ReviewThe anterior insula in autism: Under-connected and under-examined
Introduction
Autism spectrum disorders (ASDs) are developmental disorders characterized by social impairments, restricted interests, and repetitive and stereotyped behaviors, with an estimated incidence of 1:150 (Anon., 2007). An overwhelming number of theoretical accounts of autism have been offered, with relatively few attempts at synthesis across studies (Waterhouse, 2008). Despite considerable efforts to delineate precise brain functional and structural differences between individuals with ASD and typically developing individuals (Sokol and Edwards-Brown, 2004), very little is known regarding differences in large-scale brain network interactions that underlie the cognitive and behavioral symptoms of ASD. The field of autism research has been largely dominated by theories positing malfunction of individual brain regions in ASD, such as the amygdala (Adolphs et al., 2001, Baron-Cohen et al., 2000), superior temporal sulcus (STS) (Pelphrey and Carter, 2008), or fusiform gyrus (Schultz, 2005). At the other extreme, there are claims that ASD is a distributed disorder characterized by widespread abnormalities throughout the brain (Muller, 2007). Recent conceptualizations of the brain basis of ASD have taken a systems-level approach, and proposed that ASD may be explained by abnormalities in the mirror neuron system (Oberman and Ramachandran, 2007, Williams et al., 2001), the default-mode network (Kennedy and Courchesne, 2008, Kennedy et al., 2006), or both (Iacoboni, 2006). These conceptualizations, however, have primarily focused on specific brain systems and have largely ignored the critical interactions between multiple distinct brain systems, which may be important for understanding the neurobiology of a complex neurodevelopmental disorder such as ASD.
Recent work in systems neuroscience has characterized several canonical brain networks that are identifiable in both the resting (Damoiseaux et al., 2006, Seeley et al., 2007) and the active brain (Toro et al., 2008). Conceptualizing the brain as comprised of multiple, distinct, and interacting networks provides a new framework for understanding the complex symptomatology of ASD. Here we suggest that analysis of large-scale brain networks will provide a parsimonious account of the recent neuroimaging literature on ASD, and that the anterior insula (AI) is a brain region of particular interest in understanding this disorder. We discuss the rationale behind our approach, taking into account recent advances in the study of brain networks.
Section snippets
Brain under-connectivity in ASD
One of the earliest and most prominent theories of brain abnormalities underlying ASD is that the disorder is one of connectivity (Frith, 2004, Geschwind and Levitt, 2007). In post-mortem anatomical studies, Courchesne's group observed that the brains of individuals with ASD showed hyper-connectivity within frontal lobe regions, and decreased long-range connectivity and reciprocal interactions with other cortical regions. His team proposed that excessive, disorganized, and inadequately
Functions and connectivity of anterior insula
The insular cortex, located deep within the lateral sulcus of the brain, is traditionally considered to be paralimbic (Mesulam and Mufson, 1982) or “limbic integration cortex” (Augustine, 1996). This characterization stems in large part from the patterns of structural connectivity of this region, which has efferent projections to the amygdala, lateral orbital cortex, olfactory cortex, anterior cingulate cortex (ACC), and STS, and receives input from orbitofrontal, olfactory cortex, ACC and STS (
Spindle neurons: unique location and function
The AI is among the few brain regions containing a special class of neurons thought to be unique to higher primates, known as Von Economo or “spindle” neurons. These neurons have been found in humans, bonobos, chimpanzees, gorillas, and orangutans, but in no other primate species examined (Nimchinsky et al., 1999). Spindle neurons are large projection neurons with a distinctive morphology, and are thought to be a relatively recent phylogenetic specialization (Allman et al., 2002). These cells
Anterior insula as a network hub: role in switching between brain networks
Recent work using resting-state fMRI suggests that the human brain is intrinsically organized into distinct functional networks (Damoiseaux et al., 2006, Greicius et al., 2003). Resting-state functional connectivity enables the characterization of large-scale networks without contamination from cognitive tasks (Fox and Raichle, 2007, Greicius et al., 2009, Uddin et al., 2009, Vincent et al., 2006). This framework has identified at least three canonical networks: (1) an executive-control network
Anterior insula in ASD
The AI is a region that is critically involved in operations critical to social processing. While previous theories of ASD have focused on hypoactivity in regions such as the fusiform gyrus, superior temporal sulcus, or amygdala, the role of the AI is often overlooked. However, in a recent comprehensive meta-analysis of functional neuroimaging studies of social processing in ASD, Di Martino et al. (2009) demonstrated that across a group of 24 studies examining various aspects of social
Brain networks in ASD: synthesis and future directions
The study of brain connectivity, while previously only accessible by post-mortem examination of brain tissue, has been aided greatly in recent years by the development of novel methods to analyze fMRI data. Indeed, such studies now constitute quite a large percentage of the neuroimaging literature on ASD. To date, there have been reports of evidence for reduced functional connectivity between regions critical for social processing in ASD, among several others, as previously reviewed. However,
Acknowledgments
We thank Kaustubh Supekar for critical comments and suggestions. This research was supported by a fellowship from the Children's Health Research Program at the Lucille Packard Children's Hospital to L.Q.U. (Tashia and John Morgridge Endowed Postdoctoral Fellow) and grants from the National Institutes of Health (NS058899, HD047520, HD059205), and the National Science Foundation (BCS/DRL 0449927) to V.M.
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