Multi-dimensional connectivity: a conceptual and mathematical review.

The estimation of functional connectivity between regions of the brain, for example based on statistical dependencies between the time series of activity in each region, has become increasingly important in neuroimaging. Typically, multiple time series (e.g. from each voxel in fMRI data) are first reduced to a single time series that summarises the activity in a region of interest, e.g. by averaging across voxels or by taking the first principal component; an approach we call one-dimensional connectivity. However, this summary approach ignores potential multi-dimensional connectivity between two regions, and a number of recent methods have been proposed to capture such complex dependencies. Here we review the most common multi-dimensional connectivity methods, from an intuitive perspective, from a formal (mathematical) point of view, and through a number of simulated and real (fMRI and MEG) data examples that illustrate the strengths and weaknesses of each method. The paper is accompanied with both functions and scripts, which implement each method and reproduce all the examples

Disclosing large-scale directed functional connections in MEG with the multivariate phase slope index.

Abstract The phase slope index (PSI) is a method to disclose the direction of frequency-specific neural interactions from magnetoencephalographic (MEG) time series. A fundamental property of PSI is that of vanishing for linear mixing of independent neural sources. This property allows PSI to cope with the artificial instantaneous connectivity among MEG sensors or brain sources induced by the field spread. Nevertheless, PSI is limited by being a bivariate estimator of directionality as opposite to the multidimensional nature of brain activity as revealed by MEG. The purpose of this work is to provide a multivariate generalization of PSI. We termed this measure as the multivariate phase slope index (MPSI). In order to test the ability of MPSI in estimating the directionality, and to compare the MPSI results to those obtained by bivariate PSI approaches based on maximizing imaginary part of coherency and on canonical correlation analysis, we used extensive simulations. We proved that MPSI achieves the highest performance and that in a large number of simulated cases, the bivariate methods, as opposed to MPSI, do not detect a statistically significant directionality. Finally, we applied MPSI to assess seed-based directed functional connectivity in the alpha band from resting state MEG data of 61 subjects from the Human Connectome Project. The obtained results highlight a directed functional coupling in the alpha band between the primary visual cortex and several key regions of well-known resting state networks, e.g. dorsal attention network and fronto-parietal network

Analysing linear multivariate pattern transformations in neuroimaging data.

Most connectivity metrics in neuroimaging research reduce multivariate activity patterns in regions-of-interests (ROIs) to one dimension, which leads to a loss of information. Importantly, it prevents us from investigating the transformations between patterns in different ROIs. Here, we applied linear estimation theory in order to robustly estimate the linear transformations between multivariate fMRI patterns with a cross-validated ridge regression approach. We used three functional connectivity metrics that describe different features of these voxel-by-voxel mappings: goodness-of-fit, sparsity and pattern deformation. The goodness-of-fit describes the degree to which the patterns in an input region can be described as a linear transformation of patterns in an output region. The sparsity metric, which relies on a Monte Carlo procedure, was introduced in order to test whether the transformation mostly consists of one-to-one mappings between voxels in different regions. Furthermore, we defined a metric for pattern deformation, i.e. the degree to which the transformation rotates or rescales the input patterns. As a proof of concept, we applied these metrics to an event-related fMRI data set consisting of four subjects that has been used in previous studies. We focused on the transformations from early visual cortex (EVC) to inferior temporal cortex (ITC), fusiform face area (FFA) and parahippocampal place area (PPA). Our results suggest that the estimated linear mappings explain a significant amount of response variance in the three output ROIs. The transformation from EVC to ITC shows the highest goodness-of-fit, and those from EVC to FFA and PPA show the expected preference for faces and places as well as animate and inanimate objects, respectively. The pattern transformations are sparse, but sparsity is lower than would have been expected for one-to-one mappings, thus suggesting the presence of one-to-few voxel mappings. The mappings are also characterised by different levels of pattern deformations, thus indicating that the transformations differentially amplify or dampen certain dimensions of the input patterns. While our results are only based on a small number of subjects, they show that our pattern transformation metrics can describe novel aspects of multivariate functional connectivity in neuroimaging data.This work was funded by a British Academy Postdoctoral Fellowship (PS140117) to MM, by the Medical Research Council UK (SUAG/058 G101400) to OH, and conducted under the framework of the Departments of Excellence 2018–2022 initiative of the Italian Ministry of Education, University and Research for the Department of Neuroscience, Imaging and Clinical Sciences (DNISC) of the University of Chieti-Pescara

Alexithymia and Psychological Distress in Patients With Fibromyalgia and Rheumatic Disease

BACKGROUND: Fibromyalgia syndrome (FMS) is a chronic rheumatologic disease characterized by widespread musculoskeletal pain and other psychopathological symptoms which have a negative impact on patients' quality of life. FMS is frequently associated with alexithymia, a multidimensional construct characterized by difficulty in identifying feelings (DIF) and verbally communicating them difficulty describing feelings (DDF) and an externally oriented cognitive thinking style (EOT). The aim of the present study was to investigate the relationship between alexithymia, anxious and depressive symptoms and pain perception, in patients with FMS and other rheumatic diseases (RD). METHODS: The sample consisted of 127 participants (M = 25, F = 102; mean age: 51.97; SD: 11.14), of which 48 with FMS, 41 with RD and 38 healthy control group (HC). All groups underwent to a test battery investigating anxiety and depressive symptoms (HADS), pain (VAS; QUID-S/-A) and alexithymia (TAS-20). RESULTS: A high prevalence of alexithymia (TAS ≥ 61) was found in FMS (47.9%) and RD (41.5%) patients, compared to the HC group (2.6%). FMS patients showed significant higher scores than HC on DIF, DDF, EOT, anxiety and depression. The clinical sample, FMS and RD groups combined (n = 89), alexithymic patients (AL, n = 40) exhibited higher scores in pain and psychological distress compared to non-alexithymic patients (N-AL, n = 34). Regression analysis found no relationship between alexithymia and pain in AL, meanwhile pain intensity was predicted by anxiety in N-AL. CONCLUSION: While increasing clinical symptoms (pain intensity and experience, alexithymia, anxiety, and depression) in patients with fibromyalgia or rheumatic diseases, correlations were found on the one side, between alexithymia and psychological distress, on the other side, between pain experience and intensity. Meanwhile, when symptoms of psychological distress and alexithymia were subthreshold, correlations with pain experience and intensity became stronger

Non-linear Analysis of Scalp EEG by Using Bispectra: The Effect of the Reference Choice

Bispectral analysis is a signal processing technique that makes it possible to capture the non-linear and non-Gaussian properties of the EEG signals. It has found various applications in EEG research and clinical practice, including the assessment of anesthetic depth, the identification of epileptic seizures, and more recently, the evaluation of non-linear cross-frequency brain functional connectivity. However, the validity and reliability of the indices drawn from bispectral analysis of EEG signals are potentially biased by the use of a non-neutral EEG reference. The present study aims at investigating the effects of the reference choice on the analysis of the non-linear features of EEG signals through bicoherence, as well as on the estimation of cross-frequency EEG connectivity through two different non-linear measures, i.e., the cross-bicoherence and the antisymmetric cross-bicoherence. To this end, four commonly used reference schemes were considered: the vertex electrode (Cz), the digitally linked mastoids, the average reference, and the Reference Electrode Standardization Technique (REST). The reference effects were assessed both in simulations and in a real EEG experiment. The simulations allowed to investigated: (i) the effects of the electrode density on the performance of the above references in the estimation of bispectral measures; and (ii) the effects of the head model accuracy in the performance of the REST. For real data, the EEG signals recorded from 10 subjects during eyes open resting state were examined, and the distortions induced by the reference choice in the patterns of alpha-beta bicoherence, cross-bicoherence, and antisymmetric cross-bicoherence were assessed. The results showed significant differences in the findings depending on the chosen reference, with the REST providing superior performance than all the other references in approximating the ideal neutral reference. In conclusion, this study highlights the importance of considering the effects of the reference choice in the interpretation and comparison of the results of bispectral analysis of scalp EEG

A Comparative Study of the Robustness of Frequency-Domain Connectivity Measures to Finite Data Length

In this work we use numerical simulation to investigate how the temporal length of the data affects the reliability of the estimates of brain connectivity from EEG time-series. We assume that the neural sources follow a stable MultiVariate AutoRegressive model, and consider three connectivity metrics: imaginary part of coherency (IC), generalized partial directed coherence (gPDC) and frequency-domain granger causality (fGC). In order to assess the statistical significance of the estimated values, we use the surrogate data test by generating phase-randomized and autoregressive surrogate data. We first consider the ideal case where we know the source time courses exactly. Here we show how, expectedly, even exact knowledge of the source time courses is not sufficient to provide reliable estimates of the connectivity when the number of samples gets small; however, while gPDC and fGC tend to provide a larger number of false positives, the IC becomes less sensitive to the presence of connectivity. Then we proceed with more realistic simulations, where the source time courses are estimated using eLORETA, and the EEG signal is affected by biological noise of increasing intensity. Using the ideal case as a reference, we show that the impact of biological noise on IC estimates is qualitatively different from the impact on gPDC and fGC