The effect of global signal regression on DCM estimates of noise and effective connectivity from resting state fMRI

The influence of global BOLD fluctuations on resting state functional connectivity in fMRI data remains a topic of debate, with little consensus. In this study, we assessed the effects of global signal regression (GSR) on effective connectivity within and between resting state networks (RSNs) - as estimated with dynamic causal modelling (DCM) for resting state fMRI (rsfMRI). DCM incorporates a forward (generative) model that quantifies the contribution of different types of noise (including global measurement noise), effective connectivity, and (neuro)vascular processes to functional connectivity measurements. DCM analyses were applied to two different designs; namely, longitudinal and cross-sectional designs. In the modelling of longitudinal designs, we considered four extensive longitudinal resting state fMRI datasets with a total number of 20 subjects. In the analysis of cross-sectional designs, we used rsfMRI data from 361 subjects from the Human Connectome Project. We hypothesized that (1) GSR would have no discernible impact on effective connectivity estimated with DCM, and (2) GSR would be reflected in the parameters representing global measurement noise. Additionally, we performed comparative analyses of information gain with and without GSR. Our results showed negligible to small effects of GSR on effective connectivity within small (separately estimated) RSNs. However, although the effect sizes were small, there was substantial to conclusive evidence for an effect of GSR on connectivity parameters. For between-network connectivity, we found two important effects: the effect of GSR on between-network effective connectivity (averaged over all connections) was negligible to small, while the effect of GSR on individual connections was non-negligible. In the cross-sectional (but not in the longitudinal) data, some connections showed substantial to conclusive evidence for an effect of GSR. Contrary to our expectations, we found either no effect (in the longitudinal designs) or a non-specific (cross-sectional design) effect of GSR on parameters characterising (global) measurement noise. Data without GSR were found to be more informative than data with GSR; however, in small resting state networks the precision of posterior estimates was greater after GSR. In conclusion, GSR is a minor concern in DCM studies; however, quantitative interpretation of between-network connections (as opposed to average between-network connectivity) and noise parameters should be treated with some caution. The Kullback-Leibler divergence of the posterior from the prior (i.e., information gain) - together with the precision of posterior estimates - might offer a useful measure to assess the appropriateness of GSR in resting state fMRI

Disentangling causal webs in the brain using functional Magnetic Resonance Imaging: A review of current approaches

In the past two decades, functional Magnetic Resonance Imaging has been used to relate neuronal network activity to cognitive processing and behaviour. Recently this approach has been augmented by algorithms that allow us to infer causal links between component populations of neuronal networks. Multiple inference procedures have been proposed to approach this research question but so far, each method has limitations when it comes to establishing whole-brain connectivity patterns. In this work, we discuss eight ways to infer causality in fMRI research: Bayesian Nets, Dynamical Causal Modelling, Granger Causality, Likelihood Ratios, LiNGAM, Patel's Tau, Structural Equation Modelling, and Transfer Entropy. We finish with formulating some recommendations for the future directions in this area

Test-retest reliability of regression dynamic causal modeling

Regression dynamic causal modeling (rDCM) is a novel and computationally highly efficient method for inferring effective connectivity at the whole-brain level. While face and construct validity of rDCM have already been demonstrated, here we assessed its test-retest reliability-a test-theoretical property of particular importance for clinical applications-together with group-level consistency of connection-specific estimates and consistency of whole-brain connectivity patterns over sessions. Using the Human Connectome Project dataset for eight different paradigms (tasks and rest) and two different parcellation schemes, we found that rDCM provided highly consistent connectivity estimates at the group level across sessions. Second, while test-retest reliability was limited when averaging over all connections (range of mean intraclass correlation coefficient 0.24-0.42 over tasks), reliability increased with connection strength, with stronger connections showing good to excellent test-retest reliability. Third, whole-brain connectivity patterns by rDCM allowed for identifying individual participants with high (and in some cases perfect) accuracy. Comparing the test-retest reliability of rDCM connectivity estimates with measures of functional connectivity, rDCM performed favorably-particularly when focusing on strong connections. Generally, for all methods and metrics, task-based connectivity estimates showed greater reliability than those from the resting state. Our results underscore the potential of rDCM for human connectomics and clinical applications. Keywords: Connectomics; Effective connectivity; Generative model; Regression dynamic causal modeling; Test-retest reliability; rDC

Regression DCM for fMRI

The development of large-scale network models that infer the effective (directed) connectivity among neuronal populations from neuroimaging data represents a key challenge for computational neuroscience. Dynamic causal models (DCMs) of neuroimaging and electrophysiological data are frequently used for inferring effective connectivity but are presently restricted to small graphs (typically up to 10 regions) in order to keep model inversion computationally feasible. Here, we present a novel variant of DCM for functional magnetic resonance imaging (fMRI) data that is suited to assess effective connectivity in large (whole-brain) networks. The approach rests on translating a linear DCM into the frequency domain and reformulating it as a special case of Bayesian linear regression. This paper derives regression DCM (rDCM) in detail and presents a variational Bayesian inversion method that enables extremely fast inference and accelerates model inversion by several orders of magnitude compared to classical DCM. Using both simulated and empirical data, we demonstrate the face validity of rDCM under different settings of signal-to-noise ratio (SNR) and repetition time (TR) of fMRI data. In particular, we assess the potential utility of rDCM as a tool for whole-brain connectomics by challenging it to infer effective connection strengths in a simulated whole-brain network comprising 66 regions and 300 free parameters. Our results indicate that rDCM represents a computationally highly efficient approach with promising potential for inferring whole-brain connectivity from individual fMRI data

Exploratory study of the relationship between metrics derived from [18F]FDG PET and directed connectivity estimated from fMRI signals

openL'integrazione della [18F]FDG PET (tomografia a emissione di positroni con fluorodeossiglucosio) con fMRI (risonanza magnetica funzionale) costituisce un potente approccio nel neuroimaging, offrendo una visione completa dell'interazione tra il metabolismo regionale del glucosio e la connettività funzionale nel cervello umano. Per esplorare il potenziale dell'accoppiamento tra queste due tecniche è stato esaminato un database di soggetti sanitari, contenente dati fMRI e [18F]FDG PET, stimando i valori SUVR delle matrici di connettività metabolica e le matrici di connettività effettiva utilizzando un approccio DCM sparso. Le metriche ottenute utilizzando MC,EC e valori SUVR , sono state correlate a coppie e corrette con FDR e confrontate con le stesse metriche correlate formano un set di dati oncologici.The integration of [18F]FDG PET (Fluorodeoxyglucose Positron Emission Tomography) with fMRI (functional Magnetic Resonance Imaging) constitutes a powerful approach in neuroimaging, offering a comprehensive insight into the interplay between regional glucose metabolism and functional connectivity in the human brain. To explore the potential of the coupling between these two techniques a database of health subjects , containing fMRI and [18F]FDG PET data, was examined estimating Metabolic Connectivity matrices SUVR values and Effective connectivity matrices using a sparse DCM approach. The metrics obtained using MC,EC and SUVR values, were correlated in couples and corrected with FDR and compare with the same correlated metrics form an oncological dataset

Enhancing task fMRI preprocessing via individualized model-based filtering of intrinsic activity dynamics

Brain responses recorded during fMRI are thought to reflect both rapid, stimulus-evoked activity and the propagation of spontaneous activity through brain networks. In the current work, we describe a method to improve the estimation of task-evoked brain activity by first filtering-out the intrinsic propagation of pre-event activity from the BOLD signal. We do so using Mesoscale Individualized NeuroDynamic (MINDy; Singh et al. 2020b) models built from individualized resting-state data to subtract the propagation of spontaneous activity from the task-fMRI signal (MINDy-based Filtering). After filtering, time-series are analyzed using conventional techniques. Results demonstrate that this simple operation significantly improves the statistical power and temporal precision of estimated group-level effects. Moreover, use of MINDy-based filtering increased the similarity of neural activation profiles and prediction accuracy of individual differences in behavior across tasks measuring the same construct (cognitive control). Thus, by subtracting the propagation of previous activity, we obtain better estimates of task-related neural effects

Whole-brain estimates of directed connectivity for human connectomics

Connectomics is essential for understanding large-scale brain networks but requires that individual connection estimates are neurobiologically interpretable. In particular, a principle of brain organization is that reciprocal connections between cortical areas are functionally asymmetric. This is a challenge for fMRI-based connectomics in humans where only undirected functional connectivity estimates are routinely available. By contrast, whole-brain estimates of effective (directed) connectivity are computationally challenging, and emerging methods require empirical validation. Here, using a motor task at 7T, we demonstrate that a novel generative model can infer known connectivity features in a whole-brain network (>200 regions, >40,000 connections) highly efficiently. Furthermore, graph-theoretical analyses of directed connectivity estimates identify functional roles of motor areas more accurately than undirected functional connectivity estimates. These results, which can be achieved in an entirely unsupervised manner, demonstrate the feasibility of inferring directed connections in whole-brain networks and open new avenues for human connectomics

Advancing functional connectivity research from association to causation

Cognition and behavior emerge from brain network interactions, such that investigating causal interactions should be central to the study of brain function. Approaches that characterize statistical associations among neural time series-functional connectivity (FC) methods-are likely a good starting point for estimating brain network interactions. Yet only a subset of FC methods ('effective connectivity') is explicitly designed to infer causal interactions from statistical associations. Here we incorporate best practices from diverse areas of FC research to illustrate how FC methods can be refined to improve inferences about neural mechanisms, with properties of causal neural interactions as a common ontology to facilitate cumulative progress across FC approaches. We further demonstrate how the most common FC measures (correlation and coherence) reduce the set of likely causal models, facilitating causal inferences despite major limitations. Alternative FC measures are suggested to immediately start improving causal inferences beyond these common FC measures

An information-theoretic analysis of resting-state versus task fMRI

Resting-state fMRI is an increasingly popular alternative to task-based fMRI. However, a formal quantification of the amount of information provided by resting-state fMRI as opposed to active task conditions about neural responses is lacking. We conducted a systematic comparison of the quality of inferences derived from a resting-state and a task fMRI paradigm by means of Bayesian Data Comparison. In this framework, data quality is formally quantified in information-theoretic terms as the precision and amount of information provided by the data on the parameters of interest. Parameters of effective connectivity, estimated from the cross-spectral densities of resting-state- and task time series by means of dynamic causal modelling (DCM), were subjected to the analysis. Data from 50 individuals undergoing resting-state and a Theory-of-Mind task were compared, both datasets provided by the Human Connectome Project. A threshold of very strong evidence was reached in favour of the Theory-of-Mind task (>10 bits or natural units) regarding information gain, which could be attributed to the active task condition eliciting stronger effective connectivity. Extending these analyses to other tasks and cognitive systems will reveal whether the superior informative value of task-based fMRI observed here is case specific or a more general trend

The connected brain: Causality, models and intrinsic dynamics

Recently, there have been several concerted international efforts - the BRAIN initiative, European Human Brain Project and the Human Connectome Project, to name a few - that hope to revolutionize our understanding of the connected brain. Over the past two decades, functional neuroimaging has emerged as the predominant technique in systems neuroscience. This is foreshadowed by an ever increasing number of publications on functional connectivity, causal modeling, connectomics, and multivariate analyses of distributed patterns of brain responses. In this article, we summarize pedagogically the (deep) history of brain mapping. We will highlight the theoretical advances made in the (dynamic) causal modelling of brain function - that may have escaped the wider audience of this article - and provide a brief overview of recent developments and interesting clinical applications. We hope that this article will engage the signal processing community by showcasing the inherently multidisciplinary nature of this important topic and the intriguing questions that are being addressed