Cholinergic modulation supports dynamic switching of resting state networks through selective DMN suppression.

Brain activity during the resting state is widely used to examine brain organization, cognition and alterations in disease states. While it is known that neuromodulation and the state of alertness impact resting-state activity, neural mechanisms behind such modulation of resting-state activity are unknown. In this work, we used a computational model to demonstrate that change in excitability and recurrent connections, due to cholinergic modulation, impacts resting-state activity. The results of such modulation in the model match closely with experimental work on direct cholinergic modulation of Default Mode Network (DMN) in rodents. We further extended our study to the human connectome derived from diffusion-weighted MRI. In human resting-state simulations, an increase in cholinergic input resulted in a brain-wide reduction of functional connectivity. Furthermore, selective cholinergic modulation of DMN closely captured experimentally observed transitions between the baseline resting state and states with suppressed DMN fluctuations associated with attention to external tasks. Our study thus provides insight into potential neural mechanisms for the effects of cholinergic neuromodulation on resting-state activity and its dynamics.

Principal component analysis as an efficient method for capturing multivariate brain signatures of complex disorders-ENIGMA study in people with bipolar disorders and obesity.

Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables.

Global functional connectivity reorganization reflects cognitive processing speed deficits and fatigue in multiple sclerosis.

BACKGROUND AND PURPOSE: Cognitive impairment (CI) in multiple sclerosis (MS) is associated with bidirectional changes in resting-state centrality measures. However, practicable functional magnetic resonance imaging (fMRI) biomarkers of CI are still lacking. The aim of this study was to assess the graph-theory-based degree rank order disruption index (kD) and its association with cognitive processing speed as a marker of CI in patients with MS (PwMS) in a secondary cross-sectional fMRI analysis. METHODS: Differentiation between PwMS and healthy controls (HCs) using kD and its correlation with CI (Symbol Digit Modalities Test) was compared to established imaging biomarkers (regional degree, volumetry, diffusion-weighted imaging, lesion mapping). Additional associations were assessed for fatigue (Fatigue Scale for Motor and Cognitive Functions), gait and global disability. RESULTS: Analysis in 56 PwMS and 58 HCs (35/27 women, median age 45.1/40.5 years) showed lower kD in PwMS than in HCs (median -0.30/-0.06, interquartile range 0.55/0.54; p = 0.009, Mann-Whitney U test), yielding acceptable yet non-superior differentiation (area under curve 0.64). kD and degree in medial prefrontal cortex (MPFC) correlated with CI (kD/MPFC Spearman's ρ = 0.32/-0.45, p = 0.019/0.001, n = 55). kD also explained fatigue (ρ = -0.34, p = 0.010, n = 56) but neither gait nor disability. CONCLUSIONS: kD is a potential biomarker of CI and fatigue warranting further validation.

Longitudinal assessment of ventricular volume trajectories in early-stage schizophrenia: evidence of both enlargement and shrinkage.

BACKGROUND: Lateral ventricular enlargement represents a canonical morphometric finding in chronic patients with schizophrenia; however, longitudinal studies elucidating complex dynamic trajectories of ventricular volume change during critical early disease stages are sparse. METHODS: We measured lateral ventricular volumes in 113 first-episode schizophrenia patients (FES) at baseline visit (11.7 months after illness onset, SD = 12.3) and 128 age- and sex-matched healthy controls (HC) using 3T MRI. MRI was then repeated in both FES and HC one year later. RESULTS: Compared to controls, ventricular enlargement was identified in 18.6% of patients with FES (14.1% annual ventricular volume (VV) increase; 95%CI: 5.4; 33.1). The ventricular expansion correlated with the severity of PANSS-negative symptoms at one-year follow-up (p = 0.0078). Nevertheless, 16.8% of FES showed an opposite pattern of statistically significant ventricular shrinkage during ≈ one-year follow-up (-9.5% annual VV decrease; 95%CI: -23.7; -2.4). There were no differences in sex, illness duration, age of onset, duration of untreated psychosis, body mass index, the incidence of Schneiderian symptoms, or cumulative antipsychotic dose among the patient groups exhibiting ventricular enlargement, shrinkage, or no change in VV. CONCLUSION: Both enlargement and ventricular shrinkage are equally present in the early stages of schizophrenia. The newly discovered early reduction of VV in a subgroup of patients emphasizes the need for further research to understand its mechanisms.

Towards a dynamical understanding of microstate analysis of M/EEG data.

One of the interesting aspects of EEG data is the presence of temporally stable and spatially coherent patterns of activity, known as microstates, which have been linked to various cognitive and clinical phenomena. However, there is still no general agreement on the interpretation of microstate analysis. Various clustering algorithms have been used for microstate computation, and multiple studies suggest that the microstate time series may provide insight into the neural activity of the brain in the resting state. This study addresses two gaps in the literature. Firstly, by applying several state-of-the-art microstate algorithms to a large dataset of EEG recordings, we aim to characterise and describe various microstate algorithms. We demonstrate and discuss why the three "classically" used algorithms ((T)AAHC and modified K-Means) yield virtually the same results, while HMM algorithm generates the most dissimilar results. Secondly, we aim to test the hypothesis that dynamical microstate properties might be, to a large extent, determined by the linear characteristics of the underlying EEG signal, in particular, by the cross-covariance and autocorrelation structure of the EEG data. To this end, we generated a Fourier transform surrogate of the EEG signal to compare microstate properties. Here, we found that these are largely similar, thus hinting that microstate properties depend to a very high degree on the linear covariance and autocorrelation structure of the underlying EEG data. Finally, we treated the EEG data as a vector autoregression process, estimated its parameters, and generated surrogate stationary and linear data from fitted VAR. We observed that such a linear model generates microstates highly comparable to those estimated from real EEG data, supporting the conclusion that a linear EEG model can help with the methodological and clinical interpretation of both static and dynamic human brain microstate properties.

Large-scale network dynamics underlying the first few hundred milliseconds after stimulus presentation: An investigation of visual recognition memory using iEEG.

Recognition memory is the ability to recognize previously encountered objects. Even this relatively simple, yet extremely fast, ability requires the coordinated activity of large-scale brain networks. However, little is known about the sub-second dynamics of these networks. The majority of current studies into large-scale network dynamics is primarily based on imaging techniques suffering from either poor temporal or spatial resolution. We investigated the dynamics of large-scale functional brain networks underlying recognition memory at the millisecond scale. Specifically, we analyzed dynamic effective connectivity from intracranial electroencephalography while epileptic subjects (n = 18) performed a fast visual recognition memory task. Our data-driven investigation using Granger causality and the analysis of communities with the Louvain algorithm spotlighted a dynamic interplay of two large-scale networks associated with successful recognition. The first network involved the right visual ventral stream and bilateral frontal regions. It was characterized by early, predominantly bottom-up information flow peaking at 115 ms. It was followed by the involvement of another network with predominantly top-down connectivity peaking at 220 ms, mainly in the left anterior hemisphere. The transition between these two networks was associated with changes in network topology, evolving from a more segregated to a more integrated state. These results highlight that distinct large-scale brain networks involved in visual recognition memory unfold early and quickly, within the first 300 ms after stimulus onset. Our study extends the current understanding of the rapid network changes during rapid cognitive processes.

Personalized dynamic network models of the human brain as a future tool for planning and optimizing epilepsy therapy.

Epilepsy is a common neurological disorder, with one third of patients not responding to currently available antiepileptic drugs. The proportion of pharmacoresistant epilepsies has remained unchanged for many decades. To cure epilepsy and control seizures requires a paradigm shift in the development of new approaches to epilepsy diagnosis and treatment. Contemporary medicine has benefited from the exponential growth of computational modeling, and the application of network dynamics theory to understanding and treating human brain disorders. In epilepsy, the introduction of these approaches has led to personalized epileptic network modeling that can explore the patient's seizure genesis and predict the functional impact of resection on its individual network's propensity to seize. The application of the dynamic systems approach to neurostimulation therapy of epilepsy allows designing stimulation strategies that consider the patient's seizure dynamics and long-term fluctuations in the stability of their epileptic networks. In this article, we review, in a nontechnical fashion suitable for a broad neuroscientific audience, recent progress in personalized dynamic brain network modeling that is shaping the future approach to the diagnosis and treatment of epilepsy.

Sign patterns symbolization and its use in improved dependence test for complex network inference.

Inferring the dependence structure of complex networks from the observation of the non-linear dynamics of its components is among the common, yet far from resolved challenges faced when studying real-world complex systems. While a range of methods using the ordinal patterns framework has been proposed to particularly tackle the problem of dependence inference in the presence of non-linearity, they come with important restrictions in the scope of their application. Hereby, we introduce the sign patterns as an extension of the ordinal patterns, arising from a more flexible symbolization which is able to encode longer sequences with lower number of symbols. After transforming time series into sequences of sign patterns, we derive improved estimates for statistical quantities by considering necessary constraints on the probabilities of occurrence of combinations of symbols in a symbolic process with prohibited transitions. We utilize these to design an asymptotic chi-squared test to evaluate dependence between two time series and then apply it to the construction of climate networks, illustrating that the developed method can capture both linear and non-linear dependences, while avoiding bias present in the naive application of the often used Pearson correlation coefficient or mutual information.

Perturbations both trigger and delay seizures due to generic properties of slow-fast relaxation oscillators.

The mechanisms underlying the emergence of seizures are one of the most important unresolved issues in epilepsy research. In this paper, we study how perturbations, exogenous or endogenous, may promote or delay seizure emergence. To this aim, due to the increasingly adopted view of epileptic dynamics in terms of slow-fast systems, we perform a theoretical analysis of the phase response of a generic relaxation oscillator. As relaxation oscillators are effectively bistable systems at the fast time scale, it is intuitive that perturbations of the non-seizing state with a suitable direction and amplitude may cause an immediate transition to seizure. By contrast, and perhaps less intuitively, smaller amplitude perturbations have been found to delay the spontaneous seizure initiation. By studying the isochrons of relaxation oscillators, we show that this is a generic phenomenon, with the size of such delay depending on the slow flow component. Therefore, depending on perturbation amplitudes, frequency and timing, a train of perturbations causes an occurrence increase, decrease or complete suppression of seizures. This dependence lends itself to analysis and mechanistic understanding through methods outlined in this paper. We illustrate this methodology by computing the isochrons, phase response curves and the response to perturbations in several epileptic models possessing different slow vector fields. While our theoretical results are applicable to any planar relaxation oscillator, in the motivating context of epilepsy they elucidate mechanisms of triggering and abating seizures, thus suggesting stimulation strategies with effects ranging from mere delaying to full suppression of seizures.

Assessing serial dependence in ordinal patterns processes using chi-squared tests with application to EEG data analysis.

We extend Elsinger's work on chi-squared tests for independence using ordinal patterns and investigate the general class of m-dependent ordinal patterns processes, to which belong ordinal patterns processes derived from random walk, white noise, and moving average processes. We describe chi-squared asymptotically distributed statistics for such processes that take into account necessary constraints on ordinal patterns probabilities and propose a test for m-dependence, with which we are able to quantify the range of serial dependence in a process. We apply the test to epilepsy electroencephalography time series data and observe shorter m-dependence associated with seizures, suggesting that the range of serial dependence decreases during those events.

Promises and pitfalls of topological data analysis for brain connectivity analysis.

Developing sensitive and reliable methods to distinguish normal and abnormal brain states is a key neuroscientific challenge. Topological Data Analysis, despite its relative novelty, already generated many promising applications, including in neuroscience. We conjecture its prominent tool of persistent homology may benefit from going beyond analysing structural and functional connectivity to effective connectivity graphs capturing the direct causal interactions or information flows. Therefore, we assess the potential of persistent homology to directed brain network analysis by testing its discriminatory power in two distinctive examples of disease-related brain connectivity alterations: epilepsy and schizophrenia. We estimate connectivity from functional magnetic resonance imaging and electrophysiology data, employ Persistent Homology and quantify its ability to distinguish healthy from diseased brain states by applying a support vector machine to features quantifying persistent homology structure. We show how this novel approach compares to classification using standard undirected approaches and original connectivity matrices. In the schizophrenia classification, topological data analysis generally performs close to random, while classifications from raw connectivity perform substantially better; potentially due to topographical, rather than topological, specificity of the differences. In the easier task of seizure discrimination from scalp electroencephalography data, classification based on persistent homology features generally reached comparable performance to using raw connectivity, albeit with typically smaller accuracies obtained for the directed (effective) connectivity compared to the undirected (functional) connectivity. Specific applications for topological data analysis may open when direct comparison of connectivity matrices is unsuitable - such as for intracranial electrophysiology with individual number and location of measurements. While standard homology performed overall better than directed homology, this could be due to notorious technical problems of accurate effective connectivity estimation.

Long-term seizure dynamics are determined by the nature of seizures and the mutual interactions between them.

The seemingly random and unpredictable nature of seizures is a major debilitating factor for people with epilepsy. An increasing body of evidence demonstrates that the epileptic brain exhibits long-term fluctuations in seizure susceptibility, and seizure emergence seems to be a consequence of processes operating over multiple temporal scales. A deeper insight into the mechanisms responsible for long-term seizure fluctuations may provide important information for understanding the complex nature of seizure genesis. In this study, we explored the long-term dynamics of seizures in the tetanus toxin model of temporal lobe epilepsy. The results demonstrate the existence of long-term fluctuations in seizure probability, where seizures form clusters in time and are then followed by seizure-free periods. Within each cluster, seizure distribution is non-Poissonian, as demonstrated by the progressively increasing inter-seizure interval (ISI), which marks the approaching cluster termination. The lengthening of ISIs is paralleled by: increasing behavioral seizure severity, the occurrence of convulsive seizures, recruitment of extra-hippocampal structures and the spread of electrographic epileptiform activity outside of the limbic system. The results suggest that repeated non-convulsive seizures obey the 'seizures-beget-seizures' principle, leading to the occurrence of convulsive seizures, which decrease the probability of a subsequent seizure and, thus, increase the following ISI. The cumulative effect of repeated convulsive seizures leads to cluster termination, followed by a long inter-cluster period. We propose that seizures themselves are an endogenous factor that contributes to long-term fluctuations in seizure susceptibility and their mutual interaction determines the future evolution of disease activity.

Causality in Reversed Time Series: Reversed or Conserved?

The inference of causal relations between observable phenomena is paramount across scientific disciplines; however, the means for such enterprise without experimental manipulation are limited. A commonly applied principle is that of the cause preceding and predicting the effect, taking into account other circumstances. Intuitively, when the temporal order of events is reverted, one would expect the cause and effect to apparently switch roles. This was previously demonstrated in bivariate linear systems and used in design of improved causal inference scores, while such behaviour in linear systems has been put in contrast with nonlinear chaotic systems where the inferred causal direction appears unchanged under time reversal. The presented work explores the conditions under which the causal reversal happens-either perfectly, approximately, or not at all-using theoretical analysis, low-dimensional examples, and network simulations, focusing on the simplified yet illustrative linear vector autoregressive process of order one. We start with a theoretical analysis that demonstrates that a perfect coupling reversal under time reversal occurs only under very specific conditions, followed up by constructing low-dimensional examples where indeed the dominant causal direction is even conserved rather than reversed. Finally, simulations of random as well as realistically motivated network coupling patterns from brain and climate show that level of coupling reversal and conservation can be well predicted by asymmetry and anormality indices introduced based on the theoretical analysis of the problem. The consequences for causal inference are discussed.

Typicality of functional connectivity robustly captures motion artifacts in rs-fMRI across datasets, atlases, and preprocessing pipelines.

Functional connectivity analysis of resting-state fMRI data has recently become one of the most common approaches to characterizing individual brain function. It has been widely suggested that the functional connectivity matrix is a useful approximate representation of the brain's connectivity, potentially providing behaviorally or clinically relevant markers. However, functional connectivity estimates are known to be detrimentally affected by various artifacts, including those due to in-scanner head motion. Moreover, as individual functional connections generally covary only very weakly with head motion estimates, motion influence is difficult to quantify robustly, and prone to be neglected in practice. Although the use of individual estimates of head motion, or group-level correlation of motion and functional connectivity has been suggested, a sufficiently sensitive measure of individual functional connectivity quality has not yet been established. We propose a new intuitive summary index, Typicality of Functional Connectivity, to capture deviations from standard brain functional connectivity patterns. In a resting-state fMRI dataset of 245 healthy subjects, this measure was significantly correlated with individual head motion metrics. The results were further robustly reproduced across atlas granularity, preprocessing options, and other datasets, including 1,081 subjects from the Human Connectome Project. In principle, Typicality of Functional Connectivity should be sensitive also to other types of artifacts, processing errors, and possibly also brain pathology, allowing extensive use in data quality screening and quantification in functional connectivity studies as well as methodological investigations.

Causal network discovery by iterative conditioning: Comparison of algorithms.

Estimating causal interactions in complex dynamical systems is an important problem encountered in many fields of current science. While a theoretical solution for detecting the causal interactions has been previously formulated in the framework of prediction improvement, it generally requires the computation of high-dimensional information functionals-a situation invoking the curse of dimensionality with increasing network size. Recently, several methods have been proposed to alleviate this problem, based on iterative procedures for the assessment of conditional (in)dependences. In the current work, we bring a comparison of several such prominent approaches. This is done both by theoretical comparison of the algorithms using a formulation in a common framework and by numerical simulations including realistic complex coupling patterns. The theoretical analysis highlights the key similarities and differences between the algorithms, hinting on their comparative strengths and weaknesses. The method assumptions and specific properties such as false positive control and order-dependence are discussed. Numerical simulations suggest that while the accuracy of most of the algorithms is almost indistinguishable, there are substantial differences in their computational demands, ranging theoretically from polynomial to exponential complexity and leading to substantial differences in computation time in realistic scenarios depending on the density and size of networks. Based on the analysis of the algorithms and numerical simulations, we propose a hybrid approach providing competitive accuracy with improved computational efficiency.

FitzHugh-Nagumo oscillators on complex networks mimic epileptic-seizure-related synchronization phenomena.

We study patterns of partial synchronization in a network of FitzHugh-Nagumo oscillators with empirical structural connectivity measured in human subjects. We report the spontaneous occurrence of synchronization phenomena that closely resemble the ones seen during epileptic seizures in humans. In order to obtain deeper insights into the interplay between dynamics and network topology, we perform long-term simulations of oscillatory dynamics on different paradigmatic network structures: random networks, regular nonlocally coupled ring networks, ring networks with fractal connectivities, and small-world networks with various rewiring probability. Among these networks, a small-world network with intermediate rewiring probability best mimics the findings achieved with the simulations using the empirical structural connectivity. For the other network topologies, either no spontaneously occurring epileptic-seizure-related synchronization phenomena can be observed in the simulated dynamics, or the overall degree of synchronization remains high throughout the simulation. This indicates that a topology with some balance between regularity and randomness favors the self-initiation and self-termination of episodes of seizure-like strong synchronization.

Machine learning classification of first-episode schizophrenia spectrum disorders and controls using whole brain white matter fractional anisotropy.

BACKGROUND: Early diagnosis of schizophrenia could improve the outcome of the illness. Unlike classical between-group comparisons, machine learning can identify subtle disease patterns on a single subject level, which could help realize the potential of MRI in establishing a psychiatric diagnosis. Machine learning has previously been predominantly tested on gray-matter structural or functional MRI data. In this paper we used a machine learning classifier to differentiate patients with a first episode of schizophrenia-spectrum disorder (FES) from healthy controls using diffusion tensor imaging. METHODS: We applied linear support-vector machine (SVM) and traditional tract based spatial statistics between group analyses to brain fractional anisotropy (FA) data from 77 FES and 77 age and sex matched healthy controls. We also evaluated the effects of medication and symptoms on the SVM classification. RESULTS: The SVM distinguished between patients and controls with significant accuracy of 62.34% (p = 0.005). Participants with FES showed widespread FA reductions relative to controls in a large cluster (N = 56,647 voxels, corrected p = 0.002). The white matter regions, which contributed to the correct identification of participants with FES, overlapped with the regions, which showed lower FA in patients relative to controls. There was no association between the classification performance and medication or symptoms. CONCLUSIONS: Our results provide a proof of concept that SVM might help differentiate FES patients early in the course of illness from healthy controls using white-matter fractional anisotropy. As there was no effect of medications or symptoms, the SVM classification seemed to be based on trait rather than state markers and appeared to capture the lower FA in FES participants relative to controls.

Nonlinearity in stock networks.

Stock networks, constructed from stock price time series, are a well-established tool for the characterization of complex behavior in stock markets. Following Mantegna's seminal paper, the linear Pearson's correlation coefficient between pairs of stocks has been the usual way to determine network edges. Recently, possible effects of nonlinearity on the graph-theoretical properties of such networks have been demonstrated when using nonlinear measures such as mutual information instead of linear correlation. In this paper, we quantitatively characterize the nonlinearity in stock time series and the effect it has on stock network properties. This is achieved by a systematic multi-step approach that allows us to quantify the nonlinearity of coupling; correct its effects wherever it is caused by simple univariate non-Gaussianity; potentially localize in space and time any remaining strong sources of this nonlinearity; and, finally, study the effect nonlinearity has on global network properties. By applying this multi-step approach to stocks included in three prominent indices (New York Stock Exchange 100, Financial Times Stock Exchange 100, and Standard & Poor 500), we establish that the apparent nonlinearity that has been observed is largely due to univariate non-Gaussianity. Furthermore, strong nonstationarity in a few specific stocks may play a role. In particular, the sharp decrease in some stocks during the global financial crisis of 2008 gives rise to apparent nonlinear dependencies among stocks.

Chimera states in brain networks: Empirical neural vs. modular fractal connectivity.

Complex spatiotemporal patterns, called chimera states, consist of coexisting coherent and incoherent domains and can be observed in networks of coupled oscillators. The interplay of synchrony and asynchrony in complex brain networks is an important aspect in studies of both the brain function and disease. We analyse the collective dynamics of FitzHugh-Nagumo neurons in complex networks motivated by its potential application to epileptology and epilepsy surgery. We compare two topologies: an empirical structural neural connectivity derived from diffusion-weighted magnetic resonance imaging and a mathematically constructed network with modular fractal connectivity. We analyse the properties of chimeras and partially synchronized states and obtain regions of their stability in the parameter planes. Furthermore, we qualitatively simulate the dynamics of epileptic seizures and study the influence of the removal of nodes on the network synchronizability, which can be useful for applications to epileptic surgery.

Smooth information flow in temperature climate network reflects mass transport.

A directed climate network is constructed by Granger causality analysis of air temperature time series from a regular grid covering the whole Earth. Using winner-takes-all network thresholding approach, a structure of a smooth information flow is revealed, hidden to previous studies. The relevance of this observation is confirmed by comparison with the air mass transfer defined by the wind field. Their close relation illustrates that although the information transferred due to the causal influence is not a physical quantity, the information transfer is tied to the transfer of mass and energy.