The VWFA: It\u27s not just for words anymore

Reading is an important but phylogenetically new skill. While neuroimaging studies have identified brain regions used in reading, it is unclear to what extent these regions become specialized for use predominantly in reading vs. other tasks. Over the past several years, our group has published three studies addressing this question, particularly focusing on whether the putative visual word form area (VWFA) is used predominantly in reading, or whether it is used more generally in a number of tasks. Our three studies utilize a range of neuroimaging techniques, including task based fMRI experiments, a seed based resting state functional connectivity (RSFC) experiment, and a network based RSFC experiment. Overall, our studies indicate that the VWFA is not used specifically or even predominantly for reading. Rather the VWFA is a general use region that has processing properties making it particularly useful for reading, though it continues to be used in any task that requires its general processing properties. Our network based RSFC analysis extends this finding to other regions typically thought to be used predominantly for reading. Here, we review these findings and describe how the three studies complement each other. Then, we argue that conceptualizing the VWFA as a brain region with specific processing characteristics rather than a brain region devoted to a specific stimulus class, allows us to better explain the activity seen in this region during a variety of tasks. Having this type of conceptualization not only provides a better understanding of the VWFA but also provides a framework for understanding other brain regions, as it affords an explanation of function that is in keeping with the long history of studying the brain in terms of the type of information processing performed (Posner, 1978)

Task Control Signals in Pediatric Tourette Syndrome Show Evidence of Immature and Anomalous Functional Activity

Tourette Syndrome (TS) is a pediatric movement disorder that may affect control signaling in the brain. Previous work has proposed a dual-networks architecture of control processing involving a task-maintenance network and an adaptive control network (Dosenbach et al., 2008). A prior resting-state functional connectivity MRI (rs-fcMRI) analysis in TS has revealed functional immaturity in both putative control networks, with “anomalous” correlations (i.e., correlations outside the typical developmental range) limited to the adaptive control network (Church et al., 2009). The present study used functional MRI (fMRI) to study brain activity related to adaptive control (by studying start-cues signals), and to task-maintenance (by studying signals sustained across a task set). Two hypotheses from the previous rs-fcMRI results were tested. First, adaptive control (i.e., start-cue) activity will be altered in TS, including activity inconsistent with typical development (“anomalous”). Second, group differences found in task-maintenance (i.e., sustained) activity will be consistent with functional immaturity in TS. We examined regions found through a direct comparison of adolescents with and without TS, as well as regions derived from a previous investigation that showed differences between unaffected children and adults. The TS group showed decreased start-cue signal magnitude in regions where start-cue activity is unchanged over typical development, consistent with anomalous adaptive control. The TS group also had higher magnitude sustained signals in frontal cortex regions that overlapped with regions showing differences over typical development, consistent with immature task-maintenance in TS. The results demonstrate task-related fMRI signal differences anticipated by the atypical functional connectivity found previously in adolescents with TS, strengthening the evidence for functional immaturity and anomalous signaling in control networks in adolescents with TS

Studying Brain Organization via Spontaneous fMRI Signal

In recent years, some substantial advances in understanding human (and nonhuman) brain organization have emerged from a relatively unusual approach: the observation of spontaneous activity, and correlated patterns in spontaneous activity, in the “resting” brain. Most commonly, spontaneous neural activity is measured indirectly via fMRI signal in subjects who are lying quietly in the scanner, the so-called “resting state.” This Primer introduces the fMRI-based study of spontaneous brain activity, some of the methodological issues active in the field, and some ways in which resting-state fMRI has been used to delineate aspects of area-level and supra-areal brain organization

Role of the anterior insula in task-level control and focal attention

In humans, the anterior insula (aI) has been the topic of considerable research and ascribed a vast number of functional properties by way of neuroimaging and lesion studies. Here, we argue that the aI, at least in part, plays a role in domain-general attentional control and highlight studies (Dosenbach et al. 2006; Dosenbach et al. 2007) supporting this view. Additionally, we discuss a study (Ploran et al. 2007) that implicates aI in processes related to the capture of focal attention. Task-level control and focal attention may or may not reflect information processing supported by a single functional area (within the aI). Therefore, we apply a novel technique (Cohen et al. 2008) that utilizes resting state functional connectivity MRI (rs-fcMRI) to determine whether separable regions exist within the aI. rs-fcMRI mapping suggests that the ventral portion of the aI is distinguishable from more dorsal/anterior regions, which are themselves distinct from more posterior parts of the aI. When these regions are applied to functional MRI (fMRI) data, the ventral and dorsal/anterior regions support processes potentially related to both task-level control and focal attention, whereas the more posterior aI regions did not. These findings suggest that there exists some functional heterogeneity within aI that may subserve related but distinct types of higher-order cognitive processing

Manipulation of length and lexicality localizes the functional neuroanatomy of phonological processing in adult readers

In a previous study of single word reading, regions in the left supramarginal gyrus and left angular gyrus showed positive BOLD activity in children but significantly less activity in adults for high-frequency words. This developmental decrease may reflect decreased reliance on phonological processing for familiar stimuli in adults. Therefore, in the present study, variables thought to influence phonological demand (string length and lexicality) were manipulated. Length and lexicality effects in the brain were explored using both ROI and whole-brain approaches. In the ROI analysis, the supramarginal and angular regions from the previous study were applied to this study. The supramarginal region showed a significant positive effect of length, consistent with a role in phonological processing, whereas the angular region showed only negative deflections from baseline with a strong effect of lexicality and other weaker effects. At the whole-brain level, varying effects of length and lexicality and their interactions were observed in 85 regions throughout the brain. The application of hierarchical clustering analysis to the BOLD time course data derived from these regions revealed seven clusters, with potentially revealing anatomical locations. Of note, a left angular gyrus region was the sole constituent of one cluster. Taken together, these findings in adult readers (1) provide support for a widespread set of brain regions affected by lexical variables, (2) corroborate a role for phonological processing in the left supramarginal gyrus, and (3) do not support a strong role for phonological processing in the left angular gyrus

Multivariate pattern classification of pediatric Tourette syndrome using functional connectivity MRI

Tourette syndrome (TS) is a developmental neuropsychiatric disorder characterized by motor and vocal tics. Individuals with TS would benefit greatly from advances in prediction of symptom timecourse and treatment effectiveness. As a first step, we applied a multivariate method - support vector machine (SVM) classification - to test whether patterns in brain network activity, measured with resting state functional connectivity (RSFC) MRI, could predict diagnostic group membership for individuals. RSFC data from 42 children with TS (8-15 yrs) and 42 unaffected controls (age, IQ, in-scanner movement matched) were included. While univariate tests identified no significant group differences, SVM classified group membership with ~70% accuracy (p < .001). We also report a novel adaptation of SVM binary classification that, in addition to an overall accuracy rate for the SVM, provides a confidence measure for the accurate classification of each individual. Our results support the contention that multivariate methods can better capture the complexity of some brain disorders, and hold promise for predicting prognosis and treatment outcome for individuals with TS

Response of greater sage-grouse to surface coal mining and habitat conservation in association with the mine

Greater sage-grouse (Centrocercus urophasianus; sage-grouse) is a sagebrushobligate species that has experienced species-wide declines in population density and distribution. Sage-grouse habitats support human-related needs including domestic livestock grazing, urban development, and energy extraction. The U.S. Fish and Wildlife Service identified energy extraction as a range-wide sage-grouse conservation threat. Mining has been of specific concern because of observed sage-grouse population declines and impaired habitat within close proximity to the activity. Mining may be particularly problematic for small, isolated sage-grouse populations. In southwestern Utah, proactive habitat improvements and predator management have been implemented to mitigate the potential effects of surface mining on the southernmost population of sage-grouse in the United States. We evaluated sage-grouse lek attendance trends before (1991–2010) and during (2011–2016) mining on a lek located near the mine (Sink Valley lek) to assess population responses to coal mining and related mitigation activities. Changes in lek trends have been demonstrated as a valid metric to assess the effects of conservation actions on sage-grouse populations. We used a paired t-test to compare differences in male lek attendance before and during mining and analysis of variance to determine if sage-grouse densities and distance to mining changed during the mining period. We recorded bird coordinate location and the number of birds observed at each sighting location along 10 transects within the study site area. Differences in location from mining was tested using Analysis of Variance with α \u3c 0.5. There was no difference in the number of males attending the Sink Valley lek before and during mining. Population cycles were consistent over the time period sampled. With the exception of 2013, which had an unusually high number of sage-grouse found within the Sink Valley area, there were no differences in the number of birds observed at each sighting location in relation to the mine center (P = 0.37), the coal crushing facility (P = 0.34), and the mine boundary (P = 0.24). Coupled with ongoing mitigation activities including habitat restoration, pinyon-juniper (Pinus edulis, Juniperus osteosperma) removal, aggressive predator control, pre-mining acclimation to human influences, and removal of pinyon-juniper woodlands, surface coal mining had no negative effect on population cycles in the Alton/Sink Valley area

History-Adjusted Marginal Structural Models to Estimate Time-Varying Effect Modification

Much of epidemiology and clinical medicine is focused on the estimation of treatments or interventions administered over time. In such settings of longitudinal treatment, time-dependent confounding is often an important source of bias. Marginal structural models are a powerful tool for estimating the causal effect of a treatment using observational data, particularly when time-dependent confounding is present. Recent statistical work presented a generalization of marginal structural models, called history-adjusted marginal structural models. Unlike standard marginal structural models, history-adjusted marginal structural models can be used to estimate modification of treatment effects by time-varying covariates. Estimation of time-dependent causal effect modification is frequently of great practical relevance. For example, clinical researchers are often interested in how the prognostic significance of a biomarker for treatment response can change over time. This article provides a practical introduction to the implementation and interpretation of history-adjusted marginal structural models. The method is illustrated using a clinical question drawn from the treatment of HIV infection. Observational cohort data from San Francisco, California, collected between 2000 and 2004, are used to estimate the effect of time until switching antiretroviral therapy regimen among patients receiving a non-suppressive regimen, and how this effect differs depending on CD4 T cell count

Identifying Basal Ganglia Divisions in Individuals Using Resting-State Functional Connectivity MRI

Studies in non-human primates and humans reveal that discrete regions (henceforth, “divisions”) in the basal ganglia are intricately interconnected with regions in the cerebral cortex. However, divisions within basal ganglia nuclei (e.g., within the caudate) are difficult to identify using structural MRI. Resting-state functional connectivity MRI (rs-fcMRI) can be used to identify putative cerebral cortical functional areas in humans (Cohen et al., 2008). Here, we determine whether rs-fcMRI can be used to identify divisions in individual human adult basal ganglia. Putative basal ganglia divisions were generated by assigning basal ganglia voxels to groups based on the similarity of whole-brain functional connectivity correlation maps using modularity optimization, a network analysis tool. We assessed the validity of this approach by examining the spatial contiguity and location of putative divisions and whether divisions’ correlation maps were consistent with previously reported patterns of anatomical and functional connectivity. Spatially constrained divisions consistent with the dorsal caudate, ventral striatum, and dorsal caudal putamen could be identified in each subject. Further, correlation maps associated with putative divisions were consistent with their presumed connectivity. These findings suggest that, as in the cerebral cortex, subcortical divisions can be identified in individuals using rs-fcMRI. Developing and validating these methods should improve the study of brain structure and function, both typical and atypical, by allowing for more precise comparison across individuals

Spatial and temporal characteristics of error-related activity in the human brain

A number of studies have focused on the role of specific brain regions, such as the dorsal anterior cingulate cortex during trials on which participants make errors, whereas others have implicated a host of more widely distributed regions in the human brain. Previous work has proposed that there are multiple cognitive control networks, raising the question of whether error-related activity can be found in each of these networks. Thus, to examine error-related activity broadly, we conducted a meta-analysis consisting of 12 tasks that included both error and correct trials. These tasks varied by stimulus input (visual, auditory), response output (button press, speech), stimulus category (words, pictures), and task type (e.g., recognition memory, mental rotation). We identified 41 brain regions that showed a differential fMRI BOLD response to error and correct trials across a majority of tasks. These regions displayed three unique response profiles: (1) fast, (2) prolonged, and (3) a delayed response to errors, as well as a more canonical response to correct trials. These regions were found mostly in several control networks, each network predominantly displaying one response profile. The one exception to this “one network, one response profile” observation is the frontoparietal network, which showed prolonged response profiles (all in the right hemisphere), and fast profiles (all but one in the left hemisphere). We suggest that, in the place of a single localized error mechanism, these findings point to a large-scale set of error-related regions across multiple systems that likely subserve different function