Robyn L. Miller

Assessing dynamic brain graphs of time-varying connectivity in fMRI data: application to healthy controls and patients with schizophrenia

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.

Classification of schizophrenia and bipolar patients using static and dynamic resting-state fMRI brain connectivity

Recently, functional network connectivity (FNC, defined as the temporal correlation among spatially distant brain networks) has been used to examine the functional organization of brain networks in various psychiatric illnesses. Dynamic FNC is a recent extension of the conventional FNC analysis that takes into account FNC changes over short periods of time. While such dynamic FNC measures may be more informative about various aspects of connectivity, there has been no detailed head-to-head comparison of the ability of static and dynamic FNC to perform classification in complex mental illnesses. This paper proposes a framework for automatic classification of schizophrenia, bipolar and healthy subjects based on their static and dynamic FNC features. Also, we compare cross-validated classification performance between static and dynamic FNC. Results show that the dynamic FNC significantly outperforms the static FNC in terms of predictive accuracy, indicating that features from dynamic FNC have distinct advantages over static FNC for classification purposes. Moreover, combining static and dynamic FNC features does not significantly improve the classification performance over the dynamic FNC features alone, suggesting that static FNC does not add any significant information when combined with dynamic FNC for classification purposes. A three-way classification methodology based on static and dynamic FNC features discriminates individual subjects into appropriate diagnostic groups with high accuracy. Our proposed classification framework is potentially applicable to additional mental disorders.

Dynamic coherence analysis of resting fMRI data to jointly capture state-based phase, frequency, and time-domain information ☆

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.

Higher Dimensional Meta-State Analysis Reveals Reduced Resting fMRI Connectivity Dynamism in Schizophrenia Patients

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.

Lateralization of resting state networks and relationship to age and gender

Brain lateralization is a widely studied topic, however there has been little work focused on lateralization of intrinsic networks (regions showing similar patterns of covariation among voxels) in the resting brain. In this study, we evaluate resting state network lateralization in an age and gender-balanced functional magnetic resonance imaging (fMRI) dataset comprising over 600 healthy subjects ranging in age from 12 to 71. After establishing sample-wide network lateralization properties, we continue with an investigation of age and gender effects on network lateralization. All data was gathered on the same scanner and preprocessed using an automated pipeline (Scott et al., 2011). Networks were extracted via group independent component analysis (gICA) (Calhoun et al., 2001). Twenty-eight resting state networks discussed in previous (Allen et al., 2011) work were re-analyzed with a focus on lateralization. We calculated homotopic voxelwise measures of laterality in addition to a global lateralization measure, called the laterality cofactor, for each network. As expected, many of the intrinsic brain networks were lateralized. For example, the visual network was strongly right lateralized, auditory network and default mode networks were mostly left lateralized. Attentional and frontal networks included nodes that were left lateralized and other nodes that were right lateralized. Age was strongly related to lateralization in multiple regions including sensorimotor network regions precentral gyrus, postcentral gyrus and supramarginal gyrus; and visual network regions lingual gyrus; attentional network regions inferior parietal lobule, superior parietal lobule and middle temporal gyrus; and frontal network regions including the inferior frontal gyrus. Gender showed significant effects mainly in two regions, including visual and frontal networks. For example, the inferior frontal gyrus was more right lateralized in males. Significant effects of age were found in sensorimotor and visual networks on the global measure. In summary, we report a large-sample of lateralization study that finds intrinsic functional brain networks to be highly lateralized, with regions that are strongly related to gender and age locally, and with age a strong factor in lateralization, and gender exhibiting a trend-level effect on global measures of laterality.

Preserving subject variability in group fMRI analysis: performance evaluation of GICA vs. IVA

Independent component analysis (ICA) is a widely applied technique to derive functionally connected brain networks from fMRI data. Group ICA (GICA) and Independent Vector Analysis (IVA) are extensions of ICA that enable users to perform group fMRI analyses; however a full comparison of the performance limits of GICA and IVA has not been investigated. Recent interest in resting state fMRI data with potentially higher degree of subject variability makes the evaluation of the above techniques important. In this paper we compare component estimation accuracies of GICA and an improved version of IVA using simulated fMRI datasets. We systematically change the degree of inter-subject spatial variability of components and evaluate estimation accuracy over all spatial maps (SMs) and time courses (TCs) of the decomposition. Our results indicate the following: (1) at low levels of SM variability or when just one SM is varied, both GICA and IVA perform well, (2) at higher levels of SM variability or when more than one SMs are varied, IVA continues to perform well but GICA yields SM estimates that are composites of other SMs with errors in TCs, (3) both GICA and IVA remove spatial correlations of overlapping SMs and introduce artificial correlations in their TCs, (4) if number of SMs is over estimated, IVA continues to perform well but GICA introduces artifacts in the varying and extra SMs with artificial correlations in the TCs of extra components, and (5) in the absence or presence of SMs unique to one subject, GICA produces errors in TCs and IVA estimates are accurate. In summary, our simulation experiments (both simplistic and realistic) and our holistic analyses approach indicate that IVA produces results that are closer to ground truth and thereby better preserves subject variability. The improved version of IVA is now packaged into the GIFT toolbox (http://mialab.mrn.org/software/gift).

Replicability of time-varying connectivity patterns in large resting state fMRI samples

&NA; 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 brains 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. HighlightsReplicability 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.

Spatial Variance in Resting fMRI Networks of Schizophrenia Patients: An Independent Vector Analysis

Spatial variability in resting functional MRI (fMRI) brain networks has not been well studied in schizophrenia, a disease known for both neurodevelopmental and widespread anatomic changes. Motivated by abundant evidence of neuroanatomical variability from previous studies of schizophrenia, we draw upon a relatively new approach called independent vector analysis (IVA) to assess this variability in resting fMRI networks. IVA is a blind-source separation algorithm, which segregates fMRI data into temporally coherent but spatially independent networks and has been shown to be especially good at capturing spatial variability among subjects in the extracted networks. We introduce several new ways to quantify differences in variability of IVA-derived networks between schizophrenia patients (SZs = 82) and healthy controls (HCs = 89). Voxelwise amplitude analyses showed significant group differences in the spatial maps of auditory cortex, the basal ganglia, the sensorimotor network, and visual cortex. Tests for differences (HC-SZ) in the spatial variability maps suggest, that at rest, SZs exhibit more activity within externally focused sensory and integrative network and less activity in the default mode network thought to be related to internal reflection. Additionally, tests for difference of variance between groups further emphasize that SZs exhibit greater network variability. These results, consistent with our prediction of increased spatial variability within SZs, enhance our understanding of the disease and suggest that it is not just the amplitude of connectivity that is different in schizophrenia, but also the consistency in spatial connectivity patterns across subjects.

Higher dimensional analysis shows reduced dynamism of time-varying network connectivity in schizophrenia patients.

Assessments of functional connectivity between brain networks is a fixture of resting state fMRI research. Until very recently most of this work proceeded from an assumption of stationarity in resting state network connectivity. In the last few years however, interest in moving beyond this simplifying assumption has grown considerably. Applying group temporal independent component analysis (tICA) to a set of time-varying functional network connectivity (FNC) matrices derived from a large multi-site fMRI dataset (N=314; 163 healthy, 151 schizophrenia patients), we obtain a set of five basic correlation patterns (component spatial maps (SMs)) from which observed FNCs can be expressed as mutually independent linear combinations, i.e., the coefficient on each SM in the linear combination is maximally independent of the others. We study dynamic properties of network connectivity as they are reflected in this five-dimensional space, and report stark differences in connectivity dynamics between schizophrenia patients and healthy controls. We also find that the most important global differences in FNC dynamism between patient and control groups are replicated when the same dynamical analysis is performed on sets of correlation patterns obtained from either PCA or spatial ICA, giving us additional confidence in the results.

Whole-brain connectivity dynamics reflect both task-specific and individual-specific modulation: A multitask study

ABSTRACT Functional connectivity (FC) has been widely used to study the functional organization of temporally correlated and spatially distributed brain regions. Recent studies of FC dynamics, quantified by windowed correlations, provide new insights to analyze dynamic, context‐dependent reconfiguration of brain networks. A set of reoccurring whole‐brain connectivity patterns at rest, referred to as FC states, have been identified, hypothetically reflecting underlying cognitive processes or mental states. We posit that the mean FC information for a given subject represents a significant contribution to the group‐level FC dynamics. We show that the subject‐specific FC profile, termed as FC individuality, can be removed to increase sensitivity to cognitively relevant FC states. To assess the impact of the FC individuality and task‐specific FC modulation on the group‐level FC dynamics analysis, we generate and analyze group studies of four subjects engaging in four cognitive conditions (rest, simple math, two‐back memory, and visual attention task). We also propose a model to quantitatively evaluate the effect of two factors, namely, subject‐specific and task‐specific modulation on FC dynamics. We show that FC individuality is a predominant factor in group‐level FC variability, and the embedded cognitively relevant FC states are clearly visible after removing the individual’s connectivity profile. Our results challenge the current understanding of FC states and emphasize the importance of individual heterogeneity in connectivity dynamics analysis. HighlightsFC individuality (fingerprint) embedded in FC dynamics predicts subject identity.FC individuality accounts for more group‐level FC variance than task modulation.Individuality removal enables tracking task states with FC dynamics at group level.