Modeling and inference of multisubject fMRI data

Functional magnetic resonance imaging (fMRI) is a rapidly growing technique for studying the brain in action. Since its creation [1], [2], cognitive scientists have been using fMRI to understand how we remember, manipulate, and act on information in our environment. Working with magnetic resonance physicists, statisticians, and engineers, these scientists are pushing the frontiers of knowledge of how the human brain works. The design and analysis of single-subject fMRI studies has been well described. For example, [3], chapters 10 and 11 of [4], and chapters 11 and 14 of [5] all give accessible overviews of fMRI methods for one subject. In contrast, while the appropriate manner to analyze a group of subjects has been the topic of several recent papers, we do not feel it has been covered well in introductory texts and review papers. Therefore, in this article, we bring together old and new work on so-called group modeling of fMRI data using a consistent notation to make the methods more accessible and comparable

Cluster Failure Revisited: Impact of First Level Design and Data Quality on Cluster False Positive Rates

Methodological research rarely generates a broad interest, yet our work on the validity of cluster inference methods for functional magnetic resonance imaging (fMRI) created intense discussion on both the minutia of our approach and its implications for the discipline. In the present work, we take on various critiques of our work and further explore the limitations of our original work. We address issues about the particular event-related designs we used, considering multiple event types and randomisation of events between subjects. We consider the lack of validity found with one-sample permutation (sign flipping) tests, investigating a number of approaches to improve the false positive control of this widely used procedure. We found that the combination of a two-sided test and cleaning the data using ICA FIX resulted in nominal false positive rates for all datasets, meaning that data cleaning is not only important for resting state fMRI, but also for task fMRI. Finally, we discuss the implications of our work on the fMRI literature as a whole, estimating that at least 10% of the fMRI studies have used the most problematic cluster inference method (P = 0.01 cluster defining threshold), and how individual studies can be interpreted in light of our findings. These additional results underscore our original conclusions, on the importance of data sharing and thorough evaluation of statistical methods on realistic null data

Reply to Chen et al.: Parametric methods for cluster inference perform worse for two-sided t-tests

One-sided t-tests are commonly used in the neuroimaging field, but two-sided tests should be the default unless a researcher has a strong reason for using a one-sided test. Here we extend our previous work on cluster false positive rates, which used one-sided tests, to two-sided tests. Briefly, we found that parametric methods perform worse for two-sided t-tests, and that non-parametric methods perform equally well for one-sided and two-sided tests

Permutation Inference for Canonical Correlation Analysis

Canonical correlation analysis (CCA) has become a key tool for population neuroimaging, allowing investigation of associations between many imaging and non-imaging measurements. As other variables are often a source of variability not of direct interest, previous work has used CCA on residuals from a model that removes these effects, then proceeded directly to permutation inference. We show that such a simple permutation test leads to inflated error rates. The reason is that residualisation introduces dependencies among the observations that violate the exchangeability assumption. Even in the absence of nuisance variables, however, a simple permutation test for CCA also leads to excess error rates for all canonical correlations other than the first. The reason is that a simple permutation scheme does not ignore the variability already explained by previous canonical variables. Here we propose solutions for both problems: in the case of nuisance variables, we show that transforming the residuals to a lower dimensional basis where exchangeability holds results in a valid permutation test; for more general cases, with or without nuisance variables, we propose estimating the canonical correlations in a stepwise manner, removing at each iteration the variance already explained, while dealing with different number of variables in both sides. We also discuss how to address the multiplicity of tests, proposing an admissible test that is not conservative, and provide a complete algorithm for permutation inference for CCA.Comment: 49 pages, 2 figures, 10 tables, 3 algorithms, 119 reference

Increasing power for voxel-wise genome-wide association studies : the random field theory, least square kernel machines and fast permutation procedures

Imaging traits are thought to have more direct links to genetic variation than diagnostic measures based on cognitive or clinical assessments and provide a powerful substrate to examine the influence of genetics on human brains. Although imaging genetics has attracted growing attention and interest, most brain-wide genome-wide association studies focus on voxel-wise single-locus approaches, without taking advantage of the spatial information in images or combining the effect of multiple genetic variants. In this paper we present a fast implementation of voxel- and cluster-wise inferences based on the random field theory to fully use the spatial information in images. The approach is combined with a multi-locus model based on least square kernel machines to associate the joint effect of several single nucleotide polymorphisms (SNP) with imaging traits. A fast permutation procedure is also proposed which significantly reduces the number of permutations needed relative to the standard empirical method and provides accurate small p-value estimates based on parametric tail approximation. We explored the relation between 448,294 single nucleotide polymorphisms and 18,043 genes in 31,662 voxels of the entire brain across 740 elderly subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Structural MRI scans were analyzed using tensor-based morphometry (TBM) to compute 3D maps of regional brain volume differences compared to an average template image based on healthy elderly subjects. We find method to be more sensitive compared with voxel-wise single-locus approaches. A number of genes were identified as having significant associations with volumetric changes. The most associated gene was GRIN2B, which encodes the N-methyl-d-aspartate (NMDA) glutamate receptor NR2B subunit and affects both the parietal and temporal lobes in human brains. Its role in Alzheimer's disease has been widely acknowledged and studied, suggesting the validity of the approach. The various advantages over existing approaches indicate a great potential offered by this novel framework to detect genetic influences on human brains

Reply to Brown and Behrmann, Cox, et al., and Kessler et al. : Data and code sharing is the way forward for fMRI

We are glad that our paper (1) has generated intense discussions in the fMRI field (2⇓–4), on how to analyze fMRI data, and how to correct for multiple comparisons. The goal of the paper was not to disparage any specific fMRI software, but to point out that parametric statistical methods are based on a number of assumptions that are not always valid for fMRI data, and that nonparametric statistical methods (5) are a good alternative. Through AFNI’s introduction of nonparametric statistics in the function 3dttest++ (3, 6), the three most common fMRI softwares now all support nonparametric group inference [SPM through the toolbox SnPM (www2.warwick.ac.uk/fac/sci/statistics/staff/academic-research/nichols/software/snpm), and FSL through the function randomise]

A defense of using resting state fMRI as null data for estimating false positive rates

A recent Editorial by Slotnick (2017) reconsiders the findings of our paper on the accuracy of false positive rate control with cluster inference in fMRI (Eklund et al, 2016), in particular criticising our use of resting state fMRI data as a source for null data in the evaluation of task fMRI methods. We defend this use of resting fMRI data, as while there is much structure in this data, we argue it is representative of task data noise and as such analysis software should be able to accommodate this noise. We also discuss a potential problem with Slotnick’s own method

Dynamic filtering of static dipoles in magnetoencephalography

We consider the problem of estimating neural activity from measurements of the magnetic fields recorded by magnetoencephalography. We exploit the temporal structure of the problem and model the neural current as a collection of evolving current dipoles, which appear and disappear, but whose locations are constant throughout their lifetime. This fully reflects the physiological interpretation of the model. In order to conduct inference under this proposed model, it was necessary to develop an algorithm based around state-of-the-art sequential Monte Carlo methods employing carefully designed importance distributions. Previous work employed a bootstrap filter and an artificial dynamic structure where dipoles performed a random walk in space, yielding nonphysical artefacts in the reconstructions; such artefacts are not observed when using the proposed model. The algorithm is validated with simulated data, in which it provided an average localisation error which is approximately half that of the bootstrap filter. An application to complex real data derived from a somatosensory experiment is presented. Assessment of model fit via marginal likelihood showed a clear preference for the proposed model and the associated reconstructions show better localisation