Whenever neurophysiological data, such as EEG data are recorded, occurring artifacts pose an essential problem. This study addresses this issue by using imputation methods whereby whole data sets of a trial, or distinct electrodes, are not removed from the analysis of the EEG data but are replaced. We present different imputation strategies but use only two which are optimal for this particular study; predictive mean matching and data augmentation. The study addresses the as of yet unresolved question if the quality of derived brain functional networks is improved by imputation methods compared to traditional exclusion techniques which drop data, and will finally assesses the differences between the two imputation methods themselves used here. In this study, EEG data from a study evaluating dyslexia-specific therapy on a neurophysiological level were used to investigate imputation strategies in research of cortical interaction. Several recorded values were artificially declared as 'missing'. This enables the comparison of networks based on the complete data set without any missing values (pseudo ground truth) and those derived from imputation approaches in a realistic situation of disturbed data. Functional connectivity was quantified by time-variant partial directed coherence, providing a directed, temporally varying and frequency-selective connectivity measure. Based on the comparison between pseudo ground truth and networks of data with excluded missing values and data with imputed values, we found that any imputation strategy is preferable to the entire exclusion of data. The study also showed that the choice of the applied imputation algorithm impacts the resulting networks only marginally.

Identification of module structure in brain functional networks is a promising way to obtain novel insights into neural information processing, as modules correspond to delineated brain regions in which interactions are strongly increased. Tracking of network modules in time-varying brain functional networks is not yet commonly considered in neuroscience despite its potential for gaining an understanding of the time evolution of functional interaction patterns and associated changing degrees of functional segregation and integration. We introduce a general computational framework for extracting consensus partitions from defined time windows in sequences of weighted directed edge-complete networks and show how the temporal reorganization of the module structure can be tracked and visualized. Part of the framework is a new approach for computing edge weight thresholds for individual networks based on multiobjective optimization of module structure quality criteria as well as an approach for matching modules across time steps. By testing our framework using synthetic network sequences and applying it to brain functional networks computed from electroencephalographic recordings of healthy subjects that were exposed to a major balance perturbation, we demonstrate the framework's potential for gaining meaningful insights into dynamic brain function in the form of evolving network modules. The precise chronology of the neural processing inferred with our framework and its interpretation helps to improve the currently incomplete understanding of the cortical contribution for the compensation of such balance perturbations.

Background. The quantification of directed interactions within the brain and in particular their time courses are of highest interest for the investigation of epilepsy. The underlying coordinated neuronal mass activities span functionally diverse and structurally widely distributed cortical and subcortical brain regions, i.e. dynamic, distributed epileptic network can be assumed possibly not fitting in the concept of linearity. Consequently, nonlinear, time-variant, and directed connectivity and synchronization analysis could be helpful to understand processes contributing to the seizure onset and propagation.Methods. The nonlinear convergent cross mapping (CCM) quantifies directed interactions between time series by using nonlinear state space reconstruction. CCM is applied to the EEG of 18 children with temporal lobe epilepsy (TLE), i.e. directed interactions within EEG activity and within specific components of EEG activity (delta-activity and alpha-activity) are investigated. Linear time-variant multivariate AR modeling was performed for these data to test for subsequent applications of linear AR-based connectivity measures.Results. Linear MVAR models proved to be inappropriate for our data. Time-varying application of CCM revealed that statistically significant nonlinear interactions within the EEG activity and within specific components of the EEG exist in the preictal, ictal, and postictal periods. Distinct time courses of such interactions and differences in the time pattern of interactions occurring in the different components of EEG activity that we investigated discovered the high complexity of the underlying processes. No distinct results could be found concerning the presumed directionalities of interactions. Statistical relevant interactions were quantified by bootstrapping and surrogate data approach.Conclusion. Advanced nonlinear CCM approach was able to uncover time pattern of nonlinear interactions thereby possibly contributing to the further understanding of complex behavior of the brain during TLE. Our investigation may provide deeper insight into physiological state of complex networks, e.g. during the development of an epileptic seizure or the recovery in the postictal state.

Balance control is a fundamental component of human every day motor activities such as standing or walking, and its impairment is associated with an increased risk of falling. However, in humans the exact neurobiological mechanisms underlying balance control are still unclear. Specifically, although previous studies have identified a number of cortical regions that become significantly activated during real or imagined balancing, the interactions within and between the relevant cortical regions remain to be investigated. The working hypothesis of this study is that cortical networks contribute to an optimization of balance control, and that this contribution can be revealed by partial directed coherence—a time-variant, frequency-selective and directed functional connectivity analysis tool. Electroencephalographic activity was recorded in 37 subjects during single-leg balancing on a stable as well as an unstable surface. Results of this study show that in the transition from balancing on a stable surface to an unstable surface, two topographically delimitable connectivity networks (weighted directed networks) are established; one associated with the alpha and one with the theta frequency band. The theta network sequence can be described as a set of subnetworks (modules) comprising the frontal, central and parietal cortex with individual temporal and spatial developments within and between those modules. In the alpha network, the occipital electrodes O1 and O2 act as a source, and the interactions propagate predominantly in the directions from occipital to parietal and to centro-parietal areas. These important findings indicate that balance control is supported by at least two functional cortical networks.

The investigation of effective connectivity is one of the major topics in computational neuroscience to understand the interaction between spatially distributed neuronal units of the brain. Thus, a wide variety of methods has been developed during the last decades to investigate functional and effective connectivity in multivariate systems. Their spectrum ranges from model-based to model-free approaches with a clear separation into time and frequency range methods. We present in this simulation study a novel time domain approach based on Granger's principle of predictability, which allows frequency-selective considerations of directed interactions. It is based on a comparison of prediction errors of multivariate autoregressive models fitted to systematically modified time series. These modifications are based on signal decompositions, which enable a targeted cancellation of specific signal components with specific spectral properties. Depending on the embedded signal decomposition method, a frequency-selective or data-driven signal-adaptive Granger Causality Index may be derived.

The connectivity analysis of spatially highly resolved data results in networks comprising an immense number of nodes and edges which makes it hard or even impossible to investigate the high-dimensional (HD) network as a whole. A solution to this problem is offered by a connectivity-based segmentation of the HD networks into subsets of functionally similar nodes (network modules) that exhibit pronounced interaction. However, an investigation of the results at group level is problematic as identified modules are not assigned to each other across different subjects. In this work, we propose a rearrangement of the subject-specific networks into an integrative tensor which is subsequently decomposed into additive factors. This reorganization provides subject-independent networks together with subject-specific loadings enabling a group-wide segmentation of the resulting networks at the large scale.

Detecting changes of spatially high-resolution functional connectivity patterns in the brain is crucial for improving the fundamental understanding of brain function in both health and disease, yet still poses one of the biggest challenges in computational neuroscience. Currently, classical multivariate Granger Causality analyses of directed interactions between single process components in coupled systems are commonly restricted to spatially low- dimensional data, which requires a pre-selection or aggregation of time series as a preprocessing step. In this paper we propose a new fully multivariate Granger Causality approach with embedded dimension reduction that makes it possible to obtain a representation of functional connectivity for spatially high-dimensional data. The resulting functional connectivity networks may consist of several thousand vertices and thus contain more detailed information compared to connectivity networks obtained from approaches based on particular regions of interest. Our large scale Granger Causality approach is applied to synthetic and resting state fMRI data with a focus on how well network community structure, which represents a functional segmentation of the network, is preserved. It is demonstrated that a number of different community detection algorithms, which utilize a variety of algorithmic strategies and exploit topological features differently, reveal meaningful information on the underlying network module structure.

This article is part of a For-Discussion-Section of Methods of Information in Medicine about the paper "Computational Electrocardiography: Revisiting Holter ECG Monitoring" written by Thomas M. Deserno and Nikolaus Marx. It is introduced by an editorial. This article contains the combined commentaries invited to independently comment on the paper of Deserno and Marx. In subsequent issues the discussion can continue through letters to the editor.

A controversy exists on photic driving in the human visual cortex evoked by intermittent photic stimulation. Frequency entrainment and resonance phenomena are reported for frequencies higher than 12 Hz in some studies while missing in others. We hypothesized that this might be due to different experimental conditions, since both high and low intensity light stimulation were used. However, most studies do not report radiometric measurements, which makes it impossible to categorize the stimulation according to photopic, mesopic, and scotopic vision. Low intensity light stimulation might lead to scotopic vision, where rod perception dominates. In this study, we investigated photic driving for rod-dominated visual input under scotopic conditions. Twelve healthy volunteers were stimulated with low intensity light flashes at 20 stimulation frequencies, leading to rod activation only. The frequencies were multiples of the individual alpha frequency (α) of each volunteer in the range from 0.40 to 2.30(∗)α. Three hundred and six-channel whole head magnetoencephalography recordings were analyzed in time, frequency, and spatiotemporal domains with the Topographic Matching Pursuit algorithm. We found resonance phenomena and frequency entrainment for stimulations at or close to the individual alpha frequency (0.90-1.10(∗)α) and half of the alpha frequency (0.40-0.55(∗)α). No signs of resonance and frequency entrainment phenomena were revealed around 2.00(∗)α. Instead, on-responses at the beginning and off-responses at the end of each stimulation train were observed for the first time in a photic driving experiment at frequencies of 1.30-2.30(∗)α, indicating that the flicker fusion threshold was reached. All results, the resonance and entrainment as well as the fusion effects, provide evidence for rod-dominated photic driving in the visual cortex.

We address the correspondence problem which arises when applying empirical mode decomposition (EMD) to multi-trial and multi-subject data. EMD decomposes a signal into a set of narrow-band components named intrinsic mode functions (IMFs). The number of IMFs and their signal properties can be different between trials, channels and subjects. In order to assign IMFs with similar characteristics to each other, we compare two assignment methods, unbalanced assignment and k-cardinality assignment and two clustering algorithms, namely hierarchical clustering and density-based spatial clustering of applications with noise based on heart rate variability data of children with temporal lobe epilepsy.

Objective: Epileptic seizure activity influences the autonomic nervous system (ANS) in different ways. Heart rate variability (HRV) is used as indicator for alterations of the ANS. It was shown that linear, nondirected interactions between HRV and EEG activity before, during, and after epileptic seizure occur. Accordingly, investigations of directed nonlinear interactions are logical steps to provide, e.g., deeper insight into the development of seizure onsets. Methods: Convergent cross mapping (CCM) investigates nonlinear, directed interactions between time series by using nonlinear state space reconstruction. CCM is applied to simulated and clinically relevant data, i.e., interactions between HRV and specific EEG components of children with temporal lobe epilepsy (TLE). In addition, time-variant multivariate Autoregressive model (AR)-based estimation of partial directed coherence (PDC) was performed for the same data. Results: Influence of estimation parameters and time-varying behavior of CCM estimation could be demonstrated by means of simulated data. AR-based estimation of PDC failed for the investigation of our clinical data. Time-varying interval-based application of CCM on these data revealed directed interactions between HRV and delta-related EEG activity. Interactions between HRV and alpha-related EEG activity were visible but less pronounced. EEG components mainly drive HRV. The interaction pattern and directionality clearly changed with onset of seizure. Statistical relevant interactions were quantified by bootstrapping and surrogate data approach. Conclusion and Significance: In contrast to AR-based estimation of PDC CCM was able to reveal time-courses and frequency-selective views of nonlinear interactions for the further understanding of complex interactions between the epileptic network and the ANS in children with TLE.

In neuroscience, data are typically generated from neural network activity. Complex interactions between measured time series are involved, and nothing or only little is known about the underlying dynamic system. Convergent Cross Mapping (CCM) provides the possibility to investigate nonlinear causal interactions between time series by using nonlinear state space reconstruction. Aim of this study is to investigate the general applicability, and to show potentials and limitation of CCM. Influence of estimation parameters could be demonstrated by means of simulated data, whereas interval-based application of CCM on real data could be adapted for the investigation of interactions between heart rate and specific EEG components of children with temporal lobe epilepsy.

Clinical electroencephalographic (EEG) data are often contaminated by muscle and eye movement artefacts that can strongly influence the following analysis. Two existing methods (Independent Component Analysis and Robust Artefact Removal) used for the rejection of artefacts are applied to EEG data from epileptic patients. A comparison between the methods and a discussion on the results are made.

Spatially high resolved neurophysiological data commonly pose a computational and analytical problem for the identification of functional networks in the human brain. We introduce a multivariate linear Granger Causality approach with an embedded dimension reduction that enables the computation of brain networks at the large scale. In order to grasp the information about connectivity patterns contained in the resulting high-dimensional directed networks, we furthermore propose the inclusion of module detection methods from network theory that can help to identify functionally associated brain areas. As a proof of concept, the methodology is verified by means of synthetic data with known ground truth module properties. Resting state fMRI data are used to demonstrate the applicability and benefit in the case of clinical data.

Summary Objectives: Empirical mode decomposition (EMD) is a frequently used signal processing approach which adaptively decomposes a signal into a set of narrow-band components known as intrinsic mode functions (IMFs). For multi-trial, multivariate (multiple simultaneous recordings), and multi-subject analyses the number and signal properties of the IMFs can deviate from each other between trials, channels and subjects. A further processing of IMFs, e.g. a simple ensemble averaging, should determine which IMFs of one signal correspond to IMFs from another signal. When the signal properties have similar characteristics, the IMFs are assigned to each other. This problem is known as correspondence problem. Methods: From the mathematical point of view, in some cases the correspondence problem can be transformed into an assignment problem which can be solved e.g. by the Kuhn-Munkres algorithm (KMA) by which a minimal cost matching can be found. We use the KMA for solving classic assignment problems, i.e. the pairwise correspondence between two sets of IMFs of equal cardinalities, and for pairwise correspondences between two sets of IMFs with different cardinalities representing an unbalanced assignment problem which is a special case of the k-cardinality assignment problem. Results: A KMA-based approach to solve the correspondence problem was tested by using simulated, heart rate variability (HRV), and EEG data. The KMA-based results of HRV decomposition are compared with those obtained from a hierarchical cluster analysis (state-of-the-art). The major difference between the two approaches is that there is a more consistent assignment pattern using KMA. Integrating KMA into complex analysis concepts enables a comprehensive exploitation of the key advantages of the EMD. This can be demonstrated by non-linear analysis of HRV-related IMFs and by an EMD-based cross-frequency coupling analysis of the EEG data. Conclusions: The successful application to HRV and EEG analysis demonstrates that our solutions can be used for automated EMD-based processing concepts for biomedical signals.

In science and engineering mathematical modeling serves as a tool for the understanding of processes and systems and as a testing bed for several hypotheses, e.g., concerning the testing (prediction) of functional limits by simulations. A brief overview of current modeling strategies in brain research is given, spatial scales ranging from single neuron to large scale activity of and between brain regions are considered. The models are mainly time-invariant. Three time-variant modeling strategies, which enable a model-based signal analysis, are described and applied to large scale signals. The first is derived from adaptive filter theory and covers linear system and linear as well as nonlinear process models. The second is based on modeled brain source signals, i.e., the inverse problem must be solved. The third strategy consists of a generalization of Dynamic Causal Modeling (DCM); DCM is frequently used for analysis of directed interactions between brain structures. Examples are derived from neonatal electroencephalography (EEG) monitoring of preterm and fullterm newborns. A further example is based on high-density recordings of event-related potentials (ERPs) and shows the combination of a time-variant ERP-based source model, as a part of a realistic head model, with a multivariate process model to analyze the time evolution of interactions between source processes before and during the execution of a complex motoric task. In two other examples hemodynamic signals (functional magnetic resonance imaging-fMRI) are utilized for analysis of interactions between brain regions, where nonlinear, multivariate models are used.

Objective: Principle aim of this study is to investigate the performance of a matching pursuit (MP)-based bispectral analysis in the detection and quantification of quadratic phase couplings (QPC) in biomedical signals. Nonlinear approaches such as time-variant bispectral analysis are able to provide information about phase relations between oscillatory signal components. Methods: Time-variant QPC analysis is commonly performed using Gabor transform (GT) or Morlet wavelet transform (MWT), and is affected by either constant or frequency-dependent time-frequency resolution (TFR). The matched Gabor transform (MGT), which emerges from the incorporation of GT into MP, can overcome this obstacle by providing a complex time-frequency plane with an individually tailored TFR for each transient oscillatory component. QPC analysis was performed by MGT, and MWT was used as the state-of-the-art method for comparison. Results: Results were demonstrated using simulated data, which present the general case of QPC, and biomedical benchmark data with a priori knowledge about specific signal components. HRV of children during temporal lobe epilepsy and EEG during burst-interburst pattern of neonates during quiet sleep were used for the biomedical signal analysis to investigate the two main areas of biomedical signal analysis: The cardiovascular-cardiorespiratory system and neurophysiological brain activities, respectively. Simulations were able to show the applicability and reliability of the MGT for bispectral analysis. HRV and EEG analysis demonstrate the general validity of the MGT for QPC detection by quantifying statistically significant time patterns of QPC. Conclusion and Significance: Results confirm that MGT-based bispectral analysis provides significant benefits for the analysis of QPC in biomedical signals.

Objectives: Empirical mode decomposition (EMD) is a frequently used signal processing approach which adaptively decomposes a signal into a set of narrow-band components known as intrinsic mode functions (IMFs). For multi-trial, multivariate (multiple simultaneous recordings), and multi-subject analyses the number and signal properties of the IMFs can deviate from each other between trials, channels and subjects. A further processing of IMFs, e.g. a simple ensemble averaging, should determine which IMFs of one signal correspond to IMFs from another signal. When the signal properties have similar characteristics, the IMFs are assigned to each other. This problem is known as correspondence problem. Methods: From the mathematical point of view, in some cases the correspondence problem can be transformed into an assignment problem which can be solved e.g. by the Kuhn-Munkres algorithm (KMA) by which a minimal cost matching can be found. We use the KMA for solving classic assignment problems, i.e. the pairwise correspondence between two sets of IMFs of equal cardinalities, and for pairwise correspondences between two sets of IMFs with different cardinalities representing an unbalanced assignment problem which is a special case of the k-cardinality assignment problem. Results:A KMA-based approach to solve the correspondence problem was tested by using simulated, heart rate variability (HRV), and EEG data. The KMA-based results of HRV decomposition are compared with those obtained from a hierarchical cluster analysis (state-of-the-art). The major difference between the two approaches is that there is a more consistent assignment pattern using KMA. Integrating KMA into complex analysis concepts enables a comprehensive exploitation of the key advantages of the EMD. This can be demonstrated by non-linear analysis of HRV-related IMFs and by an EMD-based cross-frequency coupling analysis of the EEG data. Conclusions: The successful application to HRV and EEG analysis demonstrates that our solutions can be used for automated EMD-based processing concepts for biomedical signals.