, neurophysiology, psychology, cardiovascular systems, and sleep research. Moreover, the analysis of biosignals such as the electroencephalogram (EEG), electrocorticogram (ECoG), electrocardiogram (ECG), electrooculogram (EOG), electromyogram (EMG), or respiration signals is a very relevant element of the BioSig project. Specifically, BioSig provides solutions for data acquisition, artifact processing, quality control, feature extraction, classification, modeling, and data visualization, to name a few. In this paper, we highlight several methods to help students and researchers to work more efficiently with biomedical signals.

Recent advances in modeling and analysis of bioelectric and biomagnetic sources.

Determining the centers of electrical activity in the human body and the connectivity between different centers of activity in the brain is an active area of research. To understand brain function and the nature of cardiovascular diseases requires sophisticated methods applicable to non-invasively measured bioelectric and biomagnetic data. As it is difficult to solve for all unknown parameters at once, several strains of data analysis have been developed, each trying to solve a different part of the problem and each requiring a different set of assumptions. Current trends and results from major topics of electro- and magnetoencephalographic data analysis are presented here together with the aim of stimulating research into the unification of the different approaches. The following topics are discussed: source reconstruction using detailed finite element modeling to locate sources deep in the brain; connectivity analysis for the quantification of strength and direction of information flow between activity centers, preferably incorporating an inverse solution; the conflict between the statistical independence assumption of sources and a possible connectivity; the verification and validation of results derived from non-invasively measured data through animal studies and phantom measurements. This list already indicates the benefits of a unified view.

Time Domain Parameters as a feature for EEG-based Brain-Computer Interfaces.

Several feature types have been used with EEG-based Brain-Computer Interfaces. Among the most popular are logarithmic band power estimates with more or less subject-specific optimization of the frequency bands. In this paper we introduce a feature called Time Domain Parameter that is defined by the generalization of the Hjorth parameters. Time Domain Parameters are studied under two different conditions. The first setting is defined when no data from a subject is available. In this condition our results show that Time Domain Parameters outperform all band power features tested with all spatial filters applied. The second setting is the transition from calibration (no feedback) to feedback, in which the frequency content of the signals can change for some subjects. We compare Time Domain Parameters with logarithmic band power in subject-specific bands and show that these features are advantageous in this situation as well.

Robustly estimating the flow direction of information in complex physical systems.

We propose a new measure (phase-slope index) to estimate the direction of information flux in multivariate time series. This measure (a) is insensitive to mixtures of independent sources, (b) gives meaningful results even if the phase spectrum is not linear, and (c) properly weights contributions from different frequencies. These properties are shown in extended simulations and contrasted to Granger causality which yields highly significant false detections for mixtures of independent sources. An application to electroencephalography data (eyes-closed condition) reveals a clear front-to-back information flow.

Toward self-paced brain-computer communication: navigation through virtual worlds.

The self-paced control paradigm enables users to operate brain-computer interfaces (BCI) in a more natural way: no longer is the machine in control of the timing and speed of communication, but rather the user is. This is important to enhance the usability, flexibility, and response time of a BCI. In this work, we show how subjects, after performing cue-based feedback training (smiley paradigm), learned to navigate self-paced through the "freeSpace" virtual environment (VE). Similar to computer games, subjects had the task of picking up items by using the following navigation commands: rotate left, rotate right, and move forward ( three classes). Since the self-paced control paradigm allows subjects to make voluntary decisions on time, type, and duration of mental activity, no cues or routing directives were presented. The BCI was based only on three bipolar electroencephalogram channels and operated by motor imagery. Eye movements (electrooculogram) and electromyographic artifacts were reduced and detected online. The results of three able-bodied subjects are reported and problems emerging from self-paced control are discussed.

Comparison of adaptive features with linear discriminant classifier for Brain computer Interfaces.

Many Brain-computer Interfaces (BCI) use band-power estimates with more or less subject-specific optimization of the frequency bands. However, a number of alternative EEG features do not need to select the frequency bands; estimators for these features have been modified for an adaptive use. The popular band power estimates were compared with Adaptive AutoRegressive parameters, Hjorth, Barlow, Wackermann, Brain-Rate and a new feature type called Time Domain Parameter. The results from 21 subjects show that several features provide an equally good or even better performance, while no subject-specific optimization is needed, and they are also preferable to band power when the most discriminating frequency band of a subject is not known.

Directed cortical information flow during human object recognition: analyzing induced EEG gamma-band responses in brain's source space.

The increase of induced gamma-band responses (iGBRs; oscillations >30 Hz) elicited by familiar (meaningful) objects is well established in electroencephalogram (EEG) research. This frequency-specific change at distinct locations is thought to indicate the dynamic formation of local neuronal assemblies during the activation of cortical object representations. As analytically power increase is just a property of a single location, phase-synchrony was introduced to investigate the formation of large-scale networks between spatially distant brain sites. However, classical phase-synchrony reveals symmetric, pair-wise correlations and is not suited to uncover the directionality of interactions. Here, we investigated the neural mechanism of visual object processing by means of directional coupling analysis going beyond recording sites, but rather assessing the directionality of oscillatory interactions between brain areas directly. This study is the first to identify the directionality of oscillatory brain interactions in source space during human object recognition and suggests that familiar, but not unfamiliar, objects engage widespread reciprocal information flow. Directionality of cortical information-flow was calculated based upon an established Granger-Causality coupling-measure (partial-directed coherence; PDC) using autoregressive modeling. To enable comparison with previous coupling studies lacking directional information, phase-locking analysis was applied, using wavelet-based signal decompositions. Both, autoregressive modeling and wavelet analysis, revealed an augmentation of iGBRs during the presentation of familiar objects relative to unfamiliar controls, which was localized to inferior-temporal, superior-parietal and frontal brain areas by means of distributed source reconstruction. The multivariate analysis of PDC evaluated each possible direction of brain interaction and revealed widespread reciprocal information-transfer during familiar object processing. In contrast, unfamiliar objects entailed a sparse number of only unidirectional connections converging to parietal areas. Considering the directionality of brain interactions, the current results might indicate that successful activation of object representations is realized through reciprocal (feed-forward and feed-backward) information-transfer of oscillatory connections between distant, functionally specific brain areas.

Study of discriminant analysis applied to motor imagery bipolar data.

We present a study of linear, quadratic and regularized discriminant analysis (RDA) applied to motor imagery data of three subjects. The aim of the work was to find out which classifier can separate better these two-class motor imagery data: linear, quadratic or some function in between the linear and quadratic solutions. Discriminant analysis methods were tested with two different feature extraction techniques, adaptive autoregressive parameters and logarithmic band power estimates, which are commonly used in brain-computer interface research. Differences in classification accuracy of the classifiers were found when using different amounts of data; if a small amount was available, the best classifier was linear discriminant analysis (LDA) and if enough data were available all three classifiers performed very similar. This suggests that the effort needed to find regularizing parameters for RDA can be avoided by using LDA.

Analyzing event-related EEG data with multivariate autoregressive parameters.

Methods of spatio-temporal analysis provide important tools for characterizing several dynamic aspects of brain oscillations that are reflected in the human scalp-detected electroencephalogram (EEG). The search to identify the dynamic connectivity of brain signals within different frequency bands, in order to uncover the transient cooperation between different brain sites, converges at the potential of multivariate autoregressive (MVAR) models and their derived parameters. In fact, MVAR parameters provide a whole battery of so-called coupling measures including classic coherence (COH), partial coherence (pCOH), imaginary part of coherence (iCOH), partial-directed coherence (PDC), directed transfer function (DTF), and full frequency directed transfer function (ffDTF). All of these approaches have been developed to quantify the degree of coupling between different EEG recording positions, with the specific aim to characterize the functional interaction between neural populations within the cortex. This work addresses the application of MVAR models to event-related brain processes, including different statistical approaches, and reviews most relevant findings in the expanding field of coupling analysis. Finally, we present several examples of coupling patterns associated with certain types of movement imagery.