Patterns of Atypical Functional Connectivity and Behavioral Links in Autism Differ Between Default, Salience, and Executive Networks

Cerebral Cortex, October 2016;26: 4034–4045 doi:10.1093/cercor/bhv191 Advance Access Publication Date: 7 September 2015 Original Article ORIGINAL ARTICLE Patterns of Atypical Functional Connectivity and Behavioral Links in Autism Differ Between Default, Salience, and Executive Networks Angela E. Abbott1, Aarti Nair1,2, Christopher L. Keown1,3, Michael Datko1,3, Afrooz Jahedi1,4, Inna Fishman1 and Ralph-Axel Müller1,2 1 Brain Development Imaging Laboratory, Department of Psychology, San Diego State University, San Diego, CA, USA, 2Joint Doctoral Program in Clinical Psychology, San Diego State University and University of California, San Diego, CA, USA, 3Department of Cognitive Science, University of California, San Diego, CA, USA and 4 Computational Science Research Center, San Diego State University, San Diego, CA, USA Address correspondence to Ralph-Axel Müller, Department of Psychology, San Diego State University, 6363 Alvarado Ct., Suite 200, San Diego, CA 92120, USA. Email: Abstract Autism spectrum disorder (ASD) is characterized by atypical brain network organization, but findings have been inconsistent. While methodological and maturational factors have been considered, the network specificity of connectivity abnormalities remains incompletely understood. We investigated intrinsic functional connectivity (iFC) for four “core” functional networks— default-mode (DMN), salience (SN), and left (lECN) and right executive control (rECN). Resting-state functional MRI data from 75 children and adolescents (37 ASD, 38 typically developing [TD]) were included. Functional connectivity within and between networks was analyzed for regions of interest (ROIs) and whole brain, compared between groups, and correlated with behavioral scores. ROI analyses showed overconnectivity (ASD > TD), especially between DMN and ECN. Whole-brain results were mixed. While predominant overconnectivity was found for DMN (posterior cingulate seed) and rECN (right inferior parietal seed), predominant underconnectivity was found for SN (right anterior insula seed) and lECN (left inferior parietal seed). In the ASD group, reduced SN integrity was associated with sensory and sociocommunicative symptoms. In conclusion, atypical connectivity in ASD is network-specific, ranging from extensive overconnectivity (DMN, rECN) to extensive underconnectivity (SN, lECN). Links between iFC and behavior differed between groups. Core symptomatology in the ASD group was predominantly related to connectivity within the salience network. Key words: autism spectrum disorder, default-mode network, executive control network, functional connectivity, salience network Introduction Intrinsic connectivity networks (ICNs) are based on the coupling of spontaneous low-frequency blood oxygen level–dependent (BOLD) signal oscillations in the functional MRI signal between spatially discrete regions (Biswal et al. 1995; Beckmann et al. 2005; Fox and Raichle 2007; Damoiseaux and Greicius 2009). ICNs emerge reliably across participants and scans (Calhoun et al. 2008; Shehzad et al. 2009) and are consistent with structural connectivity (Honey et al. 2007). In development, excitatory and inhibitory functioning largely regulate network sculpting (Wang and Kriegstein 2009), giving rise to two organizing principles: functional integration (high connectivity within networks) and functional segregation (mostly low connectivity between networks) (Friston 2002). © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: Default, Salience, and Executive Networks in Autism Disruption of network-level intrinsic functional connectivity (iFC) is associated with neurocognitive deficits, including symptomatology in autism spectrum disorders (ASD) (Wass 2011; Vissers et al. 2012). ICNs supporting social, emotional, and language function have been found impaired in ASD, with reports of reduced connectivity within networks (Dinstein et al. 2011; Abrams et al. 2013; von dem Hagen et al. 2013). Across networks, overconnectivity has been found between Theory of Mind (ToM) and mirror neuron systems (Fishman et al. 2014) and between default mode and anteromedial temporal regions (Lynch et al. 2013), potentially reflecting poor network segregation (Rudie et al. 2012). A recent study contrasting task-evoked connectivity and resting-state iFC found reduced discriminability between the two conditions in ASD, associated with restricted and repetitive behaviors (Uddin et al. 2014). Overall however, no consensus as to overarching principles of functional connectivity abnormalities in ASD has been reached. Inconsistencies have been attributed to developmental factors (Uddin, Supekar, and Menon 2013), methodology (Nair et al. 2014), or regional specificity (Lynch et al. 2013). Given the breadth of functional domains affected in ASD (Müller 2007), a parsimonious model for synthesizing results has been proposed. The triple-network approach examines “core” brain networks supporting cognitive, perceptual, affective, and social functions, including the salience (SN), default-mode (DMN), and executive control networks (ECN) thought to be abnormally organized in many psychiatric disorders including ASD (Menon 2011). The current study presents a comprehensive investigation of these networks. The SN, with nodes in bilateral anterior insulae and dorsal anterior cingulate cortex, is thought to link neocortical processing networks with limbic and autonomic systems related to homeostatic, emotional, and visceral functions (Dosenbach et al. 2007; Seeley et al. 2007). It maintains dense and dynamically variable connectivity with many brain regions (Chang and Glover 2010) and heavily modulates both task-positive and task-negative networks (Sridharan et al. 2008). The SN may thus have a pivotal function in modulating cognitive state (Dosenbach et al. 2007; Seeley et al. 2007) and any compromise may lead to behavioral impairment (Greicius 2008; Uddin, Supekar, and Menon 2013). Decreased activation of SN regions has been shown in ASD during inhibition tasks (Kana et al. 2007; Agam et al. 2010) and during a skin conductance response (Eilam-Stock et al. 2014) possibly reflecting altered autonomic functioning. Furthermore, decreased connectivity has been found within this network (Kana et al. 2007; Ebisch et al. 2011) and between SN nodes and the amygdala (von dem Hagen et al. 2013). However, SN hyperconnectivity has also been reported for children with ASD aged 7–12 years (Uddin, Supekar, Lynch, et al. 2013). The DMN, or “task-negative” network, is a spatially expansive (Hagmann et al. 2008) system that is relatively inactive during overt task performance. This deactivation is diminished in ASD (Kennedy and Courchesne 2008), particularly during perceptually demanding tasks (Esposito et al. 2006; Ohta et al. 2012). Functional connectivity MRI (fcMRI) studies have shown underconnectivity between posterior and frontal DMN regions in (...truncated)