Carter Wendelken

Association of Dorsolateral Prefrontal Cortex Dysfunction With Disrupted Coordinated Brain Activity in Schizophrenia: Relationship With Impaired Cognition, Behavioral Disorganization, and Global Function

OBJECTIVE Although deficits in cognitive control are thought to contribute to the diverse cognitive and behavioral abnormalities in individuals with schizophrenia, the neural mechanisms underlying these deficits remain unclear. In this event-related functional magnetic resonance imaging (fMRI) study, the authors tested the hypothesis that during cognitive control tasks, impaired activation of the dorsolateral prefrontal cortex in schizophrenia patients is associated with disrupted coordinated activity between this prefrontal region and a distributed brain network that supports cognitive control. METHOD Through the use of an event-related design, 25 patients with first-episode schizophrenia and 24 healthy comparison subjects, matched on demographic characteristics, were assessed while performing a version of the AX continuous performance task. Functional neuroimaging data were analyzed using 1) univariate (region-of-interest blood-oxygen-level-dependent [BOLD] time series and whole brain voxel-wise regression) analysis to confirm the presence of dorsolateral prefrontal cortex dysfunction and 2) multivariate analysis to examine dorsolateral prefrontal cortex functional connectivity. In addition, correlations between dorsolateral prefrontal cortex functional connectivity and the following variables were investigated: clinical symptoms, task performance, and coordinated brain activity associated with cognitive control. RESULTS Schizophrenia patients exhibited a specific deficit in cognitive control, with significantly reduced accuracy in the BX condition relative to any other condition. Univariate fMRI revealed dorsolateral prefrontal cortex dysfunction during the high cognitive control condition. Multivariate analysis revealed significant impairment in functional connectivity between the dorsolateral prefrontal cortex and task-relevant brain regions. Significant correlations were also found between dorsolateral prefrontal cortex functional connectivity and cognitive performance, behavioral disorganization, and global functioning. CONCLUSIONS These findings suggest that there is an association between decreased dorsolateral prefrontal cortex activity and connectivity and a task-related neural network. This deficit in coordinated brain activity may result in the disabling disorganization symptoms related to impaired cognition in individuals with schizophrenia.

Brain Regions Mediating Flexible Rule Use during Development

During development, children improve at retrieving and using rules to guide their behavior and at flexibly switching between these rules. In this study, we used functional magnetic resonance imaging to examine the changes in brain function associated with developmental changes in flexible rule use. Three age groups (8–12, 13–17, and 18–25 years) performed a task in which they were cued to respond to target stimuli on the basis of simple task rules. Bivalent target stimuli were associated with different responses, depending on the rule, whereas univalent target stimuli were associated with fixed responses. The comparison of bivalent and univalent trials enabled the identification of regions modulated by demands on rule representation. The comparison of rule-switch and rule-repetition trials enabled the identification of regions involved in rule switching. We have used this task previously in adults and have shown that ventrolateral prefrontal cortex (VLPFC) and the (pre)-supplementary motor area (pre-SMA/SMA) have dissociable roles in task-switching, such that VLPFC is associated most closely with rule representation, and pre-SMA/SMA is associated with suppression of the previous task set (Crone et al., 2006a). Based on behavioral data in children (Crone et al., 2004), we had predicted that regions associated with task-set suppression would show mature patterns of activation earlier in development than regions associated with rule representation. Indeed, we found an adult-like pattern of activation in pre-SMA/SMA by adolescence, whereas the pattern of VLPFC activation differed among children, adolescents, and adults. These findings suggest that two components of task-switching—rule retrieval and task-set suppression—follow distinct neurodevelopmental trajectories.

A functional and structural study of emotion and face processing in children with autism

Children with autism exhibit impairment in the processing of socioemotional information. The amygdala, a core structure centrally involved in socioemotional functioning, has been implicated in the neuropathology of autism. We collected structural and functional magnetic resonance images (MRI) in children 8 to 12 years of age with high-functioning autism (n=12) and typical development (n=15). The functional MRI experiment involved matching facial expressions and people. Volumetric analysis of the amygdala was also performed. The results showed that children with autism exhibited intact emotion matching, while showing diminished activation of the fusiform gyrus (FG) and the amygdala. Conversely, the autism group showed deficits in person matching amidst some FG and variable amygdala activation. No significant between-group differences in the volume of the left or right amygdala were found. There were associations between age, social anxiety and amygdala volume in the children with autism such that smaller volumes were generally associated with more anxiety and younger age. In summary, the data are consistent with abnormalities in circuits involved in emotion and face processing reported in studies of older subjects with autism showing reductions in amygdala activation related to emotion processing and reduced fusiform activation involved in face processing.

Neurocognitive development of relational reasoning

Relational reasoning is an essential component of fluid intelligence, and is known to have a protracted developmental trajectory. To date, little is known about the neural changes that underlie improvements in reasoning ability over development. In this event-related functional magnetic resonance imaging (fMRI) study, children aged 8-12 and adults aged 18-25 performed a relational reasoning task adapted from Ravens Progressive Matrices. The task included three levels of relational reasoning demands: REL-0, REL-1, and REL-2. Children exhibited disproportionately lower accuracy than adults on trials that required integration of two relations (REL-2). Like adults, children engaged lateral prefrontal cortex (PFC) and parietal cortex during task performance; however, they exhibited different time courses and activation profiles, providing insight into their approach to the problems. As in prior studies, adults exhibited increased rostrolateral PFC (RLPFC) activation when relational integration was required (REL-2 > REL-1, REL-0). Children also engaged RLPFC most strongly for REL-2 problems at early stages of processing, but this differential activation relative to REL-1 trials was not sustained throughout the trial. These results suggest that the children recruited RLPFC while processing relations, but failed to use it to integrate across two relations. Relational integration is critical for solving a variety of problems, and for appreciating analogies; the current findings suggest that developmental improvements in this function rely on changes in the profile of engagement of RLPFC, as well as dorsolateral PFC and parietal cortex.

Brain is to thought as stomach is to ??: Investigating the role of rostrolateral prefrontal cortex in relational reasoning

Brain imaging studies suggest that the rostrolateral prefrontal cortex (RLPFC), is involved in relational reasoning. Functional magnetic resonance imaging (fMRI) studies involving Ravens Progressive Matrices or verbal propositional analogies indicate that the RLPFC is engaged by tasks that require integration across multiple relational structures. Several studies have shown that the RLPFC is more active when people must evaluate an analogy (e.g., Is shoe to foot as glove is to hand?) than when they must simply evaluate two individual semantic relationships, consistent with the hypothesis that this region is important for relational integration. The current fMRI investigation further explores the role of the RLPFC in reasoning and relational integration by comparing RLPFC activation across four different propositional analogy conditions. Each of the four conditions required either relation completion (e.g., Shoe is to foot as glove is to WHAT? hand) or relation comparison (e.g., Is shoe to foot as glove is to hand? yes). The RLPFC was engaged more strongly by the comparison subtask relative to completion, suggesting that the RLPFC is particularly involved in comparing relational structures.

Left, but not right, rostrolateral prefrontal cortex meets a stringent test of the relational integration hypothesis

Much of what is known about the function of human rostrolateral prefrontal cortex (RLPFC; lateral Brodmann area 10) has been pieced together from functional magnetic resonance imaging (fMRI) studies over the past decade. Christoff and colleagues previously reported on an fMRI localizer task involving relational integration that reliably engages RLPFC in individual participants (Smith, R., Keramatian, K., and Christoff, K. (2007). Localizing the rostrolateral prefrontal cortex at the individual level. NeuroImage, 36(4), 1387-1396). Here, we report on a modified version of this task that better controls for lower-level processing demands in the relational integration condition. Using identical stimulus arrays for our experimental and control conditions, we find that right RLPFC is sensitive to increasing relational processing demands, without being engaged specifically during relational integration. By contrast, left RLPFC is engaged only when participants must consider the higher-order relationship between two individual relations. We argue that the integration of disparate mental relations by left RLPFC is a fundamental process that supports higher-level cognition in humans.

Transitive inference: Distinct contributions of rostrolateral prefrontal cortex and the hippocampus

The capacity to reason about complex information is a central characteristic of human cognition. An important component of many reasoning tasks is the need to integrate multiple mental relations. Several researchers have argued that rostrolateral prefrontal cortex (RLPFC) plays a key role in relational integration. If this hypothesis is correct, then RLPFC should play a key role in transitive inference, which requires the integration of multiple relations to reach a conclusion. Thus far, however, neuroscientific research on transitive inference has focused primarily on the hippocampus. In this fMRI study, we sought to compare the roles of RLPFC and the hippocampus on a novel transitive inference paradigm. Four relations between colored balls were presented on the screen together with a target relation. Participants were asked to decide whether the target relation was correct, given the other indicated relations between balls. RLPFC, but not the hippocampus, exhibited stronger activation on trials that required relational integration as compared with trials that involved relational encoding without integration. In contrast, the hippocampus exhibited a pattern consistent with a role in relational encoding, with stronger activation on trials requiring encoding of relational predicate–argument structure as compared with trials requiring encoding of item–item associations. Functional connectivity analyses give rise to the hypothesis that RLPFC draws on hippocampal representations of mental relations during the process of relational integration.

Retrieving rules for behavior from long-term memory.

Human behavior is often dictated by rules or prescribed guides for action. Little is currently known regarding how these rules are stored in long-term memory or retrieved and implemented. Here, we examined the roles of ventrolateral prefrontal cortex (VLPFC) and posterior middle temporal gyrus (postMTG) in rule use. We tested two hypotheses: first, that knowledge about actions associated with abstract visual symbols is stored in postMTG, and second, that VLPFC is involved in the controlled retrieval of rule meanings. Subjects viewed a series of road signs during event-related fMRI data collection. Three types of signs were intermixed: highly familiar signs, novel signs whose meaning was explained to subjects prior to scanning, and novel signs whose meaning was not explained. Subjects were asked to think about the meaning of each sign as it was presented during scanning and then to give its meaning in a post-scan test. Left postMTG was more active when subjects viewed signs whose meaning they knew than signs whose meaning they did not know, consistent with a role in storing rule meanings. This region was not modulated by experience, in that it was equally engaged by newly trained and well-learned signs. In contrast, right VLPFC was more active for newly trained signs than for either well-learned or incorrect ones, consistent with a role in controlled retrieval. Left VLPFC was reliably engaged while subjects attempted to interpret the signs but did not differ according to knowledge or experience. These data implicate postMTG in rule storage and VLPFC in rule retrieval.

Neural indices of improved attentional modulation over middle childhood

The ability to control the focus of attention relies on top-down modulation of cortical activity in areas involved in stimulus processing, and this ability is critical for maintaining items in working memory in the presence of distraction. Prior research demonstrates that children are less capable of focusing attention, relative to adults, and that this ability develops significantly during middle childhood. Here, using fMRI and a face/scene working memory task adapted from Gazzaley and colleagues (Gazzaley et al. 2005), we compared top-down modulation in fifteen children (aged 8-13) and fifteen young adults (aged 19-26). Replicating prior results, in young adults, attention to scenes modulated activity in the parahippocampal place area (PPA). In addition, modulation of PPA activity increased as a function of age in children. PPA activity was also related to performance in this group, on the working memory task as well on a test of subsequent memory. Dorsolateral PFC also demonstrated increasing task-specific activation, as a function of age, in children. The present findings support the idea that childrens reduced ability to maintain items in working memory, especially in the presence of distraction, is driven by weaker top-down modulation of activity in areas involved in stimulus processing.

Rostrolateral prefrontal cortex: Domain‐general or domain‐sensitive?

The ability to jointly consider several structured mental representations, or relations, is fundamental to human cognition. Prior studies have consistently linked this capacity for relational integration to rostrolateral prefrontal cortex (RLPFC). Here, we sought to test two competing hypotheses: (1) RLPFC processes relations in a domain‐general manner, interacting with different brain regions as a function of the type of lower‐level relations that must be integrated; or (2) A dorsal‐ventral gradient exists within RLPFC, such that relational integration in the visuospatial domain involves relatively more dorsal RLPFC than integration in the semantic domain. To this end, we examined patterns of fMRI activation and functional connectivity during performance of visuospatial and semantic variants of a relational matching task. Across the two task variants, the regions that were most strongly engaged during relational comparison were left RLPFC and left intraparietal sulcus (IPS). Within left RLPFC, there was considerable overlap in activation for the semantic and visuospatial tasks. However, visuospatial task activation peaks were located dorsally to the semantic task peaks. In addition, RLPFC exhibited differential functional connectivity on the two tasks, interacting with different brain regions as a function of the type of relations being compared. While neurons throughout RLPFC may share the function of integrating diverse inputs, individual RLPFC neurons may have privileged access to particular representations depending on their anatomical inputs, organized along a dorsal‐ventral gradient. Thus, RLPFC is well‐positioned as a locus of abstraction from concrete, domain‐specific details to the general principles and rules that enable higher‐level cognition. Hum Brain Mapp, 2012.