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

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

Abnormal connectional fingerprint in schizophrenia: a novel network analysis of diffusion tensor imaging data

The graph theoretical analysis of structural magnetic resonance imaging (MRI) data has received a great deal of interest in recent years to characterize the organizational principles of brain networks and their alterations in psychiatric disorders, such as schizophrenia. However, the characterization of networks in clinical populations can be challenging, since the comparison of connectivity between groups is influenced by several factors, such as the overall number of connections and the structural abnormalities of the seed regions. To overcome these limitations, the current study employed the whole-brain analysis of connectional fingerprints in diffusion tensor imaging data obtained at 3 T of chronic schizophrenia patients (n = 16) and healthy, age-matched control participants (n = 17). Probabilistic tractography was performed to quantify the connectivity of 110 brain areas. The connectional fingerprint of a brain area represents the set of relative connection probabilities to all its target areas and is, hence, less affected by overall white and gray matter changes than absolute connectivity measures. After detecting brain regions with abnormal connectional fingerprints through similarity measures, we tested each of its relative connection probability between groups. We found altered connectional fingerprints in schizophrenia patients consistent with a dysconnectivity syndrome. While the medial frontal gyrus showed only reduced connectivity, the connectional fingerprints of the inferior frontal gyrus and the putamen mainly contained relatively increased connection probabilities to areas in the frontal, limbic, and subcortical areas. These findings are in line with previous studies that reported abnormalities in striatal–frontal circuits in the pathophysiology of schizophrenia, highlighting the potential utility of connectional fingerprints for the analysis of anatomical networks in the disorder

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

Characterising population variability in brain structure through models of whole-brain structural connectivity

Models of whole-brain connectivity are valuable for understanding neurological function. This thesis seeks to develop an optimal framework for extracting models of whole-brain connectivity from clinically acquired diffusion data. We propose new approaches for studying these models. The aim is to develop techniques which can take models of brain connectivity and use them to identify biomarkers or phenotypes of disease. The models of connectivity are extracted using a standard probabilistic tractography algorithm, modified to assess the structural integrity of tracts, through estimates of white matter anisotropy. Connections are traced between 77 regions of interest, automatically extracted by label propagation from multiple brain atlases followed by classifier fusion. The estimates of tissue integrity for each tract are input as indices in 77x77 ”connectivity” matrices, extracted for large populations of clinical data. These are compared in subsequent studies. To date, most whole-brain connectivity studies have characterised population differences using graph theory techniques. However these can be limited in their ability to pinpoint the locations of differences in the underlying neural anatomy. Therefore, this thesis proposes new techniques. These include a spectral clustering approach for comparing population differences in the clustering properties of weighted brain networks. In addition, machine learning approaches are suggested for the first time. These are particularly advantageous as they allow classification of subjects and extraction of features which best represent the differences between groups. One limitation of the proposed approach is that errors propagate from segmentation and registration steps prior to tractography. This can cumulate in the assignment of false positive connections, where the contribution of these factors may vary across populations, causing the appearance of population differences where there are none. The final contribution of this thesis is therefore to develop a common co-ordinate space approach. This combines probabilistic models of voxel-wise diffusion for each subject into a single probabilistic model of diffusion for the population. This allows tractography to be performed only once, ensuring that there is one model of connectivity. Cross-subject differences can then be identified by mapping individual subjects’ anisotropy data to this model. The approach is used to compare populations separated by age and gender

Evidence against the Detectability of a Hippocampal Place Code Using Functional Magnetic Resonance Imaging

Individual hippocampal neurons selectively increase their firing rates in specific spatial locations. As a population, these neurons provide a decodable representation of space that is robust against changes to sensory- and path-related cues. This neural code is sparse and distributed, theoretically rendering it undetectable with population recording methods such as functional magnetic resonance imaging (fMRI). Existing studies nonetheless report decoding spatial codes in the human hippocampus using such techniques. Here we present results from a virtual navigation experiment in humans in which we eliminated visual- and path-related confounds and statistical limitations present in existing studies, ensuring that any positive decoding results would represent a voxel-place code. Consistent with theoretical arguments derived from electrophysiological data and contrary to existing fMRI studies, our results show that although participants were fully oriented during the navigation task, there was no statistical evidence for a place code

Nonparametric statistical inference for functional brain information mapping

An ever-increasing number of functional magnetic resonance imaging (fMRI) studies are now using information-based multi-voxel pattern analysis (MVPA) techniques to decode mental states. In doing so, they achieve a significantly greater sensitivity compared to when they use univariate analysis frameworks. Two most prominent MVPA methods for information mapping are searchlight decoding and classifier weight mapping. The new MVPA brain mapping methods, however, have also posed new challenges for analysis and statistical inference on the group level. In this thesis, I discuss why the usual procedure of performing t-tests on MVPA derived information maps across subjects in order to produce a group statistic is inappropriate. I propose a fully nonparametric solution to this problem, which achieves higher sensitivity than the most commonly used t-based procedure. The proposed method is based on resampling methods and preserves the spatial dependencies in the MVPA-derived information maps. This enables to incorporate a cluster size control for the multiple testing problem. Using a volumetric searchlight decoding procedure and classifier weight maps, I demonstrate the validity and sensitivity of the new approach using both simulated and real fMRI data sets. In comparison to the standard t-test procedure implemented in SPM8, the new results showed a higher sensitivity and spatial specificity. The second goal of this thesis is the comparison of the two widely used information mapping approaches -- the searchlight technique and classifier weight mapping. Both methods take into account the spatially distributed patterns of activation in order to predict stimulus conditions, however the searchlight method solely operates on the local scale. The searchlight decoding technique has furthermore been found to be prone to spatial inaccuracies. For instance, the spatial extent of informative areas is generally exaggerated, and their spatial configuration is distorted. In this thesis, I compare searchlight decoding with linear classifier weight mapping, both using the formerly proposed non-parametric statistical framework using a simulation and ultra-high-field 7T experimental data. It was found that the searchlight method led to spatial inaccuracies that are especially noticeable in high-resolution fMRI data. In contrast, the weight mapping method was more spatially precise, revealing both informative anatomical structures as well as the direction by which voxels contribute to the classification. By maximizing the spatial accuracy of ultra-high-field fMRI results, such global multivariate methods provide a substantial improvement for characterizing structure-function relationships