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Mediation analysis is an important tool in the behavioral sciences for investigating the role of intermediate variables that lie in the path between a treatment and an outcome variable. The influence of the intermediate variable on the outcome is often explored using a linear structural equation model (LSEM), with model coefficients interpreted as possible effects. While there has been significant research on the topic, little work has been done when the intermediate variable (mediator) is a high-dimensional vector. In this work, we introduce a novel method for identifying potential mediators in this setting called the directions of mediation (DMs). DMs linearly combine potential mediators into a smaller number of orthogonal components, with components ranked based on the proportion of the LSEM likelihood each accounts for. This method is well suited for cases when many potential mediators are measured. Examples of high-dimensional potential mediators are brain images composed of hundreds of thousands of voxels, genetic variation measured at millions of single nucleotide polymorphisms (SNPs), or vectors of thousands of variables in large-scale epidemiological studies. We demonstrate the method using a functional magnetic resonance imaging study of thermal pain where we are interested in determining which brain locations mediate the relationship between the application of a thermal stimulus and self-reported pain. [ABSTRACT FROM AUTHOR]

Background: Individuals with comorbid posttraumatic stress disorder and major depressive disorder (PTSD-MDD) often exhibit greater functional impairment and poorer treatment response than individuals with PTSD alone. Research has not determined whether PTSD-MDD is associated with different network connectivity abnormalities than PTSD alone.Methods: We used functional magnetic resonance imaging (fMRI) to measure resting state functional connectivity (rs-FC) patterns of brain regions involved in fear and reward processing in three groups: patients with PTSD-alone (n = 27), PTSD-MDD (n = 21), and trauma-exposed healthy controls (TEHCs, n = 34). Based on previous research, seeds included basolateral amygdala (BLA), centromedial amygdala (CMA), and nucleus accumbens (NAcc).Results: Regardless of MDD comorbidity, PTSD was associated with decreased connectivity of BLA-orbitalfrontal cortex (OFC) and CMA-thalamus pathways, key to fear processing, and fear expression, respectively. PTSD-MDD, compared to PTSD-alone and TEHC, was associated with decreased connectivity across multiple amygdala and striatal-subcortical pathways: BLA-OFC, NAcc-thalamus, and NAcc-hippocampus. Further, while both the BLA-OFC and the NAcc-thalamus pathways were correlated with MDD symptoms, PTSD symptoms correlated with the amygdala pathways (BLA-OFC; CMA-thalamus) only.Conclusions: Comorbid PTSD-MDD may be associated with multifaceted functional connectivity alterations in both fear and reward systems. Clinical implications are discussed. [ABSTRACT FROM AUTHOR]

Many modern neuroimaging studies acquire large spatial images of the brain observed sequentially over time. Such data are often stored in the forms of matrices. To model these matrix-variate data we introduce a class of separable processes using explicit latent process modeling. To account for the size and two-way structure of the data, we extend principal component analysis to achieve dimensionality reduction at the individual level. We introduce necessary identifiability conditions for each model and develop scalable estimation procedures. The method is motivated by and applied to a functional magnetic resonance imaging study designed to analyze the relationship between pain and brain activity. [ABSTRACT FROM AUTHOR]

Purpose To compare language networks derived from resting-state fMRI (rs-fMRI) with task-fMRI in patients with brain tumors and investigate variables that affect rs-fMRI vs task-fMRI concordance. Materials and Methods Independent component analysis (ICA) of rs-fMRI was performed with 20, 30, 40, and 50 target components (ICA20 to ICA50) and language networks identified for patients presenting for presurgical fMRI mapping between 1/1/2009 and 7/1/2015. 49 patients were analyzed fulfilling criteria for presence of brain tumors, no prior brain surgery, and adequate task-fMRI performance. Rs-vs-task-fMRI concordance was measured using Dice coefficients across varying fMRI thresholds before and after noise removal. Multi-thresholded Dice coefficient volume under the surface (DiceVUS) and maximum Dice coefficient (MaxDice) were calculated. One-way Analysis of Variance (ANOVA) was performed to determine significance of DiceVUS and MaxDice between the four ICA order groups. Age, Sex, Handedness, Tumor Side, Tumor Size, WHO Grade, number of scrubbed volumes, image intensity root mean square (iRMS), and mean framewise displacement (FD) were used as predictors for VUS in a linear regression. Results Artificial elevation of rs-fMRI vs task-fMRI concordance is seen at low thresholds due to noise. Noise-removed group-mean DiceVUS and MaxDice improved as ICA order increased, however ANOVA demonstrated no statistically significant difference between the four groups. Linear regression demonstrated an association between iRMS and DiceVUS for ICA30-50, and iRMS and MaxDice for ICA50. Conclusion Overall there is moderate group level rs-vs-task fMRI language network concordance, however substantial subject-level variability exists; iRMS may be used to determine reliability of rs-fMRI derived language networks. Hum Brain Mapp 37:913-923, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

• Interest in measuring phase synchronization between brain regions across time. • Analysis necessitates signals be sufficiently narrow-bandpassed. • We explore data-driven mode decomposition (MD) approaches to achieve this goal. • We compare various MD approaches. • Multivariate variational mode decomposition outperforms other MD approaches. Recently, there has been significant interest in measuring time-varying functional connectivity (TVC) between different brain regions using resting-state functional magnetic resonance imaging (rs-fMRI) data. One way to assess the relationship between signals from different brain regions is to measure their phase synchronization (PS) across time. However, this requires the a priori choice of type and cut-off frequencies for the bandpass filter needed to perform the analysis. Here we explore alternative approaches based on the use of various mode decomposition (MD) techniques that provide a more data driven solution to this issue. These techniques allow for the data driven decomposition of signals jointly into narrow-band components at different frequencies, thus fulfilling the requirements needed to measure PS. We explore several variants of MD, including empirical mode decomposition (EMD), bivariate EMD (BEMD), noise-assisted multivariate EMD (na-MEMD), and introduce the use of multivariate variational mode decomposition (MVMD) in the context of estimating time-varying PS. We contrast the approaches using a series of simulations and application to rs-fMRI data. Our results show that MVMD outperforms other evaluated MD approaches, and further suggests that this approach can be used as a tool to reliably investigate time-varying PS in rs-fMRI data. [ABSTRACT FROM AUTHOR]

Recently there has been an increased interest in using fMRI data to study the dynamic nature of brain connectivity. In this setting, the activity in a set of regions of interest (ROIs) is often modeled using a multivariate Gaussian distribution, with a mean vector and covariance matrix that are allowed to vary as the experiment progresses, representing changing brain states. In this work, we introduce the Dynamic Connectivity Detection (DCD) algorithm, which is a data-driven technique to detect temporal change points in functional connectivity, and estimate a graph between ROIs for data within each segment defined by the change points. DCD builds upon the framework of the recently developed Dynamic Connectivity Regression (DCR) algorithm, which has proven efficient at detecting changes in connectivity for problems consisting of a small to medium (<50) number of regions, but which runs into computational problems as the number of regions becomes large (>100). The newly proposed DCD method is faster, requires less user input, and is better able to handle high-dimensional data. It overcomes the shortcomings of DCR by adopting a simplified sparse matrix estimation approach and a different hypothesis testing procedure to determine change points. The application of DCD to simulated data, as well as fMRI data, illustrates the efficacy of the proposed method. [ABSTRACT FROM AUTHOR]

Functional alignment between subjects is an important assumption of functional magnetic resonance imaging (fMRI) group‐level analysis. However, it is often violated in practice, even after alignment to a standard anatomical template. Hyperalignment, based on sequential Procrustes orthogonal transformations, has been proposed as a method of aligning shared functional information into a common high‐dimensional space and thereby improving inter‐subject analysis. Though successful, current hyperalignment algorithms have a number of shortcomings, including difficulties interpreting the transformations, a lack of uniqueness of the procedure, and difficulties performing whole‐brain analysis. To resolve these issues, we propose the ProMises (Procrustes von Mises–Fisher) model. We reformulate functional alignment as a statistical model and impose a prior distribution on the orthogonal parameters (the von Mises–Fisher distribution). This allows for the embedding of anatomical information into the estimation procedure by penalizing the contribution of spatially distant voxels when creating the shared functional high‐dimensional space. Importantly, the transformations, aligned images, and related results are all unique. In addition, the proposed method allows for efficient whole‐brain functional alignment. In simulations and application to data from four fMRI studies we find that ProMises improves inter‐subject classification in terms of between‐subject accuracy and interpretability compared to standard hyperalignment algorithms. [ABSTRACT FROM AUTHOR]

Placebo treatments and opiate drugs are thought to have common effects on the opioid system and pain-related brain processes. This has created excitement about the potential for expectations to modulate drug effects themselves. If drug effects differ as a function of belief, this would challenge the assumptions underlying the standard clinical trial. We conducted two studies to directly examine the relationship between expectations and opioid analgesia. We administered the opioid agonist remifentanil to human subjects during experimental thermal pain and manipulated participants' knowledge of drug delivery using an open-hidden design. This allowed us to test drug effects, expectancy (knowledge) effects, and their interactions on pain reports and pain-related responses in the brain. Remifentanil and expectancy both reduced pain, but drug effects on pain reports and fMRI activity did not interact with expectancy. Regions associated with pain processing showed drug-induced modulation during both Open and Hidden conditions, with no differences in drug effects as a function of expectation. Instead, expectancy modulated activity in frontal cortex, with a separable time course from drug effects. These findings reveal that opiates and placebo treatments both influence clinically relevant outcomes and operate without mutual interference. [ABSTRACT FROM AUTHOR]