Measuring Cognitive Flexibility with the Flexible Item Selection Task: From fMRI Adaptation to Individual Connectome Mapping.

Cognitive flexibility, the ability to appropriately adjust behavior in a changing environment, has been challenging to operationalize and validate in cognitive neuroscience studies. Here, we investigate neural activation and directed functional connectivity underlying cognitive flexibility using an fMRI-adapted version of the Flexible Item Selection Task (FIST) in adults (n = 32, ages 19-46 years). The fMRI-adapted FIST was reliable, showed comparable performance to the computer-based version of the task, and produced robust activation in frontoparietal, anterior cingulate, insular, and subcortical regions. During flexibility trials, participants directly engaged the left inferior frontal junction, which influenced activity in other cortical and subcortical regions. The strength of intrinsic functional connectivity between select brain regions was related to individual differences in performance on the FIST, but there was also significant individual variability in functional network topography supporting cognitive flexibility. Taken together, these results suggest that the FIST is a valid measure of cognitive flexibility, which relies on computations within a broad corticosubcortical network driven by inferior frontal junction engagement.

Evolution of spatial and temporal features of functional brain networks across the lifespan.

Development and aging are associated with functional changes in the brain across the lifespan. These changes manifest in a variety of spatial and temporal features of resting state functional MRI (rs-fMRI) but have seldom been explored exhaustively. We present a comprehensive study assessing age-related changes in spatial and temporal features of blind-source separated components identified by independent vector analysis (IVA) in a cross-sectional lifespan sample (ages 6-85 years). We show that while large-scale network configurations remain consistent throughout the lifespan, changes persist in both local and global organization of these networks. We show that the spatial extent of the majority of functional networks exhibits linear decreases and both positive and negative quadratic trajectories across the lifespan. Network connectivity revealed nuanced patterns of linear and quadratic relationships with age, primarily in higher order cognitive networks. We also show divergent age-related patterns across the frequency spectrum in lower and higher frequencies. Taken together, these results point to the presence of sophisticated patterns of age-related changes that have previously not been considered collectively. We suggest that established patterns of lifespan changes in rs-fMRI features may be driven by changes in the spectral composition of BOLD signals.

Chronnectomic patterns and neural flexibility underlie executive function.

Despite extensive research into executive function (EF), the precise relationship between brain dynamics and flexible cognition remains unknown. Using a large, publicly available dataset (189 participants), we find that functional connections measured throughout 56min of resting state fMRI data comprise five distinct connectivity states. Elevated EF performance as measured outside of the scanner was associated with greater episodes of more frequently occurring connectivity states, and fewer episodes of less frequently occurring connectivity states. Frequently occurring states displayed metastable properties, where cognitive flexibility may be facilitated by attenuated correlations and greater functional connection variability. Less frequently occurring states displayed properties consistent with low arousal and low vigilance. These findings suggest that elevated EF performance may be associated with the propensity to occupy more frequently occurring brain configurations that enable cognitive flexibility, while avoiding less frequently occurring brain configurations related to low arousal/vigilance states. The current findings offer a novel framework for identifying neural processes related to individual differences in executive function.

Parsing Heterogeneity of Executive Function in Typically and Atypically Developing Children: A Conceptual Replication and Exploration of Social Function.

Executive function (EF), the set of cognitive processes that govern goal-directed behavior, varies within developmental samples and clinical populations. Here, we perform a conceptual replication of prior work (Dajani et al. in Sci Rep 6:36566, 2016) in an independent sample of typically developing children (n = 183) and children with autism spectrum disorder (n = 104). Consistent with previous work, the latent profile analysis of parent-report EF measures provided evidence for three EF classes, which exhibited differential proportions of diagnostic groups. Additionally, children in the impaired EF group exhibited greater levels of social impairment. These results highlight the heterogeneity of EF ability among clinical and non-clinical populations and the link between EF and social abilities.

Neural Responses to a Putative Set-shifting Task in Children with Autism Spectrum Disorder.

While much progress has been made toward understanding the neurobiology of social and communication deficits associated with autism spectrum disorder (ASD), less is known regarding the neurobiological basis of restricted and repetitive behaviors (RRBs) central to the ASD diagnosis. Symptom severity for RRBs in ASD is associated with cognitive inflexibility. Thus, understanding the neural mechanisms underlying cognitive inflexibility in ASD is critical for tailoring therapies to treat this understudied yet pervasive symptom. Here we used a set-shifting paradigm adopted from the developmental cognitive neuroscience literature involving flexible switching between stimulus categories to examine task performance and neural responses in children with ASD. Behaviorally, we found little evidence for group differences in performance on the set-shifting task. Compared with typically developing children, children with ASD exhibited greater activation of the parahippocampal gyrus during performance on trials requiring switching. These findings suggest that children with ASD may need to recruit memory-based neural systems to a greater degree when learning to flexibly associate stimuli with responses. LAY SUMMARY: Children with autism often struggle to behave in a flexible way when faced with unexpected challenges. We examined brain responses during a task thought to involve flexible thinking and found that compared with typically developing children, those with autism relied more on brain areas involved in learning and memory to complete the task. This study helps us to understand what types of cognitive tasks are best suited for exploring the neural basis of cognitive flexibility in children with autism. Autism Res 2020, 13: 1501-1515. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

Investigating functional brain network integrity using a traditional and novel categorical scheme for neurodevelopmental disorders.

BACKGROUND: Current diagnostic systems for neurodevelopmental disorders do not have clear links to underlying neurobiology, limiting their utility in identifying targeted treatments for individuals. Here, we aimed to investigate differences in functional brain network integrity between traditional diagnostic categories (autism spectrum disorder [ASD], attention-deficit/hyperactivity disorder [ADHD], typically developing [TD]) and carefully consider the impact of comorbid ASD and ADHD on functional brain network integrity in a sample adequately powered to detect large effects. We also assess the neurobiological separability of a novel, potential alternative categorical scheme based on behavioral measures of executive function. METHOD: Five-minute resting-state fMRI data were obtained from 168 children (128 boys, 40 girls) with ASD, ADHD, comorbid ASD and ADHD, and TD children. Independent component analysis and dual regression were used to compute within- and between-network functional connectivity metrics at the individual level. RESULTS: No significant group differences in within- or between-network functional connectivity were observed between traditional diagnostic categories (ASD, ADHD, TD) even when stratified by comorbidity (ASD + ADHD, ASD, ADHD, TD). Similarly, subgroups classified by executive functioning levels showed no group differences. CONCLUSIONS: Using clinical diagnosis and behavioral measures of executive function, no differences in functional connectivity were observed among the categories examined. Despite our limited ability to detect small- to medium-sized differences between groups, this work contributes to a growing literature suggesting that traditional diagnostic categories do not define neurobiologically separable groups. Future work is necessary to ascertain the validity of the executive function-based nosology, but current results suggest that nosologies reliant on behavioral data alone may not lead to discovery of neurobiologically distinct categories.

Parsing Heterogeneity in Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder with Individual Connectome Mapping.

Traditional diagnostic systems for neurodevelopmental disorders define diagnostic categories that are heterogeneous in behavior and underlying neurobiological alterations. The goal of this study was to parse heterogeneity in a core executive function (EF), cognitive flexibility, in children with a range of abilities (N = 132; children with autism spectrum disorder, attention-deficit/hyperactivity disorder [ADHD], and typically developing children) using directed functional connectivity profiles derived from resting-state functional magnetic resonance imaging data. Brain regions activated in response to a cognitive flexibility task in adults were used to guide region-of-interest selection to estimate individual connectivity profiles in this study. We expected to find subgroups of children who differed in their network connectivity metrics and symptom measures. Unexpectedly, we did not find a stable or valid subgrouping solution, which suggests that categorical models of the neural substrates of cognitive flexibility in children may be invalid. Exploratory analyses revealed dimensional associations between network connectivity metrics and ADHD symptomatology and EF ability across the entire sample. Results shed light on the validity of conceptualizing the neural substrates of cognitive flexibility categorically in children. Ultimately, this work may provide a foundation for the development of a revised nosology focused on neurobiological substrates as an alternative to traditional symptom-based classification systems.

Atypical frontoamygdala functional connectivity in youth with autism.

Functional connectivity (FC) between the amygdala and the ventromedial prefrontal cortex underlies socioemotional functioning, a core domain of impairment in autism spectrum disorder (ASD). Although frontoamygdala circuitry undergoes dynamic changes throughout development, little is known about age-related changes in frontoamygdala networks in ASD. Here we characterize frontoamygdala resting-state FC in a cross-sectional sample (ages 7-25) of 58 typically developing (TD) individuals and 53 individuals with ASD. Contrary to hypotheses, individuals with ASD did not show different age-related patterns of frontoamygdala FC compared with TD individuals. However, overall group differences in frontoamygdala FC were observed. Specifically, relative to TD individuals, individuals with ASD showed weaker frontoamygdala FC between the right basolateral (BL) amygdala and the rostral anterior cingulate cortex (rACC). These findings extend prior work to a broader developmental range in ASD, and indicate ASD-related differences in frontoamygdala FC that may underlie core socioemotional impairments in children and adolescents with ASD.

Aberrant functional connectivity of inhibitory control networks in children with autism spectrum disorder.

Development of inhibitory control is a core component of executive function processes and a key aspect of healthy development. Children with autism spectrum disorder (ASD) show impairments in performance on inhibitory control tasks. Nevertheless, the research on the neural correlates of these impairments is inconclusive. Here, we explore the integrity of inhibitory control networks in children with ASD and typically developing (TD) children using resting state functional Magnetic Resonance Imagaing (MRI). In a large multisite sample, we find evidence for significantly greater functional connectivity (FC) of the right inferior frontal junction (rIFJ) with the posterior cingulate gyrus, and left and right frontal poles in children with ASD compared with TD children. Additionally, TD children show greater FC of rIFJ with the superior parietal lobule (SPL) compared with children with ASD. Furthermore, although higher rIFJ-SPL and rIFJ-IPL FC was related to better inhibitory control behaviors in both ASD and TD children, rIFJ-dACC FC was only associated with inhibitory control behaviors in TD children. These results provide preliminary evidence of differences in intrinsic functional networks supporting inhibitory control in children with ASD, and provide a basis for further exploration of the development of inhibitory control in children with the disorder. Autism Research 2018, 11: 1468-1478. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Inhibitory control is an important process in healthy cognitive development. Behavioral studies suggest that inhibitory control is impaired in autism spectrum disorder (ASD). However, research examining the neural correlates underlying inhibitory control differences in children with ASD is inconclusive. This study reveals differences in functional connectivity of brain networks important for inhibitory control in children with ASD compared with typically developing children. Furthermore, it relates brain network differences to parent-reported inhibitory control behaviors in children with ASD. These findings provide support for the hypothesis that differences in brain connectivity may underlie observable behavioral deficits in inhibitory control in children with the disorder.

Local brain connectivity across development in autism spectrum disorder: A cross-sectional investigation.

There is a general consensus that autism spectrum disorder (ASD) is accompanied by alterations in brain connectivity. Much of the neuroimaging work has focused on assessing long-range connectivity disruptions in ASD. However, evidence from both animal models and postmortem examination of the human brain suggests that local connections may also be disrupted in individuals with the disorder. Here, we investigated how regional homogeneity (ReHo), a measure of similarity of a voxel's timeseries to its nearest neighbors, varies across age in individuals with ASD and typically developing (TD) individuals using a cross-sectional design. Resting-state fMRI data obtained from a publicly available database were analyzed to determine group differences in ReHo between three age cohorts: children, adolescents, and adults. In typical development, ReHo across the entire brain was higher in children than in adolescents and adults. In contrast, children with ASD exhibited marginally lower ReHo than TD children, while adolescents and adults with ASD exhibited similar levels of local connectivity as age-matched neurotypical individuals. During all developmental stages, individuals with ASD exhibited lower local connectivity in sensory processing brain regions and higher local connectivity in complex information processing regions. Further, higher local connectivity in ASD corresponded to more severe ASD symptomatology. These results demonstrate that local connectivity is disrupted in ASD across development, with the most pronounced differences occurring in childhood. Developmental changes in ReHo do not mirror findings from fMRI studies of long-range connectivity in ASD, pointing to a need for more nuanced accounts of brain connectivity alterations in the disorder.

Heterogeneity of executive functions among comorbid neurodevelopmental disorders.

Executive functions (EFs) are used to set goals, plan for the future, inhibit maladaptive responses, and change behavior flexibly. Although some studies point to specific EF profiles in autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) - prevalent and often highly comorbid neurodevelopmental disorders - others have not differentiated them. The objective of the current study was to identify distinct profiles of EF across typically developing (TD) children and children with ASD and ADHD. We employed a latent profile analysis using indicators of EF (e.g., working memory, inhibition, and flexibility) in a mixed group of 8-13 year-olds including TD children (n = 128), children with ASD without ADHD (n = 30), children with ADHD (n = 93), and children with comorbid ASD and ADHD (n = 66). Three EF classes emerged: "above average," "average," and "impaired." EF classes did not reproduce diagnostic categories, suggesting that differences in EF abilities are present within the ASD and ADHD groups. Further, greater EF dysfunction predicted more severe socioemotional problems, such as anxiety/depression. These results highlight the heterogeneity of current diagnostic groups and identify an "impaired" EF group, consisting of children with both ASD and ADHD, which could specifically be targeted for EF intervention.

Demystifying cognitive flexibility: Implications for clinical and developmental neuroscience.

Cognitive flexibility, the readiness with which one can selectively switch between mental processes to generate appropriate behavioral responses, develops in a protracted manner and is compromised in several prevalent neurodevelopmental disorders. It is unclear whether cognitive flexibility arises from neural substrates distinct from the executive control network (ECN) or from the interplay of nodes within this and other networks. Here we review neuroimaging studies of cognitive flexibility, focusing on set shifting and task switching. We propose that more consistent operationalization and study of cognitive flexibility is required in clinical and developmental neuroscience. We suggest that an important avenue for future research is the characterization of the relationship between neural flexibility and cognitive flexibility in typical and atypical development.