Elsevier

Biological Psychiatry

Volume 44, Issue 6, 15 September 1998, Pages 405-412
Biological Psychiatry

Original Articles
Corpus callosum shape and size in male patients with schizophrenia

https://doi.org/10.1016/S0006-3223(98)00096-1Get rights and content

Abstract

Background: Corpus callosum (CC) morphology has recently been investigated in schizophrenia using refined imaging and analytic techniques; however, methodological problems and small sample sizes have led to inconsistent findings.

Methods: This study used a large sample of male schizophrenics (n = 79) and male controls (n = 65) to investigate size and shape of the CC on midsagittal magnetic resonance images. Size was determined by tracing the area of the CC, and shape was determined using a landmark-based analysis. In addition, the relationship between CC morphology and phenomenologic variables such as age of onset, length of illness, exposure to medications, and symptom severity was explored.

Results: After controlling for age, height, and parental socioeconomic status, there was a main effect of diagnosis on CC size (F = 5.05, df = 1,139, p < .03), with patients’ CCs being significantly smaller. No difference was found between patients and controls in CC shape (F = 1.07, df = 18,125, p > .38) or orientation (F = 0.79, df = 18,125, p > .70), using a landmark-based technique. Finally, there was a significant inverse correlation between size of CC and severity of negative symptoms.

Conclusions: These findings support previous studies that have found a decrease in size of the CC in patients with schizophrenia. Moreover, the decrement in volume is generalized, not regional, and is related to the severity of negative symptoms.

Introduction

The relationship between corpus callosum (CC) morphology and psychosis has intrigued scientists since 1844, when it was proposed as the “seat of insanity” in a treatise by A. Wigan (Clarke 1987); however, the nature of the relationship remains elusive. In the early 1970s, Rosenthal and Bigelow were the first to do a quantitative assessment of the CC in schizophrenia using postmortem tissue (Rosenthal and Bigelow 1972). In more recent years, structural brain imaging techniques have revisited the issue, often with conflicting results. To date, there have been 20 studies on the morphology of CC in patients with schizophrenia versus controls Casanova et al 1990, Colombo et al 1994, Gunther et al 1991, Hauser et al 1989, Hoff et al 1994, Kelsoe et al 1988, Matthew et al 1985, Nasrallah et al 1986, Raine et al 1990, Rossi et al 1988, Rossi et al 1989, Smith and Tamminga 1985, Smith et al 1984, Smith et al 1987, Stratta et al 1989a, Stratta et al 1989b, Uematsu and Kaiya 1988, Woodruff et al 1993, Woodruff et al 1995, Young et al 1991. The majority have shown no significant differences in CC area between patients and controls Casanova et al 1990, Colombo et al 1994, Hauser et al 1989, Kelsoe et al 1988, Matthew et al 1985, Raine et al 1990, Smith et al 1987. Two have reported an increased size of CC in patients Nasrallah et al 1986, Uematsu and Kaiya 1988, though many others, including a meta-analysis of 11 studies up through 1993 (Woodruff et al 1995), have shown that patients have a decreased size of CC Hoff et al 1994, Rossi et al 1988, Rossi et al 1989, Stratta et al 1989b, Woodruff et al 1993. The difficulties faced in obtaining accurate and reliable measurements of the CC are many and include such problems as variations produced if the magnetic resonance imaging (MRI) slice is off midline and/or at an oblique angle (Coppola et al 1995). Also, wide normal variations in the CC shape have made small sample size studies hard to interpret. In the meta-analysis by Woodruff, the mean number of patients studied was only 25, and the mean number of controls only 17. Moreover, for those studies that found a difference between patients and controls, the mean effect size was modest at .465. Finally, there has been a lack of elimination of confounds that have impact on CC morphology, such as gender Allen et al 1991, Steinmetz et al 1995, handedness (Witelson 1989), gender by diagnoses interactions (Hoff et al 1994), and age Aboitiz et al 1996, Cowell et al 1992.

In addition to the question of overall size difference between patients and controls, there are other important questions left unanswered, such as whether the change in CC volume is regional or generalized. The pattern of fibers traversing the CC has been shown to reflect the anterior–posterior topographical pattern of the cortical regions Innocenti et al 1974, Witelson 1989. In general, axons from anterior cortical regions, such as the frontal lobes, project through the anterior portion of the CC, while those from midregions, such as the temporal lobes, project through the midregion of the CC, and those from more posterior locations, such as the parietal and occipital lobe, project through the posterior region of the CC. Regional cortical abnormalities in patients with schizophrenia have most consistently focused on the decrement in volume of areas such as the frontal lobe (Andreasen et al 1994) and the temporal lobes Barta et al 1990, Falkai et al 1988, Shenton et al 1992. Therefore, it follows that these regional cortical abnormalities could be reflected in regional abnormalities within the CC; however, few studies have addressed this, and once again there is tremendous inconsistency in methodology as well as findings. In the seven studies that have evaluated regions of the CC, there are several different methods used, including measuring the width of anterior, middle, and posterior sections of the CC drawn vertically, Casanova et al 1990, Kelsoe et al 1988, width of anterior, middle, and posterior sections of the CC drawn perpendicular to the ventral contour of the CC Hauser et al 1989, Nasrallah et al 1986, both of these methods (Woodruff et al 1993), area measurements of CC tertiles (Uematsu and Kaiya 1988), and area measurements of the CC divided into five regions (Hoff et al 1994). In that there is such a range of methodology, it is not surprising that there are no consistent findings, with four studies findings no regional differences Casanova et al 1990, Hauser et al 1989, Hoff et al 1994, Kelsoe et al 1988, two showing increased width (Nasrallah et al 1986) or area of the anterior region (Uematsu and Kaiya 1988) in patients, and one finding a decreased width in the anterior width of the CC in patients versus controls (Woodruff et al 1993).

Almost all studies investigating regional abnormalities in the CC of patients with schizophrenia use a variety of methods to subdivide the corpus into various regions of the CC; however, another more reliable method is to evaluate the shape of the CC. If there were indeed regional rather than global changes in the volume of the CC in patients with schizophrenia, this would be reflected in a change of shape. Landmark-based regional analyses is one such technique recently developed that has the capacity to address issues of shape. This technique uses landmark locations as a means of morphological analyses, taking advantage of the technology that has produced sharper and more detailed images of the brain. It allows for the quantification of spatial relationships of structures, providing anatomical shape information as well as indices of displacement. A large reliability study of normal controls by our group demonstrated that landmark-based analysis was both reliable and sensitive (Arndt et al 1996). Only one schizophrenia study using landmark-based registration has been reported in the literature to date. DeQuardo et al (1996) found shape abnormality in the region of the posterior CC, upper brain stem, and quadrigeminal cistern, though with a small sample size (n = 14) and no overall test statistic.

Finally, the association between morphologic changes in the CC and correlation to clinical variables has been virtually ignored in the literature. Though one recent study has evaluated the relationship between CC morphology and neuropsychological function (auditory comprehension) (Colombo et al 1993), very few have addressed whether change in CC size is related to symptoms of the illness. Uematsu and Kaiya (1988) were the first to examine the association of CC morphology and clinical variables, finding that elongation of the CC is related to an overall unfavorable prognosis. One study by Gunther et al found no differences in size of CC between patients and controls, but did find that Crow’s type II patients (those with predominantly negative symptoms) had smaller CC than those with Crow’s type I patients (those with predominantly positive symptoms) (Gunther et al 1991). To better understand the pathology underlying brain structure and function in schizophrenia, the relationship between change in CC morphology and ensures of psychopathology is necessary and important.

This study is designed to assess corpus callosum morphology in patients with schizophrenia, eliminating many of the confounders that have led to inconsistencies in previous studies. In this study, an all-male sample eliminates the possible confound of gender. In addition, this is the largest study to date, with a sample size of 79 patients and 65 controls. Using state of the art imaging techniques, size and shape (using the landmark-based registration methodology) of the CC are evaluated. In addition, CC morphology is correlated with phenomenologic variables such as age of onset, exposure to medications, and severity of psychopathology.

Section snippets

Subjects

Male schizophrenic subjects (n = 79) were drawn from patients who had been admitted consecutively to the University of Iowa Mental Health Clinical Research Center (MHCRC) and had received a DSM-III-R diagnosis of schizophrenia by at least three research psychiatrists. Exclusion criteria included history of major head trauma, recent/past severe substance abuse, or any medical or neurological illness. Each patient’s demographic information, as well as past and current symptom history was obtained

Demographics

The demographic information for the patients and controls is shown in Table 1. There was no significant difference between the groups in height or parental socioeconomic status. Age was found to be nonsignificantly different between the schizophrenics and controls, though the patients were somewhat older (t = −1.75, df = 142, p = .08).

Total brain tissue volume

After controlling for the effects of height, parental socioeconomic status, and age, there remained a main effect of diagnosis on total brain tissue volume (F =

Discussion

This study has demonstrated a decrease in CC size in male schizophrenics when compared to healthy male controls using a computerized tracing method. This was in association with a significant decrease in overall brain tissue volume in the patient group as well. The finding of decreased CC size in the patient group is in agreement with past findings, including the meta-analyses of Woodruff et al (1995). They found in eight of 11 studies where CC size was measured (five using planimetry, five

Acknowledgements

This research was supported in part by NIMH grants MH31593, MH40856, and MHCRC 42371; The Nellie Ball Trust Fund; Iowa State Bank and Trust Company; and a Research Scientist Award, MH00625.

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