Characterization of Autism Spectrum Disorder across the Age Span by Intrinsic Network Patterns.

Autism spectrum disorder (ASD) is characterized by abnormal functional organization of brain networks, which may underlie the cognitive and social impairments observed in affected individuals. The present study characterizes unique intrinsic connectivity within- and between- neural networks in children through to adults with ASD, relative to controls. Resting state fMRI data were analyzed in 204 subjects, 102 with ASD and 102 age- and sex-matched controls (ages 7-40 years), acquired on a single scanner. ASD was assessed using the autism diagnostic observation schedule (ADOS). BOLD correlations were calculated between 47 regions of interest, spanning seven resting state brain networks. Partial least squares (PLS) analyses evaluated the association between connectivity patterns and ASD diagnosis as well as ASD severity scores. PLS demonstrated dissociable connectivity patterns in those with ASD, relative to controls. Similar patterns were observed in the whole cohort and in a subgroup analysis of subjects under 18 years of age. Greater inter-network connectivity was seen in ASD with greater intra-network connectivity in controls. In conclusion, stronger inter-network and weaker intra-network resting state-fMRI BOLD correlations characterize ASD and may differentiate control and ASD cohorts. These findings are relevant to understanding ASD as a disruption of network topology.

Developmental changes in neuromagnetic rhythms and network synchrony in autism.

OBJECTIVE: There is gathering consensus that altered connectivity is a hallmark of the autistic brain. This includes atypical neural oscillations and their coordination across brain regions, which are understood to mediate information processing and integration. It remains unclear whether and how connectivity in various neurophysiological frequency ranges develops atypically in autism spectrum disorder (ASD). METHODS: To address this in a cross-sectional sample, we recorded resting-state magnetoencephalography from 134 children and adolescents with and without ASD, and calculated resting spectral power and inter-regional synchrony (functional connectivity). RESULTS: Although no overall group differences were observed, significant alterations in linear and nonlinear age-related changes in resting oscillatory power and network synchrony were found. These differences were frequency- and region-specific and implicated brain systems thought to play a prominent role in ASD, such as the frontal cortex and cerebellum. We also found correlations between Autism Diagnostic Observation Schedule scores and the degree to which connectivity in cerebellar networks is "idiosyncratic" in an individual with autism. INTERPRETATION: We provide the first evidence that it is the curvatures of maturational changes in neurophysiological oscillations and synchrony, rather than disturbances in a particular direction, that characterize the brain function in individuals with ASD. Moreover, the patterns of idiosyncratic distortions of network synchrony relative to the group curve are associated with behavioral symptoms of ASD. Ann Neurol 2017;81:199-211.

Desynchronization of fronto-temporal networks during working memory processing in autism.

BACKGROUND: Mounting evidence suggests that autism is a network disorder, characterized by atypical brain connectivity, especially in the context of high level cognitive processes such as working memory (WM). Accordingly, atypical WM processes have been related to the social and cognitive deficits observed in children with autism spectrum disorder (ASD). METHODS: We used magnetoencephalography (MEG) to investigate connectivity differences during a high memory load (2-back) WM task between 17 children with ASD and 20 age-, sex-, and IQ-matched controls. RESULTS: We identified reduced inter-regional alpha-band (9-15 Hz) phase synchronization in children with ASD during the WM task. Reduced WM-related brain synchronization encompassed fronto-temporal networks (ps < 0.04 corrected) previously associated with challenging high-level conditions (i.e. the left insula and the anterior cingulate cortex (ACC)) and memory encoding and/or recognition (i.e. the right middle temporal gyrus and the right fusiform gyrus). Additionally, we found that reduced connectivity processes related to the right fusiform were correlated with the severity of symptoms in children with ASD, suggesting that such atypicalities could be directly related to the behavioural deficits observed. DISCUSSION: This study provides new evidence of atypical long-range synchronization in children with ASD in fronto-temporal areas that crucially contribute to challenging WM tasks, but also emotion regulation and social cognition processes. Thus, these results support the network disorder hypothesis of ASD and argue for a specific pathophysiological contribution of brain processes related to working memory and executive functions on the symptomatology of autism.

Functional connectivity changes during working memory in autism spectrum disorder: A two-year longitudinal MEG study.

Working memory impairments have been reported in adults with autism spectrum disorder (ASD) and associated with functional outcomes and social difficulties. However, little is known about the developmental trajectory of working memory in youth with ASD. The current magnetoencephalography (MEG) study is the first to examine the longitudinal development over two years of working memory networks in youth with ASD. We analysed MEG data from 32 children and adolescents with and without ASD (64 datasets; 7-14 years), all tested twice at a two-year interval, during a visual n-back task, with two loads (1- and 2-back). We performed a whole-brain functional connectivity analysis to examine the networks during the successful recognition of visual stimuli. We demonstrate that youth with ASD show decreased connectivity in the theta frequency (4-7 Hz) in the higher memory load (2-back) condition compared to typically developing (TD) controls. This hypo-connected theta network was anchored in primary visual areas with connections to frontal, parietal and limbic regions. These network differences were found despite similar task performance between ASD and TD groups. Within the TD group, we found an increase in alpha (8-14 Hz) connectivity at Time 2 compared to Time 1 in both the 1- and 2-back conditions. These findings demonstrate the continued development of working memory mechanisms over middle childhood, which were not apparent in youth with ASD. Together, our findings support a network-based approach to understanding atypical neural functioning in ASD and the developmental trajectories of working memory processes over middle childhood.

Functional changes during visuo-spatial working memory in autism spectrum disorder: 2-year longitudinal functional magnetic resonance imaging study.

This study examined functional changes longitudinally over 2 years in neural correlates associated with working memory in youth with and without autism spectrum disorder, and the impact of increasing cognitive load. We used functional magnetic resonance imaging and a visuo-spatial 1-back task with four levels of difficulty. A total of 14 children with autism spectrum disorder and 15 typically developing children (ages 7-13) were included at baseline and followed up approximately 2 years later. Despite similar task performance between groups, differences were evident in the developmental trajectories of neural responses. Typically developing children showed greater load-dependent activation which intensified over time in the frontal, parietal and occipital lobes and the right fusiform gyrus, compared to those with autism spectrum disorder. Children with autism spectrum disorder showed minimal age-related changes in load-dependent activation, but greater longitudinal load-dependent deactivation in default mode network compared to typically developing children. Results suggest inadequate modulation of neural activity with increasing cognitive demands in children with autism spectrum disorder, which does not mature into adolescence, unlike their typically developing peers. Diminished ability for children with autism spectrum disorder to modulate neural activity during this period of maturation suggests that they may be more vulnerable to the increasing complexity of social and academic demands as they progress through adolescence than their peers.

Longitudinal Examination of Everyday Executive Functioning in Children With ASD: Relations With Social, Emotional, and Behavioral Functioning Over Time.

Executive functioning (EF) deficits are well-documented in Autism Spectrum Disorder (ASD), yet little is known about the longitudinal trajectory of "everyday" EF and links to social, emotional and behavioral outcomes in ASD. This study examined the profile of everyday EF utilizing parent-reported measures over 2 years, and explored whether prior estimates of EF were related to later co-morbid psychopathology and social functioning in 39 children with ASD and 34 typically developing (TD) children (ages 7-14 years). According to parent reports, children with ASD had impaired scores of EF in all domains at both time points, and showed no significant improvement across 2 years, compared to controls. Regression analyses showed that prior estimates of behavior regulation difficulties at time 1 uniquely predicted later emotional (i.e., symptoms of anxiety/depression) and behavioral (i.e., oppositionality/aggressiveness) problems in children with ASD 2 years later. Furthermore, an improvement of metacognitive skills predicted a reduction of social difficulties over 2 years in ASD. These results imply that EF may be a potential target of intervention for preventing and reducing co-morbid psychopathology and promoting social competence in youth with ASD. Furthermore, the findings that EF related to behavior is more critical for later emotional and behavioral functioning, whereas EF related to cognition is more critical for social functioning, indicates that it may be beneficial to tailor treatment. Future studies investigating the effectiveness of EF-based interventions in improving the cognitive, psychological and social outcomes in ASD are of high priority.

Load matters: neural correlates of verbal working memory in children with autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterised by diminished social reciprocity and communication skills and the presence of stereotyped and restricted behaviours. Executive functioning deficits, such as working memory, are associated with core ASD symptoms. Working memory allows for temporary storage and manipulation of information and relies heavily on frontal-parietal networks of the brain. There are few reports on the neural correlates of working memory in youth with ASD. The current study identified the neural systems underlying verbal working memory capacity in youth with and without ASD using functional magnetic resonance imaging (fMRI). METHODS: Fifty-seven youth, 27 with ASD and 30 sex- and age-matched typically developing (TD) controls (9-16 years), completed a one-back letter matching task (LMT) with four levels of difficulty (i.e. cognitive load) while fMRI data were recorded. Linear trend analyses were conducted to examine brain regions that were recruited as a function of increasing cognitive load. RESULTS: We found similar behavioural performance on the LMT in terms of reaction times, but in the two higher load conditions, the ASD youth had lower accuracy than the TD group. Neural patterns of activations differed significantly between TD and ASD groups. In TD youth, areas classically used for working memory, including the lateral and medial frontal, as well as superior parietal brain regions, increased in activation with increasing task difficulty, while areas related to the default mode network (DMN) showed decreasing activation (i.e., deactivation). The youth with ASD did not appear to use this opposing cognitive processing system; they showed little recruitment of frontal and parietal regions across the load but did show similar modulation of the DMN. CONCLUSIONS: In a working memory task, where the load was manipulated without changing executive demands, TD youth showed increasing recruitment with increasing load of the classic fronto-parietal brain areas and decreasing involvement in default mode regions. In contrast, although they modulated the default mode network, youth with ASD did not show the modulation of increasing brain activation with increasing load, suggesting that they may be unable to manage increasing verbal information. Impaired verbal working memory in ASD would interfere with the youths' success academically and socially. Thus, determining the nature of atypical neural processing could help establish or monitor working memory interventions for ASD.

The role of executive functions in social impairment in Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by socio-communicative impairments. Executive dysfunction may explain some key characteristics of ASD, both social and nonsocial hallmarks. Limited research exists exploring the relations between executive function and social impairment in ASD and few studies have used a comparison control group. Thus, the objective of the present study was to investigate the relations between executive functioning using the Behavioral Rating Inventory of Executive Functioning (BRIEF), social impairment as measured by the Social Responsiveness Scale (SRS), and overall autistic symptomology as measured by the Autism Diagnostic Observation Schedule (ADOS) in children and adolescents with and without ASD. Seventy children and adolescents diagnosed with ASD and 71 typically developing controls were included in this study. Findings showed that behavioral regulation executive processes (i.e., inhibition, shifting, and emotional control) predicted social function in all children. However, metacognitive executive processes (i.e., initiation, working memory, planning, organization, and monitoring) predicted social function only in children with ASD and not in typically developing children. Our findings suggest a distinct metacognitive executive function-social symptom link in ASD that is not present in the typical population. Understanding components of executive functioning that contribute to the autistic symptomology, particularly in the socio-communicative domain, is crucial for developing effective interventions that target key executive processes as well as underlying behavioral symptoms.

Mapping the Network of Neuropsychological Impairment in Children with Autism Spectrum Disorder: A Graph Theoretical Analysis.

Children with autism spectrum disorder (ASD) exhibit social-communicative impairments. Less is known about the neuropsychological profile of ASD, although cognitive and neuropsychological deficits are evident. We modelled neuropsychological function in 20 children with ASD and 20 sex, age and IQ matched typically-developing controls (ages 7-14) as a network of interacting parameters. Graph theoretical analysis was applied to identify critical topographic regions within this network. Two areas were significantly stronger hubs in typically-developing children, the ability to shift attention (p < 0.001) and overall executive function (p < 0.001). Planning/organization was a stronger hub in the cognitive networks of children with ASD (p = 0.001). We show that ASD is not only characterized by impairments in various neurocognitive domains, but also alterations in their interaction.

The neural correlates of visuo-spatial working memory in children with autism spectrum disorder: effects of cognitive load.

BACKGROUND: Research on the neural bases of cognitive deficits in autism spectrum disorder (ASD) has shown that working memory (WM) difficulties are associated with abnormalities in the prefrontal cortex. However, cognitive load impacts these findings, and no studies have examined the relation between WM load and neural underpinnings in children with ASD. Thus, the current study determined the effects of cognitive load on WM, using a visuo-spatial WM capacity task in children with and without ASD with functional magnetic resonance imaging (fMRI). METHODS: We used fMRI and a 1-back colour matching task (CMT) task with four levels of difficulty to compare the cortical activation patterns associated with WM in children (7-13 years old) with high functioning autism (N = 19) and matched controls (N = 17) across cognitive load. RESULTS: Performance on CMT was comparable between groups, with the exception of one difficulty level. Using linear trend analyses, the control group showed increasing activation as a function of difficulty level in frontal and parietal lobes, particularly between the highest difficulty levels, and decreasing activation as a function of difficulty level in the posterior cingulate and medial frontal gyri. In contrast, children with ASD showed increasing activation only in posterior brain regions and decreasing activation in the posterior cingulate and medial frontal gyri, as a function of difficulty level. Significant differences were found in the precuneus, dorsolateral prefrontal cortex and medial premotor cortex, where control children showed greater positive linear relations between cortical activity and task difficulty level, particularly at the highest difficulty levels, but children with ASD did not show these trends. CONCLUSIONS: Children with ASD showed differences in activation in the frontal and parietal lobes-both critical substrates for visuo-spatial WM. Our data suggest that children with ASD rely mainly on posterior brain regions associated with visual and lower level processing, whereas controls showed activity in frontal lobes related to the classic WM network. Findings will help guide future work by localizing areas of vulnerability to developmental disturbances.