Resting-state functional brain imaging studies of network connectivity have long assumed that functional connections are stationary on the timescale of a typical scan. Interest in moving beyond this ...simplifying assumption has emerged only recently. The great hope is that training the right lens on time-varying properties of whole-brain network connectivity will shed additional light on previously concealed brain activation patterns characteristic of serious neurological or psychiatric disorders. We present evidence that multiple explicitly dynamical properties of time-varying whole-brain network connectivity are strongly associated with schizophrenia, a complex mental illness whose symptomatic presentation can vary enormously across subjects. As with so much brain-imaging research, a central challenge for dynamic network connectivity lies in determining transformations of the data that both reduce its dimensionality and expose features that are strongly predictive of important population characteristics. Our paper introduces an elegant, simple method of reducing and organizing data around which a large constellation of mutually informative and intuitive dynamical analyses can be performed. This framework combines a discrete multidimensional data-driven representation of connectivity space with four core dynamism measures computed from large-scale properties of each subject's trajectory, ie., properties not identifiable with any specific moment in time and therefore reasonable to employ in settings lacking inter-subject time-alignment, such as resting-state functional imaging studies. Our analysis exposes pronounced differences between schizophrenia patients (Nsz = 151) and healthy controls (Nhc = 163). Time-varying whole-brain network connectivity patterns are found to be markedly less dynamically active in schizophrenia patients, an effect that is even more pronounced in patients with high levels of hallucinatory behavior. To the best of our knowledge this is the first demonstration that high-level dynamic properties of whole-brain connectivity, generic enough to be commensurable under many decompositions of time-varying connectivity data, exhibit robust and systematic differences between schizophrenia patients and healthy controls.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The past few years have seen an emergence of approaches that leverage temporal changes in whole-brain patterns of functional connectivity (the chronnectome). In this chronnectome study, we ...investigate the replicability of the human brain's inter-regional coupling dynamics during rest by evaluating two different dynamic functional network connectivity (dFNC) analysis frameworks using 7 500 functional magnetic resonance imaging (fMRI) datasets. To quantify the extent to which the emergent functional connectivity (FC) patterns are reproducible, we characterize the temporal dynamics by deriving several summary measures across multiple large, independent age-matched samples. Reproducibility was demonstrated through the existence of basic connectivity patterns (FC states) amidst an ensemble of inter-regional connections. Furthermore, application of the methods to conservatively configured (statistically stationary, linear and Gaussian) surrogate datasets revealed that some of the studied state summary measures were indeed statistically significant and also suggested that this class of null model did not explain the fMRI data fully. This extensive testing of reproducibility of similarity statistics also suggests that the estimated FC states are robust against variation in data quality, analysis, grouping, and decomposition methods. We conclude that future investigations probing the functional and neurophysiological relevance of time-varying connectivity assume critical importance.
•Replicability in dynamic functional connectivity state measures was investigated.•Twenty-eight samples each with two hundred and fifty rest-fMRI datasets were studied.•State profiles were modelled using two (clustering and fuzzy meta-state) approaches.•Both approaches showed high consistency for a range of model orders.•Surrogate testing confirmed state summary measures to be statistically significant.
Many approaches for estimating functional connectivity among brain regions or networks in fMRI have been considered in the literature. More recently, studies have shown that connectivity which is ...usually estimated by calculating correlation between time series or by estimating coherence as a function of frequency has a dynamic nature, during both task and resting conditions. Sliding-window methods have been commonly used to study these dynamic properties although other approaches such as instantaneous phase synchronization have also been used for similar purposes.
Some studies have also suggested that spectral analysis can be used to separate the distinct contributions of motion, respiration and neurophysiological activity from the observed correlation. Several recent studies have merged analysis of coherence with study of temporal dynamics of functional connectivity though these have mostly been limited to a few selected brain regions and frequency bands.
Here we propose a novel data-driven framework to estimate time-varying patterns of whole-brain functional network connectivity of resting state fMRI combined with the different frequencies and phase lags at which these patterns are observed. We show that this analysis identifies both broad-band cluster centroids that summarize connectivity patterns observed in many frequency bands, as well as clusters consisting only of functional network connectivity (FNC) from a narrow range of frequencies along with associated phase profiles. The value of this approach is demonstrated by its ability to reveal significant group differences in males versus females regarding occupancy rates of cluster that would not be separable without considering the frequencies and phase lags. The method we introduce provides a novel and informative framework for analyzing time-varying and frequency specific connectivity which can be broadly applied to the study of the healthy and diseased human brain.
•Design of a framework for time–frequency analysis of coherence in rest fMRI data•We study time–frequency coherence in form of functional network connectivity (FNC).•Enables us to jointly study temporal dynamics spectral power and phase profiles of FNCs•Identification of clusters formed by such FNCs in the time–frequency domain•Reveals significant gender differences based on occupancy measures of each cluster
From a large clinical blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI) study, we report several interrelated findings involving transient supra-network brainwide ...states characterized by a saturation phenomenon we are referring to as "polarization." These are whole-brain states in which the voxelwise-normalized BOLD (vn-BOLD) activation of a large proportion of voxels is simultaneously either very high or very low. The presence of such states during a resting-state fMRI (rs-fMRI) scan is significantly anti-correlated with diagnosed schizophrenia, significantly anti-correlated with connectivity between subcortical networks and auditory, visual and sensorimotor networks and also significantly anti-correlated with contemporaneous occupancy of transient functional network connectivity states featuring broad disconnectivity or strong inhibitory connections between the default mode and other networks. Conversely, the presence of highly polarized vn-BOLD states is significantly correlated with connectivity strength between auditory, visual and sensorimotor networks and with contemporaneous occupancy of transient whole-brain patterns of strongly modularized network connectivity and diffuse hyperconnectivity. Despite their consistency with well-documented effects of schizophrenia on static and time-varying functional network connectivity, the observed relationships between polarization and network connectivity are with very few exceptions unmediated by schizophrenia diagnosis. Many differences observed between patients and controls are echoed within the patient population itself in the effect patterns of positive symptomology (e.g. hallucinations, delusions, grandiosity). Our findings highlight a particular whole-brain spatiotemporal BOLD activation phenomenon that differs markedly between healthy subjects and schizophrenia patients, one that also strongly informs time-resolved network connectivity patterns that are associated with this serious clinical disorder.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The brain is a complex, multiscale dynamical system composed of many interacting
regions. Knowledge of the spatiotemporal organization of these interactions is
critical for establishing a solid ...understanding of the brain’s functional
architecture and the relationship between neural dynamics and cognition in
health and disease. The possibility of studying these dynamics through careful
analysis of neuroimaging data has catalyzed substantial interest in methods that
estimate time-resolved fluctuations in functional connectivity (often referred
to as “dynamic” or time-varying functional connectivity; TVFC). At
the same time, debates have emerged regarding the application of TVFC analyses
to resting fMRI data, and about the statistical validity, physiological origins,
and cognitive and behavioral relevance of resting TVFC. These and other
unresolved issues complicate interpretation of resting TVFC findings and limit
the insights that can be gained from this promising new research area. This
article brings together scientists with a variety of perspectives on resting
TVFC to review the current literature in light of these issues. We introduce
core concepts, define key terms, summarize controversies and open questions, and
present a forward-looking perspective on how resting TVFC analyses can be
rigorously and productively applied to investigate a wide range of questions in
cognitive and systems neuroscience.
Metagenomic sequencing is a promising approach for identifying and characterizing organisms and their functional characteristics in complex, polymicrobial infections, such as airway infections in ...people with cystic fibrosis. These analyses are often hampered, however, by overwhelming quantities of human DNA, yielding only a small proportion of microbial reads for analysis. In addition, many abundant microbes in respiratory samples can produce large quantities of extracellular bacterial DNA originating either from biofilms or dead cells. We describe a method for simultaneously depleting DNA from intact human cells and extracellular DNA (human and bacterial) in sputum, using selective lysis of eukaryotic cells and endonuclease digestion. We show that this method increases microbial sequencing depth and, consequently, both the number of taxa detected and coverage of individual genes such as those involved in antibiotic resistance. This finding underscores the substantial impact of DNA from sources other than live bacteria in microbiological analyses of complex, chronic infection specimens.
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•Human and extracellular bacterial DNA can bias metagenomic sequencing•Hypotonic lysis, endonuclease digestion limit human and extracellular bacterial DNA•Reducing extracellular DNA optimizes metagenomic sequencing of viable bacterial cells•Increased microbial sequencing coverage improves detection of important genes
Nelson et al. describe a method for reducing both human cellular DNA and extracellular DNA (human and bacterial) in a complex respiratory sample using hypotonic lysis and endonuclease digestion. This method increases effective microbial sequencing depth and minimizes bias introduced into subsequent phylogenetic analysis by bacterial extracellular DNA.
Graph theory-based analysis has been widely employed in brain imaging studies, and altered topological properties of brain connectivity have emerged as important features of mental diseases such as ...schizophrenia. However, most previous studies have focused on graph metrics of stationary brain graphs, ignoring that brain connectivity exhibits fluctuations over time. Here we develop a new framework for accessing dynamic graph properties of time-varying functional brain connectivity in resting-state fMRI data and apply it to healthy controls (HCs) and patients with schizophrenia (SZs). Specifically, nodes of brain graphs are defined by intrinsic connectivity networks (ICNs) identified by group independent component analysis (ICA). Dynamic graph metrics of the time-varying brain connectivity estimated by the correlation of sliding time-windowed ICA time courses of ICNs are calculated. First- and second-level connectivity states are detected based on the correlation of nodal connectivity strength between time-varying brain graphs. Our results indicate that SZs show decreased variance in the dynamic graph metrics. Consistent with prior stationary functional brain connectivity works, graph measures of identified first-level connectivity states show lower values in SZs. In addition, more first-level connectivity states are disassociated with the second-level connectivity state which resembles the stationary connectivity pattern computed by the entire scan. Collectively, the findings provide new evidence about altered dynamic brain graphs in schizophrenia, which may underscore the abnormal brain performance in this mental illness.
Functional connectivity analysis of the human brain is an active area in fMRI research. It focuses on identifying meaningful brain networks that have coherent activity either during a task or in the ...resting state. These networks are generally identified either as collections of voxels whose time series correlate strongly with a pre-selected region or voxel, or using data-driven methodologies such as independent component analysis (ICA) that compute sets of maximally spatially independent voxel weightings (component spatial maps (SMs)), each associated with a single time course (TC). Studies have shown that regardless of the way these networks are defined, the activity coherence among them has a dynamic nature which is hard to estimate with global coherence analysis such as correlation or mutual information. Sliding window analyses in which functional network connectivity (FNC) is estimated separately at each time window is one of the more widely employed approaches to studying the dynamic nature of functional network connectivity (dFNC). Observed FNC patterns are summarized and replaced with a smaller set of prototype connectivity patterns ("states" or "components"), and then a dynamical analysis is applied to the resulting sequences of prototype states. In this work we are looking for a small set of connectivity patterns whose weighted contributions to the dynamically changing dFNCs are independent of each other in time. We discuss our motivation for this work and how it differs from existing approaches. Also, in a group analysis based on gender we show that males significantly differ from females by occupying significantly more combinations of these connectivity patterns over the course of the scan.
Brain oscillations and synchronicity among brain regions (brain connectivity) have been studied in resting-state (RS) and task-induced settings. RS-connectivity which captures brain functional ...integration during an unconstrained state is shown to vary with the frequency of oscillations. Indeed, high temporal resolution modalities have demonstrated both between and cross-frequency connectivity spanning across frequency bands such as theta and gamma. Despite high spatial resolution, functional magnetic resonance imaging (fMRI) suffers from low temporal resolution due to modulation with slow-varying hemodynamic response function (HRF) and also relatively low sampling rate. This limits the range of detectable frequency bands in fMRI and consequently there has been no evidence of cross-frequency dependence in fMRI data. In the present work we uncover recurring patterns of spectral power in network timecourses which provides new insight on the actual nature of frequency variation in fMRI network activations. Moreover, we introduce a new measure of dependence between pairs of rs-fMRI networks which reveals significant cross-frequency dependence between functional brain networks specifically default-mode, cerebellar and visual networks. This is the first strong evidence of cross-frequency dependence between functional networks in fMRI and our subject group analysis based on age and gender supports usefulness of this observation for future clinical applications.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alzheimer's Disease (AZD) is a neurodegenerative disease for which there is now no known effective treatment. Mild cognitive impairment (MCI) is considered a precursor to AZD and affects cognitive ...abilities. Patients with MCI have the potential to recover cognitive health, can remain mildly cognitively impaired indefinitely or eventually progress to AZD. Identifying imaging-based predictive biomarkers for disease progression in patients presenting with evidence of very mild/questionable MCI (qMCI) can play an important role in triggering early dementia intervention. Dynamic functional network connectivity (dFNC) estimated from resting-state functional magnetic resonance imaging (rs-fMRI) has been increasingly studied in brain disorder diseases. In this work, employing a recent developed a time-attention long short-term memory (TA-LSTM) network to classify multivariate time series data. A gradient-based interpretation framework, transiently-realized event classifier activation map (TEAM) is introduced to localize the group-defining “activated” time intervals over the full time series and generate the class difference map. To test the trustworthiness of TEAM, we did a simulation study to validate the model interpretative power of TEAM. We then applied this simulation-validated framework to a well-trained TA-LSTM model which predicts the progression or recovery from questionable/mild cognitive impairment (qMCI) subjects after three years from windowless wavelet-based dFNC (WWdFNC). The FNC class difference map points to potentially important predictive dynamic biomarkers. Moreover, the more highly time-solved dFNC (WWdFNC) achieves better performance in both TA-LSTM and a multivariate CNN model than dFNC based on windowed correlations between timeseries, suggesting that better temporally resolved measures can enhance the model's performance.
•Questionable mild cognitive impairment (qMCI) can be an early-stage of Alzheimer's.•LSTM-based model is trained to predict qMCI recovery vs. deterioration.•An interpretation framework is proposed to understand the model's decision, and,•Explore transient-realized dynamic biomarkers for qMCI prognostic future.•Interpretation framework's trustworthiness is extensively validated in simulations.
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