Abnormalities in MRI-measured signal intensity in the corpus callosum in schizophrenia
Introduction
Schizophrenia is thought to be associated with developmentally mediated abnormalities in interhemispheric and cortico-cortical connectivity Crow, 1998, Friston, 1998, McGlashan and Hoffman, 2000, Waddington, 1993. White matter structures, such as the corpus callosum (CC) that form a major basis of cortico-cortical connections, are likely to be affected Lim et al., 1999, Woodruff et al., 1997. The CC is the major commissural pathway between the hemispheres, and its integrity is crucial for normal interhemispheric communication (Gazzaniga, 2000). This structure has an extended maturational profile and is known to mature postnatally through adolescence and into early adulthood Giedd et al., 1996, Keshavan et al., 2002a. In vivo imaging studies David, 1994, Keshavan et al., 2002b, Woodruff et al., 1995 have indicated reductions in the size of the CC in schizophrenia suggesting pathology of this important interhemispheric pathway. Little however is known of whether there are abnormalities in callosal tissue microstructure as well.
Histological examinations of the integrity of callosal tissue in postmortem brains have not been conclusive. Studies examining the density of myelinated fibers or glial cells (Nasrallah et al., 1983) showed no differences between patient and control brains. Other histological studies have pointed to gender-specific alterations in callosal microstructure; female patients show reduced fiber density in most regions of the structure compared to males, an effect opposite to that observed in control brains (Highley et al., 1999), but few in vivo studies have examined this question.
Parameters of the magnetic resonance signal are useful indices of tissue integrity, and can be applied to the in vivo study of tissue pathology. In MRIs, T1 relaxation time is sensitive to the quantity of hydrogen protons (i.e., water) in tissue. Abnormally high MR-visible water in tissue may result from pathologies such as abnormalities in the microtubular density in the cytoarchitecture of axons (Baas, 1998), or alterations in myelination (Kendall, 1993) or fiber density. These changes in MR-visible free water will have a signature in MR parameters; increases in water will lead to increases in T1 relaxation time (Gadian, 1995), and decreases in signal intensity. Because T1 relaxation times directly affect the signal intensity (SI) in tissue (Gadian, 1995), by corollary, SI in T1-weighted images will reflect MR-“visible” free water in axons and myelin, and provide valuable information about tissue characteristics (Thatcher et al., 1996). SI analyses have been applied in the investigation of some white matter diseases such as multiple sclerosis, which are associated with decreases in SI on T1-weighted MRI scans (Kendall, 1993), as well as in patients diagnosed with obsessive compulsive disorder (MacMaster et al., 1999). In schizophrenia, increases in T1 relaxation time have been previously documented (Andreasen et al., 1991), but systematic analyses of the SI of structures like the CC have not been conducted. In this study, we examined SI measures in CC in a series of previously untreated first-episode schizophrenia patients in comparison with non-schizophrenia psychotic patients and healthy controls.
The approach adopted in this study was componential. Interhemispheric fibers in the CC are topographically organized. Fibers from the heteromodal cortex, i.e., prefrontal and the superior temporal cortices, respectively, cross in the genu and the splenium of the CC. Fibers connecting the unimodal association cortices, that is, the motor and visual cortices, cross predominantly in the body and the isthmus of the structure Delacoste et al., 1985, Pandya and Seltzer, 1986. Thus, a componential analysis of CC subregions may shed light on the specific brain regions with impaired integrity of interhemispheric connections (Keshavan et al., 2002a). Because schizophrenia has been associated with the heteromodal association cortices (Pearlson and Marsh, 1999), abnormalities in the CC might be restricted to the genu and the splenium.
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Subjects
The morphometric and the SI analyses of the CC were conducted on the T1-weighted MRI scans of 102 subjects. The population consisted of three groups: 29 patients diagnosed with first-episode schizophrenia (SCZ) (mean age=23.55 years, S.D.=6.69; 20 males/9 females), 11 patients diagnosed with first-episode non-schizophrenic psychotic disorders (Non-SCZ) (mean age=25.1 years, S.D.=7.75; 6 males/5 females) and 62 healthy controls (HC) (mean age=21.59 years, S.D.=7.54; 41 males/21 females). All
Results
The data from the five callosal subregions (genu, anterior and posterior body, isthmus, and splenium) were analyzed in a two-way multiple analysis of variance with Group (SCZ, Non-SCZ, HC) and Sex as factors. There was a significant difference in signal intensity between the Groups, Rao's R=2.56, df=10,184, p<0.007, and a trend for a difference between Sexes, Rao's R=2.06, df=5,92, p<0.08.
The differences between the Groups were significant in both the genu, F(2,96)=7.44, p<0.001, and the
Discussion
While evidence from neuroimaging and postmortem studies suggest abnormalities in callosal size Machiyama et al., 1987, Nasrallah et al., 1986, Woodruff et al., 1995, little is known whether abnormalities are also observed in the integrity of callosal tissue. Our data showed that callosal tissue in first-episode schizophrenia has reduced signal intensity in T1-weighted scans (is hypointense) compared to both non-schizophrenia psychotic subjects and healthy age-matched control subjects,
Acknowledgments
This work was supported in part by NIMH grants MH45156-01A1 and MH46614 (JWP), and 5 K08 MHO1324-04 (MDDB), a Scottish Rite Schizophrenia Foundation Grant (MSK), the Center for Neurosciences in Mental Disorders (MH 45156), and by funds received from the NIH/NCRR/GCRC (M01 RR00056). We thank Drs. Cameron Carter, Gretchen Haas, Debra M. Montrose, Elizabeth D. Radomsky, and Nina R. Schooler for their help in clinical assessments, and Elizabeth Dick, Rupal Kotwal, and Wright Bagwell for help in
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