Shared and Distinct Neuroanatomic Regions Critical for Tool-related Action Production and Recognition: Evidence from 131 Left-hemisphere Stroke Patients.

The inferior frontal gyrus and inferior parietal lobe have been characterized as human homologues of the monkey "mirror neuron" system, critical for both action production (AP) and action recognition (AR). However, data from brain lesion patients with selective impairment on only one of these tasks provide evidence of neural and cognitive dissociations. We sought to clarify the relationship between AP and AR, and their critical neural substrates, by directly comparing performance of 131 chronic left-hemisphere stroke patients on both tasks--to our knowledge, the largest lesion-based experimental investigation of action cognition to date. Using voxel-based lesion-symptom mapping, we found that lesions to primary motor and somatosensory cortices and inferior parietal lobule were associated with disproportionately impaired performance on AP, whereas lesions to lateral temporo-occipital cortex were associated with a relatively rare pattern of disproportionately impaired performance on AR. In contrast, damage to posterior middle temporal gyrus was associated with impairment on both AP and AR. The distinction between lateral temporo-occipital cortex, critical for recognition, and posterior middle temporal gyrus, important for both tasks, suggests a rough gradient from modality-specific to abstract representations in posterior temporal cortex, the first lesion-based evidence for this phenomenon. Overall, the results of this large patient study help to bring closure to a long-standing debate by showing that tool-related AP and AR critically depend on both common and distinct left hemisphere neural substrates, most of which are external to putative human mirror regions.

Regulatory T cells restrict immunity and pathology in distal tissue sites following a localized infection.

Regulatory T cells (Tregs) are well-known to mediate peripheral tolerance at homeostasis, and there is a growing appreciation for their role in modulating infectious disease immunity. Following acute and chronic infections, Tregs can restrict pathogen-specific T cell responses to limit immunopathology. However, it is unclear if Tregs mediate control of pathology and immunity in distal tissue sites during localized infections. We investigated the role of Tregs in immunity and disease in various tissue compartments in the context of "mild" vaginal Zika virus infection. We found that Tregs are critical to generating robust virus-specific CD8 T cell responses in the initial infection site. Further, Tregs limit inflammatory cytokines and immunopathology during localized infection; a dysregulated immune response in Treg-depleted mice leads to increased T cell infiltrates and immunopathology in both the vagina and the central nervous system (CNS). Importantly, these CNS infiltrates are not present at the same magnitude during infection of Treg-sufficient mice, in which there is no CNS immunopathology. Our data suggest that Tregs are necessary to generate a robust virus-specific response at the mucosal site of infection, while Treg-mediated restriction of bystander inflammation limits immunopathology both at the site of infection as well as distal tissue sites.

Action concepts in the brain: an activation likelihood estimation meta-analysis.

Many recent neuroimaging studies have investigated the representation of semantic memory for actions in the brain. We used activation likelihood estimation (ALE) meta-analyses to answer two outstanding questions about the neural basis of action concepts. First, on an "embodied" view of semantic memory, evidence to date is unclear regarding whether visual motion or motor systems are more consistently engaged by action concepts. Second, few studies have directly investigated the possibility that action concepts accessed verbally or nonverbally recruit different areas of the brain. Because our meta-analyses did not include studies requiring the perception of dynamic depictions of actions or action execution, we were able to determine whether conceptual processing alone recruits visual motion and motor systems. Significant concordance in brain regions within or adjacent to visual motion areas emerged in all meta-analyses. By contrast, we did not observe significant concordance in motor or premotor cortices in any analysis. Neural differences between action images and action verbs followed a gradient of abstraction among representations derived from visual motion information in the left lateral temporal and occipital cortex. The consistent involvement of visual motion but not motor brain regions in representing action concepts may reflect differences in the variability of experience across individuals with perceiving versus performing actions.

A bilateral frontoparietal network underlies visuospatial analogical reasoning.

Our ability to reason by analogy facilitates problem solving and allows us to communicate ideas efficiently. In this study, we examined the neural correlates of analogical reasoning and, more specifically, the contribution of rostrolateral prefrontal cortex (RLPFC) to reasoning. This area of the brain has been hypothesized to integrate relational information, as in analogy, or the outcomes of subgoals, as in multi-tasking and complex problem solving. Using fMRI, we compared visuospatial analogical reasoning to a control task that was as complex and difficult as the analogies and required the coordination of subgoals but not the integration of relations. We found that analogical reasoning more strongly activated bilateral RLPFC, suggesting that anterior prefrontal cortex is preferentially recruited by the integration of relational knowledge. Consistent with the need for inhibition during analogy, bilateral, and particularly right, inferior frontal gyri were also more active during analogy. Finally, greater activity in bilateral inferior parietal cortex during the analogy task is consistent with recent evidence for the neural basis of spatial relation knowledge. Together, these findings indicate that a network of frontoparietal areas underlies analogical reasoning; we also suggest that hemispheric differences may emerge depending on the visuospatial or verbal/semantic nature of the analogies.

From novel to familiar: tuning the brain for metaphors.

Metaphors are fundamental to creative thought and expression. Newly coined metaphors regularly infiltrate our collective vocabulary and gradually become familiar, but it is unclear how this shift from novel to conventionalized meaning happens in the brain. We investigated the neural career of metaphors in a functional magnetic resonance imaging study using extensively normed new metaphors and simulated the ordinary, gradual experience of metaphor conventionalization by manipulating participants' exposure to these metaphors. Results showed that the conventionalization of novel metaphors specifically tunes activity within bilateral inferior prefrontal cortex, left posterior middle temporal gyrus, and right postero-lateral occipital cortex. These results support theoretical accounts attributing a role for the right hemisphere in processing novel, low salience figurative meanings, but also show that conventionalization of metaphoric meaning is a bilaterally-mediated process. Metaphor conventionalization entails a decreased neural load within semantic networks rather than a hemispheric or regional shift across brain areas.

SOS! An algorithm and software for the stochastic optimization of stimuli.

The characteristics of the stimuli used in an experiment critically determine the theoretical questions the experiment can address. Yet there is relatively little methodological support for selecting optimal sets of items, and most researchers still carry out this process by hand. In this research, we present SOS, an algorithm and software package for the stochastic optimization of stimuli. SOS takes its inspiration from a simple manual stimulus selection heuristic that has been formalized and refined as a stochastic relaxation search. The algorithm rapidly and reliably selects a subset of possible stimuli that optimally satisfy the constraints imposed by an experimenter. This allows the experimenter to focus on selecting an optimization problem that suits his or her theoretical question and to avoid the tedious task of manually selecting stimuli. We detail how this optimization algorithm, combined with a vocabulary of constraints that define optimal sets, allows for the quick and rigorous assessment and maximization of the internal and external validity of experimental items. In doing so, the algorithm facilitates research using factorial, multiple/mixed-effects regression, and other experimental designs. We demonstrate the use of SOS with a case study and discuss other research situations that could benefit from this tool. Support for the generality of the algorithm is demonstrated through Monte Carlo simulations on a range of optimization problems faced by psychologists. The software implementation of SOS and a user manual are provided free of charge for academic purposes as precompiled binaries and MATLAB source files at http://sos.cnbc.cmu.edu.

Differences in rural and urban drivers' attitudes and beliefs about seat belts.

In the United States, a disproportionate number of motor vehicle crash fatalities occur in rural areas. While many factors likely contribute to the discrepancy between fatality rates in rural and urban areas, prior studies suggest that rural drivers may be more likely to engage in risky driving behaviors like seat belt non-use. Although having favorable attitudes or beliefs about seat belts increases the likelihood of wearing them, few studies have investigated the possibility that lower rates of seat belt use in rural areas may result from a greater prevalence of unfavorable seat belt attitudes and beliefs-one part of a distinct rural "traffic safety culture." In the current study, we analyzed responses from the 2016 Motor Vehicle Occupant Safety Survey (MVOSS) to test the hypotheses that rural drivers are more likely than urban drivers to hold unfavorable attitudes and beliefs about seat belts, and that these unfavorable attitudes and beliefs predict lower self-reported seat belt use. We found that rural and urban drivers differed significantly on several seat belt attitudes and beliefs and that these differences persisted after controlling for possible demographic differences between rural and urban drivers. We also found that drivers who hold less favorable attitudes and beliefs were less likely to always wear their seat belts. However, even after accounting for demographic factors and differences in attitudes and beliefs, rural drivers continued to be less likely to report full-time seat belt use than urban drivers. Our findings suggest that rural drivers should be treated as a distinct market segment for seat belt messaging and public awareness campaigns, and that interventions designed to change the unfavorable attitudes and beliefs about seat belts held by rural drivers may help reduce the disparity between rural and urban traffic fatality rates.

Bilateral functional connectivity at rest predicts apraxic symptoms after left hemisphere stroke.

Increasing evidence indicates that focal lesions following stroke cause alterations in connectivity among functional brain networks. Functional connectivity between hemispheres has been shown to be particularly critical for predicting stroke-related behavioral deficits and recovery of motor function and attention. Much less is known, however, about the relevance of interhemispheric functional connectivity for cognitive abilities like praxis that rely on strongly lateralized brain networks. In the current study, we examine correlations between symptoms of apraxia-a disorder of skilled action that cannot be attributed to lower-level sensory or motor impairments-and spontaneous, resting brain activity in functional MRI in chronic left hemisphere stroke patients and neurologically-intact control participants. Using a data-driven approach, we identified 32 regions-of-interest in which pairwise functional connectivity correlated with two distinct measures of apraxia, even when controlling for age, head motion, lesion volume, and other artifacts: overall ability to pantomime the typical use of a tool, and disproportionate difficulty pantomiming the use of tools associated with different, competing use and grasp-to-move actions (e.g., setting a kitchen timer versus picking it up). Better performance on both measures correlated with stronger interhemispheric functional connectivity. Relevant regions in the right hemisphere were often homologous to left hemisphere areas associated with tool use and action. Additionally, relative to overall pantomime accuracy, disproportionate difficulty pantomiming the use of tools associated with competing use and grasp actions was associated with weakened functional connectivity among a more strongly left-lateralized and peri-Sylvian set of brain regions. Finally, patient performance on both measures of apraxia was best predicted by a model that incorporated information about lesion location and functional connectivity, and functional connectivity continued to explain unique variance in behavior even after accounting for lesion loci. These results indicate that interhemispheric functional connectivity is relevant even for a strongly lateralized cognitive ability like praxis and emphasize the importance of the right hemisphere in skilled action.

A distributed network critical for selecting among tool-directed actions.

Tools pose a challenge to the need to select actions appropriate for task goals and environmental constraints. For many tools (e.g., calculator), actions for "using" and "grasping-to-move" conflict with each other and may compete during selection. To date, little is known about the mechanisms that enable selection between possible tool actions or their neural substrates. The study of patients with chronic left hemisphere stroke, many of whom are deficient in tool-use action (apraxic), provides an opportunity to elucidate these issues. Here, 31 such patients pantomimed or recognized tool use actions for "conflict" and "non-conflict" tools. Voxel-based lesion-symptom mapping (VLSM), lesion subtraction, and tractographic overlap analyses were used to determine brain regions necessary for selecting among tool-directed actions. Lesions to posterior middle temporal gyrus (pMTG) and anterior intraparietal sulcus (aIPS) tended to impair production of use actions similarly for both conflict and non-conflict tools. By contrast, lesions to the supramarginal gyrus (SMG), inferior frontal gyrus (IFG)/anterior insula, and superior longitudinal fasciculus (SLF) specifically impaired production of use actions for conflict tools. Patients' errors on conflict tools suggested inappropriate selection of grasping actions and difficulty selecting single actions. Use/grasp conflict had no effect on action recognition. We suggest that the SMG/SLF/IFG pathway implements biased competition between possible tool actions, while aIPS and pMTG compute the structure-based and skilled use actions, respectively, that constitute input to this competitive process. This is the first study to demonstrate a reliable link between a characteristic of single tools (i.e., their association with different use and grasp actions) and action selection difficulties. Additionally, the data allow us to posit an SMG-involved subtype of apraxia characterized by an inability to resolve action competition.

Corrigendum: The role of action representations in thematic object relations.

[This corrects the article on p. 140 in vol. 8, PMID: 24672461.].

Uncovering the architecture of action semantics.

Despite research suggesting that stored sensorimotor information about tool use is a component of the semantic representations of tools, little is known about the action features or organizing principles that underlie this knowledge. We used methods similar to those applied in other semantic domains to examine the "architecture" of action semantic knowledge. In Experiment 1, participants sorted photographs of tools into groups according to the similarity of their associated "use" actions and rated tools on dimensions related to action. The results suggest that the magnitude of arm movement, configuration of the hand, and manner of motion during tool use play a role in determining how tools cluster in action "semantic space." In Experiment 2, we validated the architecture uncovered in Experiment 1 using an implicit semantic task for which tool use knowledge was not ostensibly relevant (blocked cyclic word-picture matching). Using stimuli from Experiment 1, we found that participants performed more poorly during blocks of trials containing tools used with similar versus unrelated actions, and the amount of semantic interference depended on the magnitude of action similarity among tools. Thus, the degree of featural overlap between tool use actions plays a role in determining the overall semantic similarity of tools.

The specificity of action knowledge in sensory and motor systems.

Neuroimaging studies have found that sensorimotor systems are engaged when participants observe actions or comprehend action language. However, most of these studies have asked the binary question of whether action concepts are embodied or not, rather than whether sensory and motor areas of the brain contain graded amounts of information during putative action simulations. To address this question, we used repetition suppression (RS) functional magnetic resonance imaging to determine if functionally-localized motor movement and visual motion regions-of-interest (ROI) and two anatomical ROIs (inferior frontal gyrus, IFG; left posterior middle temporal gyrus, pMTG) were sensitive to changes in the exemplar (e.g., two different people "kicking") or representational format (e.g., photograph or schematic drawing of someone "kicking") within pairs of action images. We also investigated whether concrete versus more symbolic depictions of actions (i.e., photographs or schematic drawings) yielded different patterns of activation throughout the brain. We found that during a conceptual task, sensory and motor systems represent actions at different levels of specificity. While the visual motion ROI did not exhibit RS to different exemplars of the same action or to the same action depicted by different formats, the motor movement ROI did. These effects are consistent with "person-specific" action simulations: if the motor system is recruited for action understanding, it does so by activating one's own motor program for an action. We also observed significant repetition enhancement within the IFG ROI to different exemplars or formats of the same action, a result that may indicate additional cognitive processing on these trials. Finally, we found that the recruitment of posterior brain regions by action concepts depends on the format of the input: left lateral occipital cortex and right supramarginal gyrus responded more strongly to symbolic depictions of actions than concrete ones.

The role of action representations in thematic object relations.

A number of studies have explored the role of associative/event-based (thematic) and categorical (taxonomic) relations in the organization of object representations. Recent evidence suggests that thematic information may be particularly important in determining relationships between manipulable artifacts. However, although sensorimotor information is on many accounts an important component of manipulable artifact representations, little is known about the role that action may play during the processing of semantic relationships (particularly thematic relationships) between multiple objects. In this study, we assessed healthy and left hemisphere stroke participants to explore three questions relevant to object relationship processing. First, we assessed whether participants tended to favor thematic relations including action (Th+A, e.g., wine bottle-corkscrew), thematic relationships without action (Th-A, e.g., wine bottle-cheese), or taxonomic relationships (Tax, e.g., wine bottle-water bottle) when choosing between them in an association judgment task with manipulable artifacts. Second, we assessed whether the underlying constructs of event relatedness, action relatedness, and categorical relatedness determined the choices that participants made. Third, we assessed the hypothesis that degraded action knowledge and/or damage to temporo-parietal cortex, a region of the brain associated with the representation of action knowledge, would reduce the influence of action on the choice task. Experiment 1 showed that explicit ratings of event, action, and categorical relatedness were differentially predictive of healthy participants' choices, with action relatedness determining choices between Th+A and Th-A associations above and beyond event and categorical ratings. Experiment 2 focused more specifically on these Th+A vs. Th-A choices and demonstrated that participants with left temporo-parietal lesions, a brain region known to be involved in sensorimotor processing, were less likely than controls and tended to be less likely than patients with lesions sparing that region to use action relatedness in determining their choices. These data indicate that action knowledge plays a critical role in processing of thematic relations for manipulable artifacts.

The functional neuroanatomy of actions.

Our current understanding of the neural basis of semantic memory is informed primarily by studies of concrete objects. However, conceptual knowledge encompasses many other, albeit less concrete, domains. This article reviews evidence from neuroimaging and patient studies that speaks to the neural basis of action concepts and the words that refer to them. These data highlight 2 important principles governing the neural instantiation of semantic knowledge. First, the organization of conceptual representations in the brain parallels perception and action. Action concepts are at least partially represented within modality-specific areas responsible for the perception and execution of dynamic actions. Second, unimodal sensory and motor cortices act as "points of entry" for more abstract action knowledge. Increasingly abstract conceptual knowledge derived from these modalities is represented in brain areas located anterior and centripetal to modality-specific regions. Extending research on the neural basis of semantics to include dynamic and relational aspects of the world gives us a more complete appreciation of the range of cognitive and communication impairments that may be experienced by patients with neurologic disease.