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

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

Learning and comparing functional connectomes across subjects

Functional connectomes capture brain interactions via synchronized fluctuations in the functional magnetic resonance imaging signal. If measured during rest, they map the intrinsic functional architecture of the brain. With task-driven experiments they represent integration mechanisms between specialized brain areas. Analyzing their variability across subjects and conditions can reveal markers of brain pathologies and mechanisms underlying cognition. Methods of estimating functional connectomes from the imaging signal have undergone rapid developments and the literature is full of diverse strategies for comparing them. This review aims to clarify links across functional-connectivity methods as well as to expose different steps to perform a group study of functional connectomes

Neural connectivity in syntactic movement processing

Linguistic theory suggests non-canonical sentences subvert the dominant agent-verb-theme order in English via displacement of sentence constituents to argument (NP-movement) or non-argument positions (wh-movement). Both processes have been associated with the left inferior frontal gyrus and posterior superior temporal gyrus, but differences in neural activity and connectivity between movement types have not been investigated. In the current study, functional magnetic resonance imaging data were acquired from 21 adult participants during an auditory sentence-picture verification task using passive and active sentences contrasted to isolate NP-movement, and object- and subject-cleft sentences contrasted to isolate wh-movement. Then, functional magnetic resonance imaging data from regions common to both movement types were entered into a dynamic causal modeling analysis to examine effective connectivity for wh-movement and NP-movement. Results showed greater left inferior frontal gyrus activation for Wh > NP-movement, but no activation for NP > Wh-movement. Both types of movement elicited activity in the opercular part of the left inferior frontal gyrus, left posterior superior temporal gyrus, and left medial superior frontal gyrus. The dynamic causal modeling analyses indicated that neither movement type significantly modulated the connection from the left inferior frontal gyrus to the left posterior superior temporal gyrus, nor vice-versa, suggesting no connectivity differences between wh- and NP-movement. These findings support the idea that increased complexity of wh-structures, compared to sentences with NP-movement, requires greater engagement of cognitive resources via increased neural activity in the left inferior frontal gyrus, but both movement types engage similar neural networks.This work was supported by the NIH-NIDCD, Clinical Research Center Grant, P50DC012283 (PI: CT), and the Graduate Research Grant and School of Communication Graduate Ignition Grant from Northwestern University (awarded to EE). (P50DC012283 - NIH-NIDCD, Clinical Research Center Grant; Graduate Research Grant and School of Communication Graduate Ignition Grant from Northwestern University)Published versio

Improving Reliability of Subject-Level Resting-State fMRI Parcellation with Shrinkage Estimators

A recent interest in resting state functional magnetic resonance imaging (rsfMRI) lies in subdividing the human brain into anatomically and functionally distinct regions of interest. For example, brain parcellation is often used for defining the network nodes in connectivity studies. While inference has traditionally been performed on group-level data, there is a growing interest in parcellating single subject data. However, this is difficult due to the low signal-to-noise ratio of rsfMRI data, combined with typically short scan lengths. A large number of brain parcellation approaches employ clustering, which begins with a measure of similarity or distance between voxels. The goal of this work is to improve the reproducibility of single-subject parcellation using shrinkage estimators of such measures, allowing the noisy subject-specific estimator to "borrow strength" in a principled manner from a larger population of subjects. We present several empirical Bayes shrinkage estimators and outline methods for shrinkage when multiple scans are not available for each subject. We perform shrinkage on raw intervoxel correlation estimates and use both raw and shrinkage estimates to produce parcellations by performing clustering on the voxels. Our proposed method is agnostic to the choice of clustering method and can be used as a pre-processing step for any clustering algorithm. Using two datasets---a simulated dataset where the true parcellation is known and is subject-specific and a test-retest dataset consisting of two 7-minute rsfMRI scans from 20 subjects---we show that parcellations produced from shrinkage correlation estimates have higher reliability and validity than those produced from raw estimates. Application to test-retest data shows that using shrinkage estimators increases the reproducibility of subject-specific parcellations of the motor cortex by up to 30%.Comment: body 21 pages, 11 figure