Original articleParacingulate morphologic differences in males with established schizophrenia: a magnetic resonance imaging morphometric study
Introduction
Converging evidence from psychopharmacological, postmortem and functional imaging studies suggests that dysfunction of the anterior cingulate cortex (ACC) plays an important role in the pathophysiology of schizophrenia Benes 1993, Tamminga et al 2000; however, structural imaging studies of the ACC in schizophrenia have yielded inconsistent results. For example, studies report bilateral Goldstein et al 1999, Noga et al 1995, left- (Ohnuma et al 1997), or right-sided (Szeszko et al 1999) reductions in ACC volume, or no reduction at all Uematsu and Kaiya 1989, Young et al 1991.
These inconsistent structural imaging findings may be due to the marked inter-individual variation in the location, extent, and complexity of the sulci/gyri within the ACC. Specifically, there is marked inter-individual variation in the presence or absence of the paracingulate sulcus/gyrus Ide et al 1999, Paus et al 1996b, Yücel et al 2001, often considered a part of the ACC. The majority of volumetric studies of the ACC in schizophrenia do not detail whether the paracingulate was included in the measurement Ohnuma et al 1997, Uematsu and Kaiya 1989, Young et al 1991. One study that has reported separate measures for the ACC and paracingulate regions used a parcellation method (Goldstein et al 1999) to approximate architectonic and functional subdivisions of the cerebral cortex, based on specific, primarily sulcal, anatomical landmarks (Caviness et al 1996). A limitation of this methodology is that it does not account for the individual morphologic variability of this region, particularly given that the paracingulate sulcus (PCS) is not always clearly evident Ide et al 1999, Paus et al 1996b, Yücel et al 2002. Studies that have taken this issue into consideration have either included the PCS as a part of the ACC (Noga et al 1995) or excluded it to improve measurement reliability (Szeszko et al 1999). The latter approach is problematic in the light of evidence to suggest that gray-matter volume in the anterior segment of the cingulate sulcus is negatively correlated with the gray-matter volume of the PCS (Paus et al 1996a). This process, whereby the size of one region affects that of its neighbor, has been termed “compensation” Connoly 1940, Connoly 1950. In summary, the inconsistent findings with respect to ACC volumes may be a methodological consequence of the decision to include or exclude the paracingulate region.
An alternative approach that avoids the limitations of the volumetric method is to examine aspects of gross morphology, such as the complexity and organization of gyri and sulci. We have recently described a reliable method to categorize the highly varied surface features of the ACC in a study of a large group of healthy volunteers (Yücel et al 2001), which found that the ACC of males was characterized by an asymmetric sulcal pattern with increased folding in the left hemisphere, consistent with previous postmortem studies Ide et al 1999, Weinberg 1905 and one other magnetic resonance imaging (MRI) based study (Paus et al 1996b).
The possibility that anatomical brain asymmetries are associated with neurodevelopmental processes was raised by Crichton-Brown in the 19th century (Crichton-Browne 1879), while the possibility that mental disturbances might be associated with disturbances in the normal pattern of brain asymmetry was raised nearly a century ago (Southard 1915). More recently, Crow has put forward a detailed theory that suggests an intimate relationship between the mechanisms that determine asymmetrical brain development during neurodevelopment and the disease process in schizophrenia (Crow et al 1989). In accordance with this theory, an absence or reversal of normal anatomical brain asymmetries has been described, particularly in the temporal lobe and in males Bilder et al 1994, Crow 1990, Crow et al 1989, Falkai et al 1992, Kwon et al 1999, Petty 1999. Given that these asymmetries are apparent by the second trimester of gestation (Chi et al 1977), these findings have been used as evidence to suggest a disruption of early corticogenesis in the affected patient; however, cerebral volume (which is often used to derive measures of anatomical brain asymmetry) is influenced by a number of factors throughout life, including normal aging Giedd et al 1996, Pfefferbaum et al 1994, life experiences (e.g., learning to play music at an early age); (Schlaug et al 1995), nutritional factors (Dalman and Cullberg 1999), alcohol/substance abuse Pfefferbaum et al 1997, Wilson et al 2000, and neuroleptic medication Chakos et al 1994, Keshavan et al 1994. In contrast, while cerebral folding also occurs during the second and third trimester Chi et al 1977, Huang 1991, it remains relatively stable after birth Armstrong et al 1995, Magnotta et al 1999. Consequently, examining cerebral sulcal/gyral patterns (and their asymmetries), rather than volumes, may provide a more robust marker of the contribution of neurodevelopmental factors to the etiology of schizophrenia. In the present study, we used high-resolution structural MRI to examine ACC morphology in patients with established schizophrenia in comparison with healthy controls. Based on the current literature and existing clinical evidence, we hypothesized that there would be an abnormality of ACC morphology in schizophrenia, which may be evident as disturbed cerebral folding/sulcal asymmetry.
Section snippets
Subjects
Of the 143 subjects meeting the inclusion criteria before scanning, 130 were included in the study. Thirteen subjects were excluded after MR scanning: 10 patients with established schizophrenia (4—excessive MRI artifact; 2—lesion; 1—infarction; 1—contusion; 2—diagnosis revised); and 3 control subjects (2—excessive MRI artifact; 1—cyst).
Fifty-five patients with established schizophrenia (SZ) were recruited from either the general community (n = 8), or from inpatient (n = 39) and outpatient (n =
Demographic characteristics
Comparison of the two groups revealed that controls were younger (t = 3.74, df = 128, p < .001), more highly educated (t = 6.65, df = 97, p < .001) and had higher premorbid IQs (t = 3.21, SD = 62, p < .01) than patients. Correlational analyses showed that age, duration of illness and age at illness onset in the SZ group were not significantly associated with left or right hemispheric folding. Cortical folding of the left and right hemispheres was highly correlated within each group (Control: r
Discussion
There are two major findings of this study of ACC morphology in males with schizophrenia compared with control subjects. Firstly, while control subjects exhibited a left-greater-than-right asymmetry, SZ patients showed a more symmetric pattern in overall cerebral folding. This reduction in asymmetry was explained by reduced folding of the left hemisphere. Secondly, males with SZ were less likely to show normal ACC sulcal asymmetry, which was explained by reduced folding of the left ACC. These
Acknowledgements
We would like to thank Cathleen Geoghegan for her assistance with data collection. Murat Yücel was funded by a Ph.D. scholarship from La Trobe University, Bundoora, Australia. Geoffrey W. Stuart was supported by a NARSAD Young Investigator Award. This research was also supported by the Cognitive Neuropsychiatry Unit at the Mental Health Research Institute (MHRI), the National Health and Medical Research Council, the Australian Communications and Computing Institute, the Jack Brockhoff
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