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.

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.

Taking the 4D Nature of fMRI Data Into Account Promises Significant Gains in Data Completion.

Functional magnetic resonance imaging (fMRI) is a powerful, noninvasive tool that has significantly contributed to the understanding of the human brain. FMRI data provide a sequence of whole-brain volumes over time and hence are inherently four dimensional (4D). Missing data in fMRI experiments arise from image acquisition limits, susceptibility and motion artifacts or during confounding noise removal. Hence, significant brain regions may be excluded from the data, which can seriously undermine the quality of subsequent analyses due to the significant number of missing voxels. We take advantage of the four dimensional (4D) nature of fMRI data through a tensor representation and introduce an effective algorithm to estimate missing samples in fMRI data. The proposed Riemannian nonlinear spectral conjugate gradient (RSCG) optimization method uses tensor train (TT) decomposition, which enables compact representations and provides efficient linear algebra operations. Exploiting the Riemannian structure boosts algorithm performance significantly, as evidenced by the comparison of RSCG-TT with state-of-the-art stochastic gradient methods, which are developed in the Euclidean space. We thus provide an effective method for estimating missing brain voxels and, more importantly, clearly show that taking the full 4D structure of fMRI data into account provides important gains when compared with three-dimensional (3D) and the most commonly used two-dimensional (2D) representations of fMRI data.

Relationship between Dynamic Blood-Oxygen-Level-Dependent Activity and Functional Network Connectivity: Characterization of Schizophrenia Subgroups.

Aim: In this work, we propose the novel use of adaptively constrained independent vector analysis (acIVA) to effectively capture the temporal and spatial properties of dynamic blood-oxygen-level-dependent (BOLD) activity (dBA), and we efficiently quantify the spatial property of dBA (sdBA). We also propose to incorporate dBA into the study of brain dynamics to gain insight into activity-connectivity co-evolution patterns. Introduction: Studies of the dynamics of the human brain using functional magnetic resonance imaging (fMRI) have enabled the identification of unique functional network connectivity (FNC) states and provided new insights into mental disorders. There is evidence showing that both BOLD activity, which is captured by fMRI, and FNC are related to mental and cognitive processes. However, a few studies have evaluated the inter-relationships of these two domains of function. Moreover, the identification of subgroups of schizophrenia has gained significant clinical importance due to a need to study the heterogeneity of schizophrenia. Methods: We design a simulation study to verify the effectiveness of acIVA and apply acIVA to the dynamic study of resting-state fMRI data collected from individuals with schizophrenia and healthy controls (HCs) to investigate the relationship between dBA and dynamic FNC (dFNC). Results: The simulation study demonstrates that acIVA accurately captures the spatial variability and provides an efficient quantification of sdBA. The fMRI analysis yields synchronized sdBA-temporal property of dBA (tdBA) patterns and shows that the dBA and dFNC are significantly correlated in the spatial domain. Using these dynamic features, we identify schizophrenia subgroups with significant differences in terms of their clinical symptoms. Conclusion: We find that brain function is abnormally organized in schizophrenia compared with HCs since there are less synchronized sdBA-tdBA patterns in schizophrenia and schizophrenia prefers a component that merges multiple brain regions. Identification of schizophrenia subgroups using dynamic features inspires the use of neuroimaging in studying the heterogeneity of disorders. Impact statement This work introduces the use of joint blind source separation for the study of brain dynamics to enable efficient quantification of the spatial property of dynamic blood-oxygen-level-dependent (BOLD) activity to provide insight into the relationship of dynamic BOLD activity and dynamic functional network connectivity. The identification of subgroups of schizophrenia using dynamic features allows the study of heterogeneity of schizophrenia, emphasizing the importance of functional magnetic resonance imaging analysis in the study of brain activity and functional connectivity to gain a better understanding of the human brain, especially the brain with a mental disorder.

Graph-theoretical analysis identifies transient spatial states of resting-state dynamic functional network connectivity and reveals dysconnectivity in schizophrenia.

BACKGROUND: Dynamic functional network connectivity (dFNC) summarizes associations among time-varying brain networks and is widely used for studying dynamics. However, most previous studies compute dFNC using temporal variability while spatial variability started receiving increasing attention. It is hence desirable to investigate spatial variability and the interaction between temporal and spatial variability. NEW METHOD: We propose to use an adaptive variant of constrained independent vector analysis to simultaneously capture temporal and spatial variability, and introduce a goal-driven scheme for addressing a key challenge in dFNC analysis---determining the number of transient states. We apply our methods to resting-state functional magnetic resonance imaging data of schizophrenia patients (SZs) and healthy controls (HCs). RESULTS: The results show spatial variability provides more features discriminative between groups than temporal variability. A comprehensive study of graph-theoretical (GT) metrics determines the optimal number of spatial states and suggests centrality as a key metric. Four networks yield significantly different levels of involvement in SZs and HCs. The high involvement of a component that relates to multiple distributed brain regions highlights dysconnectivity in SZ. One frontoparietal component and one frontal component demonstrate higher involvement in HCs, suggesting a more efficient cognitive control system relative to SZs. COMPARISON WITH EXISTING METHODS: Spatial variability is more informative than temporal variability. The proposed goal-driven scheme determines the optimal number of states in a more interpretable way by making use of discriminative features. CONCLUSION: GT analysis is promising in dFNC analysis as it identifies distinctive transient spatial states of dFNC and reveals unique biomedical patterns in SZs.

Adaptive constrained independent vector analysis: An effective solution for analysis of large-scale medical imaging data.

There is a growing need for flexible methods for the analysis of large-scale functional magnetic resonance imaging (fMRI) data for the estimation of global signatures that summarize the population while preserving individual-specific traits. Independent vector analysis (IVA) is a data-driven method that jointly estimates global spatio-temporal patterns from multi-subject fMRI data, and effectively preserves subject variability. However, as we show, IVA performance is negatively affected when the number of datasets and components increases especially when there is low component correlation across the datasets. We study the problem and its relationship with respect to correlation across the datasets, and propose an effective method for addressing the issue by incorporating reference information of the estimation patterns into the formulation, as a guidance in high dimensional scenarios. Constrained IVA (cIVA) provides an efficient framework for incorporating references, however its performance depends on a user-defined constraint parameter, which enforces the association between the reference signals and estimation patterns to a fixed level. We propose adaptive cIVA (acIVA) that tunes the constraint parameter to allow flexible associations between the references and estimation patterns, and enables incorporating multiple reference signals, without enforcing inaccurate conditions. Our results indicate that acIVA can reliably estimate high-dimensional multivariate sources from large-scale simulated datasets, when compared with standard IVA. It also successfully extracts meaningful functional networks from a large-scale fMRI dataset for which standard IVA did not converge. The method also efficiently captures subject-specific information, which is demonstrated through observed gender differences in spectral power, higher spectral power in males at low frequencies and in females at high frequencies, within the motor, attention, visual and default mode networks.

Identification of Subgroup Differences Using IVA: Application to fMRI Data Fusion.

In application to functional magnetic resonance imaging (fMRI) data analysis, a number of data fusion algorithms have shown success in extracting interpretable brain networks that can distinguish two groups such two populations-patients with mental disorder and the healthy controls. However, there are situations where more than two groups exist such as the fusion of multi-task fMRI data. Therefore, in this work we propose the use of IVA to effectively extract information that is able to distinguish across multiple groups when applied to data fusion. The performance of IVA is investigated using a simulated fMRI-like data. The simulation results illustrate that IVA with multivariate Laplacian distribution and second-order statistics (IVA-L-SOS) yields better performance compared to joint independent component analysis and IVA with multivariate Gaussian distribution in terms of both estimation accuracy and robustness. When applied to real multi-task fMRI data, IVA-L-SOS successfully extract task-related brain networks that are able to distinguish three tasks.

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.

Spatial Dynamic Functional Connectivity Analysis Identifies Distinctive Biomarkers in Schizophrenia.

Dynamic functional network connectivity (dFNC) analysis is a widely-used to study associations between dynamic functional correlations and cognitive abilities. Traditional methods analyze time-varying association of different spatial networks while assuming that the spatial network itself is stationary. However, there has been very little work focused on voxelwise spatial variability. Exploiting the variability across both the temporal and spatial domains provide a more promising direction to obtain reliable dynamic functional patterns. However, methods for extracting time-varying spatio-temporal patterns from large-scale functional magnetic resonance imaging (fMRI) data present some challenges, such as degradation in performance with respect to increase in size of the data, estimation of the number of dynamic components, and the potential sensitivity of the resulting dFNCs to selection of the networks. In this work, we implement subsequent extraction of exemplars and dynamics using a constrained independent vector analysis, a data-driven method that efficiently estimates spatial and temporal dynamics from large-scale resting-state fMRI data. We explore the benefits of analyzing spatial dFNC (sdFNC) patterns over temporal dFNC (tdFNC) patterns in the context of differentiating healthy controls and patients with schizophrenia. Our results indicate that for resting-state fMRI data, sdFNC patterns were able to better classify patients and controls, and yield more distinguishing features compared with tdFNC patterns. We also estimate structured patterns of connectivity/states using sdFNC patterns, an area that has not been studied so far, and observe that sdFNC was able to successfully capture distinct information from healthy controls and patients with schizophrenia. In addition, sdFNC patterns were also able to identify functional patterns that associate with signs of paranoia and abnormalities in the patients group. We also observe that patients with schizophrenia tend to switch to or stay in a state corresponding to a hyperconnected brain network.

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.