@article {843, title = {Cloak and DAG: a response to the comments on our comment.}, journal = {Neuroimage}, volume = {76}, year = {2013}, month = {2013 Aug 1}, pages = {446-9}, abstract = {

Our original comment (Lindquist and Sobel, 2011) made explicit the types of assumptions neuroimaging researchers are making when directed graphical models (DGMs), which include certain types of structural equation models (SEMs), are used to estimate causal effects. When these assumptions, which many researchers are not aware of, are not met, parameters of these models should not be interpreted as effects. Thus it is imperative that neuroimaging researchers interested in issues involving causation, for example, effective connectivity, consider the plausibility of these assumptions for their particular problem before using SEMs. In cases where these additional assumptions are not met, researchers may be able to use other methods and/or design experimental studies where the use of unrealistic assumptions can be avoided. Pearl does not disagree with anything we stated. However, he takes exception to our use of potential outcomes{\textquoteright} notation, which is the standard notation used in the statistical literature on causal inference, and his comment is devoted to promoting his alternative conventions. Glymour{\textquoteright}s comment is based on three claims that he inappropriately attributes to us. Glymour is also more optimistic than us about the potential of using directed graphical models (DGMs) to discover causal relations in neuroimaging research; we briefly address this issue toward the end of our rejoinder.

}, keywords = {Artifacts, Brain, Computer Simulation, Humans, Image Interpretation, Computer-Assisted, Meta-Analysis as Topic}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2011.11.027}, author = {Lindquist, Martin A and Sobel, Michael E} } @article {839, title = {An fMRI-based neurologic signature of physical pain.}, journal = {N Engl J Med}, volume = {368}, year = {2013}, month = {2013 Apr 11}, pages = {1388-97}, abstract = {

BACKGROUND: Persistent pain is measured by means of self-report, the sole reliance on which hampers diagnosis and treatment. Functional magnetic resonance imaging (fMRI) holds promise for identifying objective measures of pain, but brain measures that are sensitive and specific to physical pain have not yet been identified.

METHODS: In four studies involving a total of 114 participants, we developed an fMRI-based measure that predicts pain intensity at the level of the individual person. In study 1, we used machine-learning analyses to identify a pattern of fMRI activity across brain regions--a neurologic signature--that was associated with heat-induced pain. The pattern included the thalamus, the posterior and anterior insulae, the secondary somatosensory cortex, the anterior cingulate cortex, the periaqueductal gray matter, and other regions. In study 2, we tested the sensitivity and specificity of the signature to pain versus warmth in a new sample. In study 3, we assessed specificity relative to social pain, which activates many of the same brain regions as physical pain. In study 4, we assessed the responsiveness of the measure to the analgesic agent remifentanil.

RESULTS: In study 1, the neurologic signature showed sensitivity and specificity of 94\% or more (95\% confidence interval [CI], 89 to 98) in discriminating painful heat from nonpainful warmth, pain anticipation, and pain recall. In study 2, the signature discriminated between painful heat and nonpainful warmth with 93\% sensitivity and specificity (95\% CI, 84 to 100). In study 3, it discriminated between physical pain and social pain with 85\% sensitivity (95\% CI, 76 to 94) and 73\% specificity (95\% CI, 61 to 84) and with 95\% sensitivity and specificity in a forced-choice test of which of two conditions was more painful. In study 4, the strength of the signature response was substantially reduced when remifentanil was administered.

CONCLUSIONS: It is possible to use fMRI to assess pain elicited by noxious heat in healthy persons. Future studies are needed to assess whether the signature predicts clinical pain. (Funded by the National Institute on Drug Abuse and others.).

}, keywords = {Adult, Analgesics, Opioid, Artificial Intelligence, Brain, brain mapping, Female, Hot Temperature, Humans, Magnetic Resonance Imaging, Male, Pain, Pain Measurement, Piperidines, ROC Curve, Sensitivity and Specificity, Young Adult}, issn = {1533-4406}, doi = {10.1056/NEJMoa1204471}, author = {Wager, Tor D and Atlas, Lauren Y and Lindquist, Martin A and Roy, Mathieu and Woo, Choong-Wan and Kross, Ethan} } @article {841, title = {Dissociable influences of opiates and expectations on pain.}, journal = {J Neurosci}, volume = {32}, year = {2012}, month = {2012 Jun 6}, pages = {8053-64}, abstract = {

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{\textquoteright} 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.

}, keywords = {Analgesics, Opioid, Anticipation, Psychological, Behavior, brain mapping, Dose-Response Relationship, Drug, Female, Hemodynamics, Hot Temperature, Humans, Image Processing, Computer-Assisted, Injections, Intravenous, Linear Models, Magnetic Resonance Imaging, Male, Pain, Pain Measurement, Piperidines, Young Adult}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.0383-12.2012}, author = {Atlas, Lauren Y and Whittington, Robert A and Lindquist, Martin A and Wielgosz, Joe and Sonty, Nomita and Wager, Tor D} } @article {842, title = {Dynamic connectivity regression: determining state-related changes in brain connectivity.}, journal = {Neuroimage}, volume = {61}, year = {2012}, month = {2012 Jul 16}, pages = {907-20}, abstract = {

Most statistical analyses of fMRI data assume that the nature, timing and duration of the psychological processes being studied are known. However, often it is hard to specify this information a priori. In this work we introduce a data-driven technique for partitioning the experimental time course into distinct temporal intervals with different multivariate functional connectivity patterns between a set of regions of interest (ROIs). The technique, called Dynamic Connectivity Regression (DCR), detects temporal change points in functional connectivity and estimates a graph, or set of relationships between ROIs, for data in the temporal partition that falls between pairs of change points. Hence, DCR allows for estimation of both the time of change in connectivity and the connectivity graph for each partition, without requiring prior knowledge of the nature of the experimental design. Permutation and bootstrapping methods are used to perform inference on the change points. The method is applied to various simulated data sets as well as to an fMRI data set from a study (N=26) of a state anxiety induction using a socially evaluative threat challenge. The results illustrate the method{\textquoteright}s ability to observe how the networks between different brain regions changed with subjects{\textquoteright} emotional state.

}, keywords = {Algorithms, Brain, brain mapping, Computer Simulation, Emotions, Humans, Image Interpretation, Computer-Assisted, Magnetic Resonance Imaging, Neural Pathways}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2012.03.070}, author = {Cribben, Ivor and Haraldsdottir, Ragnheidur and Atlas, Lauren Y and Wager, Tor D and Lindquist, Martin A} } @article {844, title = {Estimating and testing variance components in a multi-level GLM.}, journal = {Neuroimage}, volume = {59}, year = {2012}, month = {2012 Jan 2}, pages = {490-501}, abstract = {

Most analysis of multi-subject fMRI data is concerned with determining whether there exists a significant population-wide {\textquoteright}activation{\textquoteright} in a comparison between two or more conditions. This is typically assessed by testing the average value of a contrast of parameter estimates (COPE) against zero in a general linear model (GLM) analysis. However, important information can also be obtained by testing whether there exist significant individual differences in effect magnitude between subjects, i.e. whether the variance of a COPE is significantly different from zero. Intuitively, such a test amounts to testing whether inter-individual differences are larger than would be expected given the within-subject error variance. We compare several methods for estimating variance components, including a) a na{\"\i}ve estimate using ordinary least squares (OLS); b) linear mixed effects in R (LMER); c) a novel Matlab implementation of iterative generalized least squares (IGLS) and its restricted maximum likelihood variant (RIGLS). All methods produced reasonable estimates of within- and between-subject variance components, with IGLS providing an attractive balance between sensitivity and appropriate control of false positives. Finally, we use the IGLS method to estimate inter-subject variance in a perfusion fMRI study (N=18) of social evaluative threat, and show evidence for significant inter-individual differences in ventromedial prefrontal cortex (VMPFC), amygdala, hippocampus and medial temporal lobes, insula, and brainstem, with predicted inverse coupling between VMPFC and the midbrain periaqueductal gray only when high inter-individual variance was used to define the seed for functional connectivity analyses. In sum, tests of variance provides a way of selecting regions that show significant inter-individual variability for subsequent analyses that attempt to explain those individual differences.

}, keywords = {Brain, brain mapping, Humans, Image Interpretation, Computer-Assisted, Linear Models, Magnetic Resonance Imaging, Models, Neurological, Sensitivity and Specificity}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2011.07.077}, author = {Lindquist, Martin A and Spicer, Julie and Asllani, Iris and Wager, Tor D} } @article {845, title = {Graphical models, potential outcomes and causal inference: comment on Ramsey, Spirtes and Glymour.}, journal = {Neuroimage}, volume = {57}, year = {2011}, month = {2011 Jul 15}, pages = {334-6}, abstract = {

Ramsey, Spirtes and Glymour (RSG) critique a method proposed by Neumann et al. (2010) for the discovery of functional networks from fMRI meta-analysis data. We concur with this critique, but are unconvinced that directed graphical models (DGMs) are generally useful for estimating causal effects. We express our reservations using the "potential outcomes" framework for causal inference widely used in statistics.

}, keywords = {Artifacts, Brain, Computer Simulation, Humans, Image Interpretation, Computer-Assisted, Meta-Analysis as Topic}, issn = {1095-9572}, doi = {10.1016/j.neuroimage.2010.10.020}, author = {Lindquist, Martin A and Sobel, Michael E} } @article {846, title = {Brain mediators of predictive cue effects on perceived pain.}, journal = {J Neurosci}, volume = {30}, year = {2010}, month = {2010 Sep 29}, pages = {12964-77}, abstract = {

Information about upcoming pain strongly influences pain experience in experimental and clinical settings, but little is known about the brain mechanisms that link expectation and experience. To identify the pathways by which informational cues influence perception, analyses must jointly consider both the effects of cues on brain responses and the relationship between brain responses and changes in reported experience. Our task and analysis strategy were designed to test these relationships. Auditory cues elicited expectations for barely painful or highly painful thermal stimulation, and we assessed how cues influenced human subjects{\textquoteright} pain reports and brain responses to matched levels of noxious heat using functional magnetic resonance imaging. We used multilevel mediation analysis to identify brain regions that (1) are modulated by predictive cues, (2) predict trial-to-trial variations in pain reports, and (3) formally mediate the relationship between cues and reported pain. Cues influenced heat-evoked responses in most canonical pain-processing regions, including both medial and lateral pain pathways. Effects on several regions correlated with pretask expectations, suggesting that expectancy plays a prominent role. A subset of pain-processing regions, including anterior cingulate cortex, anterior insula, and thalamus, formally mediated cue effects on pain. Effects on these regions were in turn mediated by cue-evoked anticipatory activity in the medial orbitofrontal cortex (OFC) and ventral striatum, areas not previously directly implicated in nociception. These results suggest that activity in pain-processing regions reflects a combination of nociceptive input and top-down information related to expectations, and that anticipatory processes in OFC and striatum may play a key role in modulating pain processing.

}, keywords = {Adult, Brain, Cognition, Cues, Female, Hot Temperature, Humans, Male, Pain, Pain Threshold, Perception, Physical Stimulation}, issn = {1529-2401}, doi = {10.1523/JNEUROSCI.0057-10.2010}, author = {Atlas, Lauren Y and Bolger, Niall and Lindquist, Martin A and Wager, Tor D} }