Multimodal fusion of multiple rest fMRI networks and MRI gray matter via parallel multilink joint ICA reveals highly significant function/structure coupling in Alzheimer's disease.

In this article, we focus on estimating the joint relationship between structural magnetic resonance imaging (sMRI) gray matter (GM), and multiple functional MRI (fMRI) intrinsic connectivity networks (ICNs). To achieve this, we propose a multilink joint independent component analysis (ml-jICA) method using the same core algorithm as jICA. To relax the jICA assumption, we propose another extension called parallel multilink jICA (pml-jICA) that allows for a more balanced weight distribution over ml-jICA/jICA. We assume a shared mixing matrix for both the sMRI and fMRI modalities, while allowing for different mixing matrices linking the sMRI data to the different ICNs. We introduce the model and then apply this approach to study the differences in resting fMRI and sMRI data from patients with Alzheimer's disease (AD) versus controls. The results of the pml-jICA yield significant differences with large effect sizes that include regions in overlapping portions of default mode network, and also hippocampus and thalamus. Importantly, we identify two joint components with partially overlapping regions which show opposite effects for AD versus controls, but were able to be separated due to being linked to distinct functional and structural patterns. This highlights the unique strength of our approach and multimodal fusion approaches generally in revealing potentially biomarkers of brain disorders that would likely be missed by a unimodal approach. These results represent the first work linking multiple fMRI ICNs to GM components within a multimodal data fusion model and challenges the typical view that brain structure is more sensitive to AD than fMRI.

Independent Component and Graph Theory Analyses Reveal Normalized Brain Networks on Resting-State Functional MRI After Working Memory Training in People With HIV.

BACKGROUND: Cognitive training may partially reverse cognitive deficits in people with HIV (PWH). Previous functional MRI (fMRI) studies demonstrate that working memory training (WMT) alters brain activity during working memory tasks, but its effects on resting brain network organization remain unknown. PURPOSE: To test whether WMT affects PWH brain functional connectivity in resting-state fMRI (rsfMRI). STUDY TYPE: Prospective. POPULATION: A total of 53 PWH (ages 50.7 ± 1.5 years, two women) and 53 HIV-seronegative controls (SN, ages 49.5 ± 1.6 years, six women). FIELD STRENGTH/SEQUENCE: Axial single-shot gradient-echo echo-planar imaging at 3.0 T was performed at baseline (TL1), at 1-month (TL2), and at 6-months (TL3), after WMT. ASSESSMENT: All participants had rsfMRI and clinical assessments (including neuropsychological tests) at TL1 before randomization to Cogmed WMT (adaptive training, n = 58: 28 PWH, 30 SN; nonadaptive training, n = 48: 25 PWH, 23 SN), 25 sessions over 5-8 weeks. All assessments were repeated at TL2 and at TL3. The functional connectivity estimated by independent component analysis (ICA) or graph theory (GT) metrics (eigenvector centrality, etc.) for different link densities (LDs) were compared between PWH and SN groups at TL1 and TL2. STATISTICAL TESTS: Two-way analyses of variance (ANOVA) on GT metrics and two-sample t-tests on FC or GT metrics were performed. Cognitive (eg memory) measures were correlated with eigenvector centrality (eCent) using Pearson's correlations. The significance level was set at P < 0.05 after false discovery rate correction. RESULTS: The ventral default mode network (vDMN) eCent differed between PWH and SN groups at TL1 but not at TL2 (P = 0.28). In PWH, vDMN eCent changes significantly correlated with changes in the memory ability in PWH (r = -0.62 at LD = 50%) and vDMN eCent before training significantly correlated with memory performance changes (r = 0.53 at LD = 50%). DATA CONCLUSION: ICA and GT analyses showed that adaptive WMT normalized graph properties of the vDMN in PWH. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: 1.

Identification of Homogeneous Subgroups from Resting-State fMRI Data.

The identification of homogeneous subgroups of patients with psychiatric disorders can play an important role in achieving personalized medicine and is essential to provide insights for understanding neuropsychological mechanisms of various mental disorders. The functional connectivity profiles obtained from functional magnetic resonance imaging (fMRI) data have been shown to be unique to each individual, similar to fingerprints; however, their use in characterizing psychiatric disorders in a clinically useful way is still being studied. In this work, we propose a framework that makes use of functional activity maps for subgroup identification using the Gershgorin disc theorem. The proposed pipeline is designed to analyze a large-scale multi-subject fMRI dataset with a fully data-driven method, a new constrained independent component analysis algorithm based on entropy bound minimization (c-EBM), followed by an eigenspectrum analysis approach. A set of resting-state network (RSN) templates is generated from an independent dataset and used as constraints for c-EBM. The constraints present a foundation for subgroup identification by establishing a connection across the subjects and aligning subject-wise separate ICA analyses. The proposed pipeline was applied to a dataset comprising 464 psychiatric patients and discovered meaningful subgroups. Subjects within the identified subgroups share similar activation patterns in certain brain areas. The identified subgroups show significant group differences in multiple meaningful brain areas including dorsolateral prefrontal cortex and anterior cingulate cortex. Three sets of cognitive test scores were used to verify the identified subgroups, and most of them showed significant differences across subgroups, which provides further confirmation of the identified subgroups. In summary, this work represents an important step forward in using neuroimaging data to characterize mental disorders.

A Scalable Approach to Independent Vector Analysis by Shared Subspace Separation for Multi-Subject fMRI Analysis.

Joint blind source separation (JBSS) has wide applications in modeling latent structures across multiple related datasets. However, JBSS is computationally prohibitive with high-dimensional data, limiting the number of datasets that can be included in a tractable analysis. Furthermore, JBSS may not be effective if the data's true latent dimensionality is not adequately modeled, where severe overparameterization may lead to poor separation and time performance. In this paper, we propose a scalable JBSS method by modeling and separating the "shared" subspace from the data. The shared subspace is defined as the subset of latent sources that exists across all datasets, represented by groups of sources that collectively form a low-rank structure. Our method first provides the efficient initialization of the independent vector analysis (IVA) with a multivariate Gaussian source prior (IVA-G) specifically designed to estimate the shared sources. Estimated sources are then evaluated regarding whether they are shared, upon which further JBSS is applied separately to the shared and non-shared sources. This provides an effective means to reduce the dimensionality of the problem, improving analyses with larger numbers of datasets. We apply our method to resting-state fMRI datasets, demonstrating that our method can achieve an excellent estimation performance with significantly reduced computational costs.

Dynamical Synergies of Multidigit Hand Prehension.

Hand prehension requires highly coordinated control of contact forces. The high-dimensional sensorimotor system of the human hand operates at ease, but poses several challenges when replicated in artificial hands. This paper investigates how the dynamical synergies, coordinated spatiotemporal patterns of contact forces, contribute to the hand grasp, and whether they could potentially capture the force primitives in a low-dimensional space. Ten right-handed subjects were recruited to grasp and hold mass-varied objects. The contact forces during this multidigit prehension were recorded using an instrumented grip glove. The dynamical synergies were derived using principal component analysis (PCA). The contact force patterns during the grasps were reconstructed using the first few synergies. The significance of the dynamical synergies, the influence of load forces and task configurations on the synergies were explained. This study also discussed the contribution of biomechanical constraints on the first few synergies and the current challenges and possible applications of the dynamical synergies in the design and control of exoskeletons. The integration of the dynamical synergies into exoskeletons will be realized in the near future.

Reconstructing Synergy-Based Hand Grasp Kinematics from Electroencephalographic Signals.

Brain-machine interfaces (BMIs) have become increasingly popular in restoring the lost motor function in individuals with disabilities. Several research studies suggest that the CNS may employ synergies or movement primitives to reduce the complexity of control rather than controlling each DoF independently, and the synergies can be used as an optimal control mechanism by the CNS in simplifying and achieving complex movements. Our group has previously demonstrated neural decoding of synergy-based hand movements and used synergies effectively in driving hand exoskeletons. In this study, ten healthy right-handed participants were asked to perform six types of hand grasps representative of the activities of daily living while their neural activities were recorded using electroencephalography (EEG). From half of the participants, hand kinematic synergies were derived, and a neural decoder was developed, based on the correlation between hand synergies and corresponding cortical activity, using multivariate linear regression. Using the synergies and the neural decoder derived from the first half of the participants and only cortical activities from the remaining half of the participants, their hand kinematics were reconstructed with an average accuracy above 70%. Potential applications of synergy-based BMIs for controlling assistive devices in individuals with upper limb motor deficits, implications of the results in individuals with stroke and the limitations of the study were discussed.

Association of Neuroimaging Data with Behavioral Variables: A Class of Multivariate Methods and Their Comparison Using Multi-Task FMRI Data.

It is becoming increasingly common to collect multiple related neuroimaging datasets either from different modalities or from different tasks and conditions. In addition, we have non-imaging data such as cognitive or behavioral variables, and it is through the association of these two sets of data-neuroimaging and non-neuroimaging-that we can understand and explain the evolution of neural and cognitive processes, and predict outcomes for intervention and treatment. Multiple methods for the joint analysis or fusion of multiple neuroimaging datasets or modalities exist; however, methods for the joint analysis of imaging and non-imaging data are still in their infancy. Current approaches for identifying brain networks related to cognitive assessments are still largely based on simple one-to-one correlation analyses and do not use the cross information available across multiple datasets. This work proposes two approaches based on independent vector analysis (IVA) to jointly analyze the imaging datasets and behavioral variables such that multivariate relationships across imaging data and behavioral features can be identified. The simulation results show that our proposed methods provide better accuracy in identifying associations across imaging and behavioral components than current approaches. With functional magnetic resonance imaging (fMRI) task data collected from 138 healthy controls and 109 patients with schizophrenia, results reveal that the central executive network (CEN) estimated in multiple datasets shows a strong correlation with the behavioral variable that measures working memory, a result that is not identified by traditional approaches. Most of the identified fMRI maps also show significant differences in activations across healthy controls and patients potentially providing a useful signature of mental disorders.

Data Fusion-Based Musculoskeletal Synergies in the Grasping Hand.

The hypothesis that the central nervous system (CNS) makes use of synergies or movement primitives in achieving simple to complex movements has inspired the investigation of different types of synergies. Kinematic and muscle synergies have been extensively studied in the literature, but only a few studies have compared and combined both types of synergies during the control and coordination of the human hand. In this paper, synergies were extracted first independently (called kinematic and muscle synergies) and then combined through data fusion (called musculoskeletal synergies) from 26 activities of daily living in 22 individuals using principal component analysis (PCA) and independent component analysis (ICA). By a weighted linear combination of musculoskeletal synergies, the recorded kinematics and the recorded muscle activities were reconstructed. The performances of musculoskeletal synergies in reconstructing the movements were compared to the synergies reported previously in the literature by us and others. The results indicate that the musculoskeletal synergies performed better than the synergies extracted without fusion. We attribute this improvement in performance to the musculoskeletal synergies that were generated on the basis of the cross-information between muscle and kinematic activities. Moreover, the synergies extracted using ICA performed better than the synergies extracted using PCA. These musculoskeletal synergies can possibly improve the capabilities of the current methodologies used to control high dimensional prosthetics and exoskeletons.

Independent vector analysis for common subspace analysis: Application to multi-subject fMRI data yields meaningful subgroups of schizophrenia.

The extraction of common and distinct biomedical signatures among different populations allows for a more detailed study of the group-specific as well as distinct information of different populations. A number of subspace analysis algorithms have been developed and successfully applied to data fusion, however they are limited to joint analysis of only a couple of datasets. Since subspace analysis is very promising for analysis of multi-subject medical imaging data as well, we focus on this problem and propose a new method based on independent vector analysis (IVA) for common subspace extraction (IVA-CS) for multi-subject data analysis. IVA-CS leverages the strength of IVA in identification of a complete subspace structure across multiple datasets along with an efficient solution that uses only second-order statistics. We propose a subset analysis approach within IVA-CS to mitigate issues in estimation in IVA due to high dimensionality, both in terms of components estimated and the number of datasets. We introduce a scheme to determine a desirable size for the subset that is high enough to exploit the dependence across datasets and is not affected by the high dimensionality issue. We demonstrate the success of IVA-CS in extracting complex subset structures and apply the method to analysis of functional magnetic resonance imaging data from 179 subjects and show that it successfully identifies shared and complementary brain patterns from patients with schizophrenia (SZ) and healthy controls group. Two components with linked resting-state networks are identified to be unique to the SZ group providing evidence of functional dysconnectivity. IVA-CS also identifies subgroups of SZs that show significant differences in terms of their brain networks and clinical symptoms.

A Shared Vision for Machine Learning in Neuroscience.

With ever-increasing advancements in technology, neuroscientists are able to collect data in greater volumes and with finer resolution. The bottleneck in understanding how the brain works is consequently shifting away from the amount and type of data we can collect and toward what we actually do with the data. There has been a growing interest in leveraging this vast volume of data across levels of analysis, measurement techniques, and experimental paradigms to gain more insight into brain function. Such efforts are visible at an international scale, with the emergence of big data neuroscience initiatives, such as the BRAIN initiative (Bargmann et al., 2014), the Human Brain Project, the Human Connectome Project, and the National Institute of Mental Health's Research Domain Criteria initiative. With these large-scale projects, much thought has been given to data-sharing across groups (Poldrack and Gorgolewski, 2014; Sejnowski et al., 2014); however, even with such data-sharing initiatives, funding mechanisms, and infrastructure, there still exists the challenge of how to cohesively integrate all the data. At multiple stages and levels of neuroscience investigation, machine learning holds great promise as an addition to the arsenal of analysis tools for discovering how the brain works.

A new blind source separation framework for signal analysis and artifact rejection in functional Near-Infrared Spectroscopy.

In the analysis of functional Near-Infrared Spectroscopy (fNIRS) signals from real-world scenarios, artifact rejection is essential. However, currently there exists no gold-standard. Although a plenitude of methodological approaches implicitly assume the presence of latent processes in the signals, elaborate Blind-Source-Separation methods have rarely been applied. A reason are challenging characteristics such as Non-instantaneous and non-constant coupling, correlated noise and statistical dependencies between signal components. We present a novel suitable BSS framework that tackles these issues by incorporating A) Independent Component Analysis methods that exploit both higher order statistics and sample dependency, B) multimodality, i.e., fNIRS with accelerometer signals, and C) Canonical-Correlation Analysis with temporal embedding. This enables analysis of signal components and rejection of motion-induced physiological hemodynamic artifacts that would otherwise be hard to identify. We implement a method for Blind Source Separation and Accelerometer based Artifact Rejection and Detection (BLISSA2RD). It allows the analysis of a novel n-back based cognitive workload paradigm in freely moving subjects, that is also presented in this manuscript. We evaluate on the corresponding data set and simulated ground truth data, making use of metrics based on 1st and 2nd order statistics and SNR and compare with three established methods: PCA, Spline and Wavelet-based artifact removal. Across 17 subjects, the method is shown to reduce movement induced artifacts by up to two orders of magnitude, improves the SNR of continuous hemodynamic signals in single channels by up to 10dB, and significantly outperforms conventional methods in the extraction of simulated Hemodynamic Response Functions from strongly contaminated data. The framework and methods presented can serve as an introduction to a new type of multivariate methods for the analysis of fNIRS signals and as a blueprint for artifact rejection in complex environments beyond the applied paradigm.

The role of diversity in data-driven analysis of multi-subject fMRI data: Comparison of approaches based on independence and sparsity using global performance metrics.

Data-driven methods have been widely used in functional magnetic resonance imaging (fMRI) data analysis. They extract latent factors, generally, through the use of a simple generative model. Independent component analysis (ICA) and dictionary learning (DL) are two popular data-driven methods that are based on two different forms of diversity-statistical properties of the data-statistical independence for ICA and sparsity for DL. Despite their popularity, the comparative advantage of emphasizing one property over another in the decomposition of fMRI data is not well understood. Such a comparison is made harder due to the differences in the modeling assumptions between ICA and DL, as well as within different ICA algorithms where each algorithm exploits a different form of diversity. In this paper, we propose the use of objective global measures, such as time course frequency power ratio, network connection summary, and graph theoretical metrics, to gain insight into the role that different types of diversity have on the analysis of fMRI data. Four ICA algorithms that account for different types of diversity and one DL algorithm are studied. We apply these algorithms to real fMRI data collected from patients with schizophrenia and healthy controls. Our results suggest that no one particular method has the best performance using all metrics, implying that the optimal method will change depending on the goal of the analysis. However, we note that in none of the scenarios we test the highly popular Infomax provides the best performance, demonstrating the cost of exploiting limited form of diversity.

Parallel group ICA+ICA: Joint estimation of linked functional network variability and structural covariation with application to schizophrenia.

There is growing evidence that rather than using a single brain imaging modality to study its association with physiological or symptomatic features, the field is paying more attention to fusion of multimodal information. However, most current multimodal fusion approaches that incorporate functional magnetic resonance imaging (fMRI) are restricted to second-level 3D features, rather than the original 4D fMRI data. This trade-off is that the valuable temporal information is not utilized during the fusion step. Here we are motivated to propose a novel approach called "parallel group ICA+ICA" that incorporates temporal fMRI information from group independent component analysis (GICA) into a parallel independent component analysis (ICA) framework, aiming to enable direct fusion of first-level fMRI features with other modalities (e.g., structural MRI), which thus can detect linked functional network variability and structural covariations. Simulation results show that the proposed method yields accurate intermodality linkage detection regardless of whether it is strong or weak. When applied to real data, we identified one pair of significantly associated fMRI-sMRI components that show group difference between schizophrenia and controls in both modalities, and this linkage can be replicated in an independent cohort. Finally, multiple cognitive domain scores can be predicted by the features identified in the linked component pair by our proposed method. We also show these multimodal brain features can predict multiple cognitive scores in an independent cohort. Overall, results demonstrate the ability of parallel GICA+ICA to estimate joint information from 4D and 3D data without discarding much of the available information up front, and the potential for using this approach to identify imaging biomarkers to study brain disorders.

A window-less approach for capturing time-varying connectivity in fMRI data reveals the presence of states with variable rates of change.

Functional connectivity during the resting state has been shown to change over time (i.e., has a dynamic connectivity). However, resting-state fluctuations, in contrast to task-based experiments, are not initiated by an external stimulus. Consequently, a more complicated method needs to be designed to measure the dynamic connectivity. Previous approaches have been based on assumptions regarding the nature of the underlying dynamic connectivity to compensate for this knowledge gap. The most common assumption is what we refer to as locality assumption. Under a locality assumption, a single connectivity state can be estimated from data that are close in time. This assumption is so natural that it has been either explicitly or implicitly embedded in many current approaches to capture dynamic connectivity. However, an important drawback of methods using this assumption is they are unable to capture dynamic changes in connectivity beyond the embedded rate while, there has been no evidence that the rate of change in brain connectivity matches the rates enforced by this assumption. In this study, we propose an approach that enables us to capture functional connectivity with arbitrary rates of change, varying from very slow to the theoretically maximum possible rate of change, which is only imposed by the sampling rate of the imaging device. This method allows us to observe unique patterns of connectivity that were not observable with previous approaches. As we explain further, these patterns are also significantly correlated to the age and gender of study subjects, which suggests they are also neurobiologically related.

Application of Graph Theory to Assess Static and Dynamic Brain Connectivity: Approaches for Building Brain Graphs.

Human brain connectivity is complex. Graph theory based analysis has become a powerful and popular approach for analyzing brain imaging data, largely because of its potential to quantitatively illuminate the networks, the static architecture in structure and function, the organization of dynamic behavior over time, and disease related brain changes. The first step in creating brain graphs is to define the nodes and edges connecting them. We review a number of approaches for defining brain nodes including fixed versus data-driven nodes. Expanding the narrow view of most studies which focus on static and/or single modality brain connectivity, we also survey advanced approaches and their performances in building dynamic and multi-modal brain graphs. We show results from both simulated and real data from healthy controls and patients with mental illnesse. We outline the advantages and challenges of these various techniques. By summarizing and inspecting recent studies which analyzed brain imaging data based on graph theory, this article provides a guide for developing new powerful tools to explore complex brain networks.

Independent Vector Analysis for SSVEP Signal Enhancement, Detection, and Topographical Mapping.

Steady state visual evoked potentials (SSVEPs) have been identified as an effective solution for brain computer interface (BCI) systems as well as for neurocognitive investigations. SSVEPs can be observed in the scalp-based recordings of electroencephalogram signals, and are one component buried amongst the normal brain signals and complex noise. We present a novel method for enhancing and improving detection of SSVEPs by leveraging the rich joint blind source separation framework using independent vector analysis (IVA). IVA exploits the diversity within each dataset while preserving dependence across all the datasets. This approach is shown to enhance the detection of SSVEP signals across a range of frequencies and subjects for BCI systems. Furthermore, we show that IVA enables improved topographic mapping of the SSVEP propagation providing a promising new tool for neuroscience and neurocognitive research.

Sample-poor estimation of order and common signal subspace with application to fusion of medical imaging data.

Due to their data-driven nature, multivariate methods such as canonical correlation analysis (CCA) have proven very useful for fusion of multimodal neurological data. However, being able to determine the degree of similarity between datasets and appropriate order selection are crucial to the success of such techniques. The standard methods for calculating the order of multimodal data focus only on sources with the greatest individual energy and ignore relations across datasets. Additionally, these techniques as well as the most widely-used methods for determining the degree of similarity between datasets assume sufficient sample support and are not effective in the sample-poor regime. In this paper, we propose to jointly estimate the degree of similarity between datasets and their order when few samples are present using principal component analysis and canonical correlation analysis (PCA-CCA). By considering these two problems simultaneously, we are able to minimize the assumptions placed on the data and achieve superior performance in the sample-poor regime compared to traditional techniques. We apply PCA-CCA to the pairwise combinations of functional magnetic resonance imaging (fMRI), structural magnetic resonance imaging (sMRI), and electroencephalogram (EEG) data drawn from patients with schizophrenia and healthy controls while performing an auditory oddball task. The PCA-CCA results indicate that the fMRI and sMRI datasets are the most similar, whereas the sMRI and EEG datasets share the least similarity. We also demonstrate that the degree of similarity obtained by PCA-CCA is highly predictive of the degree of significance found for components generated using CCA.

Comparison of PCA approaches for very large group ICA.

Large data sets are becoming more common in fMRI and, with the advent of faster pulse sequences, memory efficient strategies for data reduction via principal component analysis (PCA) turn out to be extremely useful, especially for widely used approaches like group independent component analysis (ICA). In this commentary, we discuss results and limitations from a recent paper on the topic and attempt to provide a more complete perspective on available approaches as well as discussing various issues to consider related to PCA for very large group ICA. We also provide an analysis of computation time, memory use, and number of dataloads for a variety of approaches under multiple scenarios of small and extremely large data sets.

Multi-modal data fusion using source separation: Two effective models based on ICA and IVA and their properties.

Fusion of information from multiple sets of data in order to extract a set of features that are most useful and relevant for the given task is inherent to many problems we deal with today. Since, usually, very little is known about the actual interaction among the datasets, it is highly desirable to minimize the underlying assumptions. This has been the main reason for the growing importance of data-driven methods, and in particular of independent component analysis (ICA) as it provides useful decompositions with a simple generative model and using only the assumption of statistical independence. A recent extension of ICA, independent vector analysis (IVA) generalizes ICA to multiple datasets by exploiting the statistical dependence across the datasets, and hence, as we discuss in this paper, provides an attractive solution to fusion of data from multiple datasets along with ICA. In this paper, we focus on two multivariate solutions for multi-modal data fusion that let multiple modalities fully interact for the estimation of underlying features that jointly report on all modalities. One solution is the Joint ICA model that has found wide application in medical imaging, and the second one is the the Transposed IVA model introduced here as a generalization of an approach based on multi-set canonical correlation analysis. In the discussion, we emphasize the role of diversity in the decompositions achieved by these two models, present their properties and implementation details to enable the user make informed decisions on the selection of a model along with its associated parameters. Discussions are supported by simulation results to help highlight the main issues in the implementation of these methods.