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Impact of methodological variables on functional connectivity findings in autism spectrum disorders.

ABSTRACT: Growing evidence suggests that Autism Spectrum Disorder (ASD) involves abnormalities of multiple functional networks. Neuroimaging studies of ASD have therefore increasingly focused on connectivity. Many functional connectivity (fcMRI) studies have reported network underconnectivity in children and adults with ASD. However, there are notable inconsistencies, with some studies reporting overconnectivity. A previous literature survey suggested that a few methodological factors play a crucial role in differential fcMRI outcomes. Using three ASD data sets (two task-related, one resting state) from 54 ASD and 51 typically developing (TD) participants (ages 9-18 years), we examined the impact of four methodological factors: type of pipeline (co-activation vs. intrinsic analysis, related to temporal filtering and removal of task-related effects), seed selection, field of view (whole brain vs. limited ROIs), and dataset. Significant effects were found for type of pipeline, field of view, and dataset. Notably, for each dataset results ranging from robust underconnectivity to robust overconnectivity were detected, depending on the type of pipeline, with intrinsic fcMRI analyses (low bandpass filter and task regressor) predominantly yielding overconnectivity in ASD, but co-activation analyses (no low bandpass filter or task removal) mostly generating underconnectivity findings. These results suggest that methodological variables have dramatic impact on group differences reported in fcMRI studies. Improved awareness of their implications appears indispensible in fcMRI studies when inferences about "underconnectivity" or "overconnectivity" in ASD are made. In the absence of a gold standard for functional connectivity, the combination of different methodological approaches promises a more comprehensive understanding of connectivity in ASD.

SUBMITTER: Nair A

PROVIDER: S-EPMC5708536 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Autism spectrum disorders (ASDs) are a group of heterogeneous neurodevelopmental disorders that are highly heritable and are associated with impaired dynamic functional connectivity (DFC). However, the molecular mechanisms behind DFC alterations remain largely unknown. Eighty-eight patients with ASDs and 87 demographically matched typical controls (TCs) from the Autism Brain Imaging Data Exchange II database were included in this study. A seed-based sliding window approach was then performed to investigate the DFC changes in each of the 29 seeds in 10 classic resting-state functional networks and the whole brain. Subsequently, the relationships between DFC alterations in patients with ASDs and their symptom severity were assessed. Finally, transcription-neuroimaging association analyses were conducted to explore the molecular mechanisms of DFC disruptions in patients with ASDs. Compared with TCs, patients with ASDs showed significantly increased DFC between the right dorsolateral prefrontal cortex (DLPFC) and left fusiform/lingual gyrus, between the DLPFC and the superior temporal gyrus, between the right frontal eye field (FEF) and left middle frontal gyrus, between the FEF and the right angular gyrus, and between the left intraparietal sulcus and the right middle temporal gyrus. Moreover, significant relationships between DFC alterations and symptom severity were observed. Furthermore, the genes associated with DFC changes in ASDs were identified by performing gene-wise across-sample spatial correlation analysis between gene expression extracted from six donors' brain of the Allen Human Brain Atlas and case-control DFC difference. In enrichment analysis, these genes were enriched for processes associated with synaptic signaling and voltage-gated ion channels and calcium pathways; also, these genes were highly expressed in autistic disorder, chronic alcoholic intoxication and several disorders related to depression. These results not only demonstrated higher DFC in patients with ASDs but also provided novel insight into the molecular mechanisms underlying these alterations.

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Impact of methodological variables on functional connectivity findings in autism spectrum disorders.

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