Autism as a neural systems disorder: A theory of frontal-posterior underconnectivity

Just, Marcel Adam; Keller, Timothy A.; Malave, Vicente L.; Kana, Rajesh K.; Varma, Sashank

doi:10.1016/j.neubiorev.2012.02.007

Cited by 494 publications

(466 citation statements)

References 143 publications

(234 reference statements)

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“…The big picture emerging from those reports is lowered FC between frontal and posterior brain regions (see Vissers, Cohen, & Geurts, 2012 for a review), as formulated in the underconnectivity theory of autism (Just, Keller, Malave, Kana, & Varma, 2012). …”

Section: Introductionmentioning

confidence: 99%

Brain dynamics in ASD during movie‐watching show idiosyncratic functional integration and segregation

Bolton

Jochaut

Giraud

et al. 2018

Human Brain Mapping

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To refine our understanding of autism spectrum disorders (ASD), studies of the brain in dynamic, multimodal and ecological experimental settings are required. One way to achieve this is to compare the neural responses of ASD and typically developing (TD) individuals when viewing a naturalistic movie, but the temporal complexity of the stimulus hampers this task, and the presence of intrinsic functional connectivity (FC) may overshadow movie‐driven fluctuations. Here, we detected inter‐subject functional correlation (ISFC) transients to disentangle movie‐induced functional changes from underlying resting‐state activity while probing FC dynamically. When considering the number of significant ISFC excursions triggered by the movie across the brain, connections between remote functional modules were more heterogeneously engaged in the ASD population. Dynamically tracking the temporal profiles of those ISFC changes and tying them to specific movie subparts, this idiosyncrasy in ASD responses was then shown to involve functional integration and segregation mechanisms such as response inhibition, background suppression, or multisensory integration, while low‐level visual processing was spared. Through the application of a new framework for the study of dynamic experimental paradigms, our results reveal a temporally localized idiosyncrasy in ASD responses, specific to short‐lived episodes of long‐range functional interplays.

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Section: Introductionmentioning

confidence: 99%

Brain dynamics in ASD during movie‐watching show idiosyncratic functional integration and segregation

Bolton

Jochaut

Giraud

et al. 2018

Human Brain Mapping

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“…Such theories include reduced communication between frontal and posterior brain regions (Just et al, 2012), increased local FC along with reduced long-range FC (Belmonte et al, 2004;Courchesne & Pierce, 2005), and an abnormal developmental trajectory of FC in relation to typically developing (TD) individuals (Nomi & Uddin, 2015;Uddin et al, 2013b). However, complex patterns of both increased and decreased FC have been found in neuroimaging studies of ASD, and results are inconsistent across studies (see Hull et al, 2016;Picci et al, 2016;and Uddin et al, 2013b for reviews).…”

Section: Introductionmentioning

confidence: 99%

Functional connectivity-based subtypes of individuals with and without autism spectrum disorder

Easson

Fatima

McIntosh

2017

Preprint

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Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder that is characterized by impairments in social communication and restricted and repetitive behaviours.Neuroimaging studies of individuals with ASD have shown complex patterns of functional connectivity (FC), with no clear consensus on defining brain-behaviour attributes of different subtypes of the disorder. In these studies, "static FC", a metric that considers correlations across the entire time series for a given region, was used. Emerging evidence shows that FC changes over time; this "dynamic FC" can allow for unique detection of the temporal variability of functional connections over time. Here, we used k-means clustering, an unsupervised machine learning algorithm, to characterize two subtypes of ASD based on distinct patterns of static and dynamic FC. A multivariate statistical approach was then implemented to determine optimal relationships between FC patterns and group membership or behaviour. The main objective was to characterize differences in static and dynamic FC between subtypes of ASD defined in a fully data-driven manner, and between subtypes and typically developing individuals. Subtype 2 was defined by increased FC within resting-state networks and decreased FC across networks for static FC, global increases in temporal stability of dynamic FC, and robust relationships between FC and several behaviours, relative to Subtype 1. Further, both ASD subtypes exhibited different patterns of static and dynamic FC compared to controls, particularly within default mode, sensorimotor, and occipital networks. Static and dynamic FC metrics provided both overlapping and unique information about the nature of FC differences between subtypes, and between both subtypes and controls. Our results demonstrate the value of considering FC-based subtypes of ASD to elucidate different relationships between brain and behaviour among individuals with this disorder, and have important clinical implications for catering treatments and behavioural interventions to specific subtypes.

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“…Answering these questions is difficult because the disorder is multifactorial in nature with multiple genetic variants and environmental factors contributing to the core symptoms (10)(11)(12)(13). To face this challenge, extensive efforts have been made to identify the targeting and functional convergence of the autism-risk genes, such as those involved in translation regulation (14)(15)(16) and long-range connectivity among different brain regions (17)(18)(19). These targets and functions provide a better biological basis for elucidating the causal paths between risk genes and the disorders of autism.…”

mentioning

confidence: 99%

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

Dong

Wang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The etiology of autism is so complicated because it involves the effects of variants of several hundred risk genes along with the contribution of environmental factors. Therefore, it has been challenging to identify the causal paths that lead to the core autistic symptoms such as social deficit, repetitive behaviors, and behavioral inflexibility. As an alternative approach, extensive efforts have been devoted to identifying the convergence of the targets and functions of the autism-risk genes to facilitate mapping out causal paths. In this study, we used a reversal-learning task to measure behavioral flexibility in Drosophila and determined the effects of loss-of-function mutations in multiple autism-risk gene homologs in flies. Mutations of five autism-risk genes with diversified molecular functions all led to a similar phenotype of behavioral inflexibility indicated by impaired reversal-learning. These reversal-learning defects resulted from the inability to forget or rather, specifically, to activate Rac1 (Ras-related C3 botulinum toxin substrate 1)-dependent forgetting. Thus, behavior-evoked activation of Rac1-dependent forgetting has a converging function for autism-risk genes.A utism spectrum disorders are common polygenic neurodevelopmental disorders diagnosed by a cluster of core clinical syndromes characterized by impaired social interaction, communication deficits, and behavioral inflexibility (1-3). A large number of autism-risk genes have been identified through different genetic approaches (4-8). These candidate genes play highly diversified roles in synaptic organization, transmission, intracellular signaling pathways, and protein expression regulation, among others (9). How do variants of these risk genes lead to the core symptoms of autism? Are there causal paths that can determine the onset of autism? Answering these questions is difficult because the disorder is multifactorial in nature with multiple genetic variants and environmental factors contributing to the core symptoms (10-13). To face this challenge, extensive efforts have been made to identify the targeting and functional convergence of the autism-risk genes, such as those involved in translation regulation (14-16) and long-range connectivity among different brain regions (17)(18)(19). These targets and functions provide a better biological basis for elucidating the causal paths between risk genes and the disorders of autism.The aim of the this study was to determine whether Rac1 (Rasrelated C3 botulinum toxin substrate 1)-dependent forgetting is a functional converging point for autism-risk genes. This idea was inspired by two clues. First, inhibition of Rac1 activity in Drosophila leads to the failure to activate Rac1-dependent forgetting, resulting in behavioral inflexibility as assayed through a reversal-learning task (20). Behavioral inflexibility has been observed frequently in the clinical studies of autism patients (21,22), and children with autism are reported to have impaired reversal-learning, although they can learn new beh...

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Autism as a neural systems disorder: A theory of frontal-posterior underconnectivity

Cited by 494 publications

References 143 publications

Brain dynamics in ASD during movie‐watching show idiosyncratic functional integration and segregation

Brain dynamics in ASD during movie‐watching show idiosyncratic functional integration and segregation

Functional connectivity-based subtypes of individuals with and without autism spectrum disorder

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

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