Vince D. Calhoun

A method for making group inferences from functional MRI data using independent component analysis.

Independent component analysis (ICA) is a promising analysis method that is being increasingly applied to fMRI data. A principal advantage of this approach is its applicability to cognitive paradigms for which detailed models of brain activity are not available. Independent component analysis has been successfully utilized to analyze single‐subject fMRI data sets, and an extension of this work would be to provide for group inferences. However, unlike univariate methods (e.g., regression analysis, Kolmogorov–Smirnov statistics), ICA does not naturally generalize to a method suitable for drawing inferences about groups of subjects. We introduce a novel approach for drawing group inferences using ICA of fMRI data, and present its application to a simple visual paradigm that alternately stimulates the left or right visual field. Our group ICA analysis revealed task‐related components in left and right visual cortex, a transiently task‐related component in bilateral occipital/parietal cortex, and a non‐task‐related component in bilateral visual association cortex. We address issues involved in the use of ICA as an fMRI analysis method such as: (1) How many components should be calculated? (2) How are these components to be combined across subjects? (3) How should the final results be thresholded and/or presented? We show that the methodology we present provides answers to these questions and lay out a process for making group inferences from fMRI data using independent component analysis. Hum. Brain Mapping 14:140–151, 2001.

Dynamic functional connectivity: promise, issues, and interpretations.

The brain must dynamically integrate, coordinate, and respond to internal and external stimuli across multiple time scales. Non-invasive measurements of brain activity with fMRI have greatly advanced our understanding of the large-scale functional organization supporting these fundamental features of brain function. Conclusions from previous resting-state fMRI investigations were based upon static descriptions of functional connectivity (FC), and only recently studies have begun to capitalize on the wealth of information contained within the temporal features of spontaneous BOLD FC. Emerging evidence suggests that dynamic FC metrics may index changes in macroscopic neural activity patterns underlying critical aspects of cognition and behavior, though limitations with regard to analysis and interpretation remain. Here, we review recent findings, methodological considerations, neural and behavioral correlates, and future directions in the emerging field of dynamic FC investigations.

Tracking Whole-Brain Connectivity Dynamics in the Resting State

Spontaneous fluctuations are a hallmark of recordings of neural signals, emergent over time scales spanning milliseconds and tens of minutes. However, investigations of intrinsic brain organization based on resting-state functional magnetic resonance imaging have largely not taken into account the presence and potential of temporal variability, as most current approaches to examine functional connectivity (FC) implicitly assume that relationships are constant throughout the length of the recording. In this work, we describe an approach to assess whole-brain FC dynamics based on spatial independent component analysis, sliding time window correlation, and k-means clustering of windowed correlation matrices. The method is applied to resting-state data from a large sample (n = 405) of young adults. Our analysis of FC variability highlights particularly flexible connections between regions in lateral parietal and cingulate cortex, and argues against a labeling scheme where such regions are treated as separate and antagonistic entities. Additionally, clustering analysis reveals unanticipated FC states that in part diverge strongly from stationary connectivity patterns and challenge current descriptions of interactions between large-scale networks. Temporal trends in the occurrence of different FC states motivate theories regarding their functional roles and relationships with vigilance/arousal. Overall, we suggest that the study of time-varying aspects of FC can unveil flexibility in the functional coordination between different neural systems, and that the exploitation of these dynamics in further investigations may improve our understanding of behavioral shifts and adaptive processes.

Selective changes of resting-state networks in individuals at risk for Alzheimer's disease

Alzheimers disease (AD) is a neurodegenerative disorder that prominently affects cerebral connectivity. Assessing the functional connectivity at rest, recent functional MRI (fMRI) studies reported on the existence of resting-state networks (RSNs). RSNs are characterized by spatially coherent, spontaneous fluctuations in the blood oxygen level-dependent signal and are made up of regional patterns commonly involved in functions such as sensory, attention, or default mode processing. In AD, the default mode network (DMN) is affected by reduced functional connectivity and atrophy. In this work, we analyzed functional and structural MRI data from healthy elderly (n = 16) and patients with amnestic mild cognitive impairment (aMCI) (n = 24), a syndrome of high risk for developing AD. Two questions were addressed: (i) Are any RSNs altered in aMCI? (ii) Do changes in functional connectivity relate to possible structural changes? Independent component analysis of resting-state fMRI data identified eight spatially consistent RSNs. Only selected areas of the DMN and the executive attention network demonstrated reduced network-related activity in the patient group. Voxel-based morphometry revealed atrophy in both medial temporal lobes (MTL) of the patients. The functional connectivity between both hippocampi in the MTLs and the posterior cingulate of the DMN was present in healthy controls but absent in patients. We conclude that in individuals at risk for AD, a specific subset of RSNs is altered, likely representing effects of ongoing early neurodegeneration. We interpret our finding as a proof of principle, demonstrating that functional brain disorders can be characterized by functional-disconnectivity profiles of RSNs.

A review of group ICA for fMRI data and ICA for joint inference of imaging, genetic, and ERP data.

Independent component analysis (ICA) has become an increasingly utilized approach for analyzing brain imaging data. In contrast to the widely used general linear model (GLM) that requires the user to parameterize the data (e.g. the brains response to stimuli), ICA, by relying upon a general assumption of independence, allows the user to be agnostic regarding the exact form of the response. In addition, ICA is intrinsically a multivariate approach, and hence each component provides a grouping of brain activity into regions that share the same response pattern thus providing a natural measure of functional connectivity. There are a wide variety of ICA approaches that have been proposed, in this paper we focus upon two distinct methods. The first part of this paper reviews the use of ICA for making group inferences from fMRI data. We provide an overview of current approaches for utilizing ICA to make group inferences with a focus upon the group ICA approach implemented in the GIFT software. In the next part of this paper, we provide an overview of the use of ICA to combine or fuse multimodal data. ICA has proven particularly useful for data fusion of multiple tasks or data modalities such as single nucleotide polymorphism (SNP) data or event-related potentials. As demonstrated by a number of examples in this paper, ICA is a powerful and versatile data-driven approach for studying the brain.

A Baseline for the Multivariate Comparison of Resting-State Networks

As the size of functional and structural MRI datasets expands, it becomes increasingly important to establish a baseline from which diagnostic relevance may be determined, a processing strategy that efficiently prepares data for analysis, and a statistical approach that identifies important effects in a manner that is both robust and reproducible. In this paper, we introduce a multivariate analytic approach that optimizes sensitivity and reduces unnecessary testing. We demonstrate the utility of this mega-analytic approach by identifying the effects of age and gender on the resting-state networks (RSNs) of 603 healthy adolescents and adults (mean age: 23.4 years, range: 12–71 years). Data were collected on the same scanner, preprocessed using an automated analysis pipeline based in SPM, and studied using group independent component analysis. RSNs were identified and evaluated in terms of three primary outcome measures: time course spectral power, spatial map intensity, and functional network connectivity. Results revealed robust effects of age on all three outcome measures, largely indicating decreases in network coherence and connectivity with increasing age. Gender effects were of smaller magnitude but suggested stronger intra-network connectivity in females and more inter-network connectivity in males, particularly with regard to sensorimotor networks. These findings, along with the analysis approach and statistical framework described here, provide a useful baseline for future investigations of brain networks in health and disease.

A method for functional network connectivity among spatially independent resting-state components in schizophrenia

Functional connectivity of the brain has been studied by analyzing correlation differences in time courses among seed voxels or regions with other voxels of the brain in healthy individuals as well as in patients with brain disorders. The spatial extent of strongly temporally coherent brain regions co-activated during rest has also been examined using independent component analysis (ICA). However, the weaker temporal relationships among ICA component time courses, which we operationally define as a measure of functional network connectivity (FNC), have not yet been studied. In this study, we propose an approach for evaluating FNC and apply it to functional magnetic resonance imaging (fMRI) data collected from persons with schizophrenia and healthy controls. We examined the connectivity and latency among ICA component time courses to test the hypothesis that patients with schizophrenia would show increased functional connectivity and increased lag among resting state networks compared to controls. Resting state fMRI data were collected and the inter-relationships among seven selected resting state networks (identified using group ICA) were evaluated by correlating each subjects ICA time courses with one another. Patients showed higher correlation than controls among most of the dominant resting state networks. Patients also had slightly more variability in functional connectivity than controls. We present a novel approach for quantifying functional connectivity among brain networks identified with spatial ICA. Significant differences between patient and control connectivity in different networks were revealed possibly reflecting deficiencies in cortical processing in patients.

Estimating the Number of Independent Components for Functional Magnetic Resonance Imaging Data

Multivariate analysis methods such as independent component analysis (ICA) have been applied to the analysis of functional magnetic resonance imaging (fMRI) data to study brain function. Because of the high dimensionality and high noise level of the fMRI data, order selection, i.e., estimation of the number of informative components, is critical to reduce over/underfitting in such methods. Dependence among fMRI data samples in the spatial and temporal domain limits the usefulness of the practical formulations of information‐theoretic criteria (ITC) for order selection, since they are based on likelihood of independent and identically distributed (i.i.d.) data samples. To address this issue, we propose a subsampling scheme to obtain a set of effectively i.i.d. samples from the dependent data samples and apply the ITC formulas to the effectively i.i.d. sample set for order selection. We apply the proposed method on the simulated data and show that it significantly improves the accuracy of order selection from dependent data. We also perform order selection on fMRI data from a visuomotor task and show that the proposed method alleviates the over‐estimation on the number of brain sources due to the intrinsic smoothness and the smooth preprocessing of fMRI data. We use the software package ICASSO (Himberg et al. [ 2004 ]: Neuroimage 22:1214–1222) to analyze the independent component (IC) estimates at different orders and show that, when ICA is performed at overestimated orders, the stability of the IC estimates decreases and the estimation of task related brain activations show degradation. Hum Brain Mapp, 2007.

Spatial and Temporal Independent Component Analysis of Functional MRI Data Containing a Pair of Task-Related Waveforms

Independent component analysis (ICA) is a technique that attempts to separate data into maximally independent groups. Achieving maximal independence in space or time yields two varieties of ICA meaningful for functional MRI (fMRI) applications: spatial ICA (SICA) and temporal ICA (TICA). SICA has so far dominated the application of ICA to fMRI. The objective of these experiments was to study ICA with two predictable components present and evaluate the importance of the underlying independence assumption in the application of ICA. Four novel visual activation paradigms were designed, each consisting of two spatiotemporal components that were either spatially dependent, temporally dependent, both spatially and temporally dependent, or spatially and temporally uncorrelated, respectively. Simulated data were generated and fMRI data from six subjects were acquired using these paradigms. Data from each paradigm were analyzed with regression analysis in order to determine if the signal was occurring as expected. Spatial and temporal ICA were then applied to these data, with the general result that ICA found components only where expected, e.g., S(T)ICA “failed” (i.e., yielded independent components unrelated to the “self‐evident” components) for paradigms that were spatially (temporally) dependent, and “worked” otherwise. Regression analysis proved a useful “check” for these data, however strong hypotheses will not always be available, and a strength of ICA is that it can characterize data without making specific modeling assumptions. We report a careful examination of some of the assumptions behind ICA methodologies, provide examples of when applying ICA would provide difficult‐to‐interpret results, and offer suggestions for applying ICA to fMRI data especially when more than one task‐related component is present in the data.Hum. Brain Mapping 13:43–53, 2001.

Alterations in Memory Networks in Mild Cognitive Impairment and Alzheimer's Disease: An Independent Component Analysis

Memory function is likely subserved by multiple distributed neural networks, which are disrupted by the pathophysiological process of Alzheimers disease (AD). In this study, we used multivariate analytic techniques to investigate memory-related functional magnetic resonance imaging (fMRI) activity in 52 individuals across the continuum of normal aging, mild cognitive impairment (MCI), and mild AD. Independent component analyses revealed specific memory-related networks that activated or deactivated during an associative memory paradigm. Across all subjects, hippocampal activation and parietal deactivation demonstrated a strong reciprocal relationship. Furthermore, we found evidence of a nonlinear trajectory of fMRI activation across the continuum of impairment. Less impaired MCI subjects showed paradoxical hyperactivation in the hippocampus compared with controls, whereas more impaired MCI subjects demonstrated significant hypoactivation, similar to the levels observed in the mild AD subjects. We found a remarkably parallel curve in the pattern of memory-related deactivation in medial and lateral parietal regions with greater deactivation in less-impaired MCI and loss of deactivation in more impaired MCI and mild AD subjects. Interestingly, the failure of deactivation in these regions was also associated with increased positive activity in a neocortical attentional network in MCI and AD. Our findings suggest that loss of functional integrity of the hippocampal-based memory systems is directly related to alterations of neural activity in parietal regions seen over the course of MCI and AD. These data may also provide functional evidence of the interaction between neocortical and medial temporal lobe pathology in early AD.