Functional connectivity of the insula in the resting brain
Graphical Abstract
Research Highlights
► The insula can be parcellated in two clusters and an intermediate transitional area. ► Anterior ventral insula is functional connected to the salience detection network. ► Posterior dorsal insula is functional connected to a visuomotor integration network. ► The timecourses of the two networks are partially anticorrelated.
Introduction
First described by anatomist J.C. Reil (1809), the human insular cortex (also known as the insula, Island of Reil, Brodmann areas 13 to 16) forms a distinct lobe located deep inside the lateral sulcus of the Sylvian fissure, and is hidden by the frontal and temporal opercula (Ture et al., 1999). Relative to that in the macaque, the insula is disproportionately increased in humans (Craig, 2008). Five to seven oblique gyri can be identified on the surface of the insula: these converge inferiorly, giving the appearance of the folds of a fan. A central insular sulcus, in which lies the main branch of the middle cerebral artery (Flynn et al., 1999), divides the lobe into an anterior and a posterior half.
Cytoarchitectonics and myeloarchitectonic can identify three major subdivisions in the insular cortex in humans and primates (Mesulam and Mufson, 1982a, Augustine, 1985, Ture et al., 1999, Bonthius et al., 2005), connected to the frontal, parietal, and temporal lobes, and especially to the cingulate gyrus (Augustine, 1996, Mesulam and Mufson, 1982a, Mesulam and Mufson, 1982b, Mufson and Mesulam, 1982, Vogt et al., 1987). Two of these, one antero-inferior and the other posterior, can be differentiated with histochemical staining for cytochrome oxidase, acetylcholinesterase and nicotinamide dinucleotide phosphate-diaphorase (Rivier and Clarke, 1997). The antero-inferior has a special relationship with rostral anterior cingulated cortex of Vogt (1993, 2004). The subdivisions of the insula also display different patterns of thalamic projections: for instance, in rhesus monkeys and in squirrel monkeys, the posterior subdivision receives a dense, coarse plexus of thalamic projections, that arise from the suprageniculate-limitans nucleus and fill all of layers IV to IIIa, whereas the thalamic projections to the middle field arise in the ventroposterior inferior nucleus, and form a finer plexus in layers IV and III (Jones and Burton, 1976).
The insula has been involved in processing visceral motor/sensory, gustatory, olfactory, vestibular/auditory, visual, verbal, pain, sensory/motor information, and inputs related to music and eating, and modulating attention and emotion; (Augustine, 1996, Brooks et al., 2005, Cole et al., 2006, Craig, 2002, Craig, 2003, Craig, 2004, Critchley et al., 2004, Devinsky et al., 1995, Lamm and Singer, 2010, Mutschler et al., 2009, Olausson et al., 2005, Ostrowsky et al., 2002, Pollatos et al., 2007, Schweinhardt et al., 2006). And finally, Flynn et al. (1999) have shown that the insula also participates in conditioned aversive learning, affective and motivational components of pain perception, mood stability, sleep, stress induced immunosuppression and language.
The advent of functional magnetic resonance imaging (fMRI) has enabled analyses of cortical connectivity in humans in vivo. In fact, spontaneous activity has been demonstrated with functional imaging techniques in various species. FMRI allows to visualize large-scale, spatial patterns of such intrinsic activity (Biswal et al., 1995, Vincent et al., 2007). “Functional connectivity” (FC) highlights differences among correlational methods of inferring brain connectivity, and defines “the temporal correlations across cortical regions”, which represent an index of brain function (Friston et al., 1993, Horwitz, 2003). The temporal correlation between fluctuations in different areas is then often taken as a measure of functional connectivity. The term “resting state” refers to the condition of an individual lying in the scanner in absence of stimuli or tasks. Spontaneous resting state fluctuations of the Blood Oxygen Level Dependent (BOLD) fMRI signals show patterns of synchronous activation/deactivation that are coherent within anatomically and functionally related areas of the brain (Damoiseaux et al., 2006, Fox et al., 2005, Greicius et al., 2003, Hampson et al., 2002, Vincent et al., 2007). Intrinsic functional brain connectivity, as revealed by low-frequency spontaneous fluctuations in the time courses of fMRI signals, has recently drawn much interest. Domains of correlated activity, often referred as resting state networks (RSNs), identified within the cerebral cortex, are related to specific types of sensory, motor and cognitive functions (Beckmann et al., 2005, Cauda et al., 2010b, Damoiseaux et al., 2006; see Fox and Raichle, 2007 for a review). Recently, this technique was further validated by showing very unlikely that RSNs are produced artifactually, by aliasing of cardiac and respiratory cycles; in fact, RSNs are localized in the gray matter and are likely related to ongoing neuronal activity (De Luca et al., 2006). Moreover, RSNs display changes in BOLD signals that are comparable to task-related ones, i.e. up to 3% are consistent across individuals, and are stable across repeated sessions (Damoiseaux et al., 2006).
In the present study we use resting state FC (rsFC) and seed-region of interest (ROIs) correlation analysis to investigate the correlations in BOLD fluctuations between specific ROIs of the insular cortex and those of other brain areas. We show that the anterior and the posterior insular areas belong to two distinct functional networks; in addition to confirming the functional connections of these two regions with the anterior and posterior cingulate cortex, respectively (Taylor et al., 2008), we provide for the first time a detailed description of their other connectivity and provide evidence for a lateralization in these networks.
Section snippets
Subjects
Seventeen healthy right-handed volunteers (8 males; mean = 54 years old; SD = 19.1 years), free of neurological or psychiatric disorders, not taking medications known to alter brain activity, and with no history of drug or alcohol abuse, participated in the study. Written informed consent was obtained from each subject, in accordance with the Declaration of Helsinki. The study was approved by our institutional committee of the University of Torino on ethical use of human subjects. All subjects
Results
One subject was excluded from the analyses because of a movement that exceeded the limits subsequently indicated. No patients were reported having fallen asleep during the scanning. Thus the revised demographic of the subjects was as follows: sixteen right-handed healthy volunteers (8 males; mean = 53 years old; SD = 19 years). An ANCOVA correlational analysis between each subject-specific ROI-generated map by age and gender revealed no significant correlation among them (q < 0.05 FDR (Genovese et al.,
Discussion
Even though there are several studies reporting the functional connectivity of the insula with the cingulated cortex, its relationships with other brain areas remain elusive in humans. Therefore, we decided to use rsFC to elucidate in details its connectivity, in terms of cortical and subcortical areas, and also of lateralization. The temporal correlation between slow fluctuations of intrinsic activity in different regions observed in this study relates to resting state, and cannot be used to
Conclusions
Resting brain studies confirm and extend the notion that the human insula can be divided into two functionally distinct areas, the anterior and the posterior, which belong to two different functional networks, one related to the limbic functions and the other related to sensorimotor integration. We have described the two networks at cortical and subcortical levels, extending the already known involvement of the insular cortex in brain connectivity. Moreover, we have shown that the two patterns
Acknowledgments
We wish to thank all the subjects who participated in this study. This work was supported by Regione Piemonte, bando Scienze Umane e Sociali 2008, L.R. n. 4/2006 and was submitted in partial fulfillment of the requirements for the doctoral degree (FC).
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