On spurious and real fluctuations of dynamic functional connectivity during rest.

Functional brain networks reconfigure spontaneously during rest. Such network dynamics can be studied by dynamic functional connectivity (dynFC); i.e., sliding-window correlations between regional brain activity. Key parameters-such as window length and cut-off frequencies for filtering-are not yet systematically studied. In this letter we provide the fundamental theory from signal processing to address these parameter choices when estimating and interpreting dynFC. We guide the reader through several illustrative cases, both simple analytical models and experimental fMRI BOLD data. First, we show how spurious fluctuations in dynFC can arise due to the estimation method when the window length is shorter than the largest wavelength present in both signals, even for deterministic signals with a fixed relationship. Second, we study how real fluctuations of dynFC can be explained using a frequency-based view, which is particularly instructive for signals with multiple frequency components such as fMRI BOLD, demonstrating that fluctuations in sliding-window correlation emerge by interaction between frequency components similar to the phenomenon of beat frequencies. We conclude with practical guidelines for the choice and impact of the window length.

Anatomically-adapted graph wavelets for improved group-level fMRI activation mapping.

A graph based framework for fMRI brain activation mapping is presented. The approach exploits the spectral graph wavelet transform (SGWT) for the purpose of defining an advanced multi-resolutional spatial transformation for fMRI data. The framework extends wavelet based SPM (WSPM), which is an alternative to the conventional approach of statistical parametric mapping (SPM), and is developed specifically for group-level analysis. We present a novel procedure for constructing brain graphs, with subgraphs that separately encode the structural connectivity of the cerebral and cerebellar gray matter (GM), and address the inter-subject GM variability by the use of template GM representations. Graph wavelets tailored to the convoluted boundaries of GM are then constructed as a means to implement a GM-based spatial transformation on fMRI data. The proposed approach is evaluated using real as well as semi-synthetic multi-subject data. Compared to SPM and WSPM using classical wavelets, the proposed approach shows superior type-I error control. The results on real data suggest a higher detection sensitivity as well as the capability to capture subtle, connected patterns of brain activity.

Disentangling dynamic networks: Separated and joint expressions of functional connectivity patterns in time.

Resting-state functional connectivity (FC) is highly variable across the duration of a scan. Groups of coevolving connections, or reproducible patterns of dynamic FC (dFC), have been revealed in fluctuating FC by applying unsupervised learning techniques. Based on results from k-means clustering and sliding-window correlations, it has recently been hypothesized that dFC may cycle through several discrete FC states. Alternatively, it has been proposed to represent dFC as a linear combination of multiple FC patterns using principal component analysis. As it is unclear whether sparse or nonsparse combinations of FC patterns are most appropriate, and as this affects their interpretation and use as markers of cognitive processing, the goal of our study was to evaluate the impact of sparsity by performing an empirical evaluation of simulated, task-based, and resting-state dFC. To this aim, we applied matrix factorizations subject to variable constraints in the temporal domain and studied both the reproducibility of ensuing representations of dFC and the expression of FC patterns over time. During subject-driven tasks, dFC was well described by alternating FC states in accordance with the nature of the data. The estimated FC patterns showed a rich structure with combinations of known functional networks enabling accurate identification of three different tasks. During rest, dFC was better described by multiple FC patterns that overlap. The executive control networks, which are critical for working memory, appeared grouped alternately with externally or internally oriented networks. These results suggest that combinations of FC patterns can provide a meaningful way to disentangle resting-state dFC.

Principal components of functional connectivity: a new approach to study dynamic brain connectivity during rest.

Functional connectivity (FC) as measured by correlation between fMRI BOLD time courses of distinct brain regions has revealed meaningful organization of spontaneous fluctuations in the resting brain. However, an increasing amount of evidence points to non-stationarity of FC; i.e., FC dynamically changes over time reflecting additional and rich information about brain organization, but representing new challenges for analysis and interpretation. Here, we propose a data-driven approach based on principal component analysis (PCA) to reveal hidden patterns of coherent FC dynamics across multiple subjects. We demonstrate the feasibility and relevance of this new approach by examining the differences in dynamic FC between 13 healthy control subjects and 15 minimally disabled relapse-remitting multiple sclerosis patients. We estimated whole-brain dynamic FC of regionally-averaged BOLD activity using sliding time windows. We then used PCA to identify FC patterns, termed "eigenconnectivities", that reflect meaningful patterns in FC fluctuations. We then assessed the contributions of these patterns to the dynamic FC at any given time point and identified a network of connections centered on the default-mode network with altered contribution in patients. Our results complement traditional stationary analyses, and reveal novel insights into brain connectivity dynamics and their modulation in a neurodegenerative disease.

Validation of the Asthma Predictive Index and comparison with simpler clinical prediction rules.

BACKGROUND: The loose and stringent Asthma Predictive Indices (API), developed in Tucson, are popular rules to predict asthma in preschool children. To be clinically useful, they require validation in different settings. OBJECTIVE: To assess the predictive performance of the API in an independent population and compare it with simpler rules based only on preschool wheeze. METHODS: We studied 1954 children of the population-based Leicester Respiratory Cohort, followed up from age 1 to 10 years. The API and frequency of wheeze were assessed at age 3 years, and we determined their association with asthma at ages 7 and 10 years by using logistic regression. We computed test characteristics and measures of predictive performance to validate the API and compare it with simpler rules. RESULTS: The ability of the API to predict asthma in Leicester was comparable to Tucson: for the loose API, odds ratios for asthma at age 7 years were 5.2 in Leicester (5.5 in Tucson), and positive predictive values were 26% (26%). For the stringent API, these values were 8.2 (9.8) and 40% (48%). For the simpler rule early wheeze, corresponding values were 5.4 and 21%; for early frequent wheeze, 6.7 and 36%. The discriminative ability of all prediction rules was moderate (c statistic ≤ 0.7) and overall predictive performance low (scaled Brier score < 20%). CONCLUSION: Predictive performance of the API in Leicester, although comparable to the original study, was modest and similar to prediction based only on preschool wheeze. This highlights the need for better prediction rules.

Canonical cerebellar graph wavelets and their application to FMRI activation mapping.

Wavelet-based statistical parametric mapping (WSPM) is an extension of the classical approach in fMRI activation mapping that combines wavelet processing with voxel-wise statistical testing. We recently showed how WSPM, using graph wavelets tailored to the full gray-matter (GM) structure of each individual's brain, can improve brain activity detection compared to using the classical wavelets that are only suited for the Euclidian grid. However, in order to perform analysis on a subject-invariant graph, canonical graph wavelets should be designed in normalized brain space. We here introduce an approach to define a fixed template graph of the cerebellum, an essential component of the brain, using the SUIT cerebellar template. We construct a corresponding set of canonical cerebellar graph wavelets, and adopt them in the analysis of both synthetic and real data. Compared to classical SPM, WSPM using cerebellar graph wavelets shows superior type-I error control, an empirical higher sensitivity on real data, as well as the potential to capture subtle patterns of cerebellar activity.