Decreased volume of left and total anterior insular lobule in schizophrenia

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Abstract

The insula is anatomically situated to be critically involved in many bio-behavioral functions impaired in schizophrenia. Furthermore, its total volume has been shown to be reduced in schizophrenia. In the present study, we tested the hypothesis that in schizophrenia it is the anterior insular lobule (aINSlbl) rather than the posterior insular lobule (pINSlbl) that is smaller, given that limbic system abnormalities are central in schizophrenia and that the affiliations of the limbic system are principally with the anterior insular lobule. We used T1-weighted high resolution magnetic resonance imaging (MRI) to measure the cortical volume of the left and right anterior and posterior insular subdivisions. The subjects included a sample of healthy community controls (N = 40) and chronic patients with DSM-III-R schizophrenia (N = 41). We correlated insula volumes with positive and negative symptoms. We found that the total aINSlbl, and the left aINSlbl in particular, were significantly volumetrically smaller in schizophrenia compared to controls, and significantly correlated with bizarre behavior. Given that the anterior insular lobule offers anatomic features that allow for MRI-based morphometric analysis, namely its central and circular sulci, this brain structure provides a useful model to test hypotheses regarding genotype–phenotype relationships in schizophrenia using the anterior insular lobule as a candidate endophenotype.

Introduction

As the study of brain alterations in schizophrenia has evolved, an increasing number of structures are being identified as abnormal. These include abnormalities of volume and shape of the ventricular system, hippocampus and parahippocampal gyrus, thalamus, cingulate gyrus, insula, cerebellum and various cortical regions including the dorsolateral prefrontal and orbitofrontal cortices and superior temporal gyrus (Goldstein et al., 1999, Lawrie and Abukmeil, 1998, McCarley et al., 1999, Seidman et al., 2003, Shenton et al., 2001, Wright et al., 2000). In addition, because the panoply of symptoms in schizophrenia is so extensive (including somatosensory, motor, cognitive, affective, olfactory and autonomic functions), it is likely that multiple networks underlying these functional systems are impaired in the illness (Andreasen et al., 1999, Seidman, 1983).

One of these structures, the insula, is anatomically situated to be critically involved in many bio-behavioral functions impaired in schizophrenia. Furthermore, the volume of the insula has been shown, by our group and others, to be smaller in volume in schizophrenia than in controls (Crespo-Facorro et al., 2000, Goldstein et al., 1999, Kasai et al., 2003, Kim et al., 2003, Kubicki et al., 2002, Paillere-Martinot et al., 2001, Sigmundsson et al., 2001, Wright et al., 1999). In this paper, we address the role of the insula in schizophrenia from an anatomical perspective discussing its physiological and behavioral implications. We were particularly interested in the behavioral importance for schizophrenia of the anterior–posterior dimension.

The insula of Reil, or insula, is a cerebral cortical structure buried in the depth of the Sylvian fissure (Reil, 1809) (see Fig. 1). It has an elliptical shape and is delimited by the circular sulcus that has a ventral (or inferior) and a dorsal (or superior) limb that merge posteriorly but not anteriorly where they disperse at the limen insula. The insula has an anterior lobule with three or four short gyri (anterior insular lobule, or aINSlbl) and a posterior lobule with two long gyri (posterior insular lobule, or pINSlbl) (see Fig. 1). These two groups of gyri are separated at the level of the central sulcus of the insula (Bailey and von Bonin, 1951, Brodmann, 1994, Dejerine, 1895, Gray, 1985, Papez, 1929, Ture et al., 1999, Varnavas and Grand, 1999). The peculiar cytoarchitectonic arrangement of the insula consists of an agranular innermost, ventral-anterior region, a dysgranular intermediate portion, and an outer, dorsal-posterior granular, isocortical compartment. The cytoarchitectonic composition of the insula is reflected to a certain extent in its morphology, making the anterior insula the equivalent of the agranular and adjacent dysgranular insula, whereas the posterior insula represents the granular and adjacent dysgranular insula (Augustine, 1996, Mesulam and Mufson, 1982a, Mesulam and Mufson, 1985, Sanides, 1968, Sanides, 1972, Shi and Cassell, 1998).

The anterior insula is connected to piriform, orbitofrontal, temporopolar and parahippocampal regions, and the posterior insula is connected to extrastriate and temporal regions, the lower precentral and postcentral gyri and multimodal association frontal and parietal cortices (Aggleton et al., 1980, Augustine, 1996, Jones and Powell, 1970, Mesulam and Mufson, 1982b, Mufson and Mesulam, 1982, Pandya et al., 1971, Pandya and Seltzer, 1982, Pandya and Vignolo, 1971, Shi and Cassell, 1998, Van Hoesen and Pandya, 1975, Van Hoesen et al., 1975). The anterior insula is related to olfactory, gustatory and autonomic functions as well as experience of temperature and pain (Craig et al., 2000, Critchley et al., 2000, Critchley et al., 2002, Evans et al., 2002, Hoffman and Rasmussen, 1953, Mayberg et al., 1999, Penfield and Faulk, 1955, Phillips et al., 1997, Poellinger et al., 2001, Porro et al., 2002, Reiman, 1997, Sanfey et al., 2003, Savic et al., 2002, Showers and Lauer, 1961, Stoleru et al., 1999, Sudakov et al., 1971, Suzuki et al., 2001, Treede et al., 2000), whereas the posterior insula is related to somatosensory, visual and motor functions (Downar et al., 2002, Francis et al., 2000, Juliano et al., 1983, Karnath et al., 2000, McGlone et al., 2002, Robinson and Burton, 1980, Ruben et al., 2001, Showers and Lauer, 1961, Treede et al., 2000). Though the insula is considered to be involved with aspects of language processing, the specific affiliations of the insula subdivisions in this regard are a subject of controversy (Augustine, 1996, Baxter et al., 2003, Cereda et al., 2002, Damasio and Damasio, 1980, Dronkers, 1996, Duffau et al., 2000, Fiebach et al., 2002, Goldstein, 1948, Goodglass, 1993, Heim et al., 2002, Ingham et al., 2000, Marien et al., 2001, Marshall et al., 1996, Ojemann and Whitaker, 1978, Price, 2000, Riecker et al., 2000a, Riecker et al., 2000b, Shuren, 1993).

The anterior insula's role in olfactory, gustatory and autonomic functions suggests that from a behavioral point of view the anterior insula is critically involved in emotion and body regulation (anterior “limbic insula”), whereas the posterior insula is more strongly associated with somatosensory, visual and skeletal-motor functions, providing a basis for its involvement in language related functions. Along with other paralimbic areas such as the orbitofrontal, the temporopolar and the piriform cortices, the insula plays a key role in integrating perceptual experiences and affect to produce balanced behavior. At a clinical level, the disruption of this balance could well result in the manifestation of ictal experiences (seizures) and may be associated with psychotic states and other psychiatric syndromes (Baumgartner et al., 2000, Gastaut et al., 2001, Hoffman and Rasmussen, 1953, Isnard et al., 2000, Kaada, 1960, Kaada et al., 1949, Shimizu, 2001). In general, because the insula is so highly connected with cortical, limbic and paralimbic structures affected in schizophrenia, it too is likely to be dysfunctional in the disease.

In this study, we extended previous work by investigating the neurobiological segregation of the insula, in terms of its anatomy and behavioral correlates (Mesulam and Mufson, 1985), in relationship to schizophrenia. We used magnetic resonance imaging (MRI) anatomic ROI-based semi-automated morphometric analysis (Caviness et al., 1999, Caviness et al., 1996, Filipek et al., 1994) to test the hypothesis that in schizophrenia it is the aINSlbl that is smaller rather than the pINSlbl, given that limbic system abnormalities are central in schizophrenia and histological, connectional and functional affiliations of the limbic system are principally with the aINSlbl. We also evaluated the relationship of insula volume to positive and negative symptoms.

Section snippets

Subjects

The sample included a sub-sample of healthy controls (N = 40) and patients with schizophrenia (N = 41) studied, in part, in previous work (Goldstein et al., 1999, Goldstein et al., 2001, Goldstein et al., 2002, Seidman et al., 1999, Seidman et al., 2002). Data from the subdivision of the insula in patients with schizophrenia have not been published previously. In this study, we began with 48 controls and 46 patients with schizophrenia who had insula volumes measured. Seven controls and one patient

Demographic and clinical characteristics in patients and controls

The groups did not differ significantly on ethnicity, handedness, or years of parental education. The patient group contained a higher proportion of males, was significantly older, had less education, and lower IQ scores. However, the mean score for controls on the WRAT-R reading subtest, an estimate of premorbid intelligence, was well within the normal range and not significantly higher in controls than in the patients (see Table 1). Patients with schizophrenia were rated as having mild to

Summary of our findings

We investigated the volumetric alteration of the insula in schizophrenia, taking into account the cytoarchitectonic composition and anatomical connections in a fashion that reflects the functional and behavioral affiliations of the insula. Thus, we defined and measured two distinct sub-units, namely, an anterior and a posterior insular parcellation unit (aINSlbl and pINSlbl respectively). Results in this study demonstrated that the anterior insular lobules, especially the left aINSlbl, were

Acknowledgments

Preparation of this article was supported in part by grants from the: National Association for Research in Schizophrenia and Depression (NARSAD) to Dr. Nikos Makris; NARSAD and Stanley Medical Research Institute to Dr. Larry J. Seidman; National Institute of Mental Health RO1 MH 56956 to Dr. Jill M. Goldstein; the Fairway Trust to Dr. David Kennedy, a NARSAD Distinguished Investigator Award and National Institute of Mental Health Grants MH 43518 and 46318 to Dr. Ming T. Tsuang, and by the

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