Elsevier

Biological Psychiatry

Volume 54, Issue 11, 1 December 2003, Pages 1171-1180
Biological Psychiatry

Original article
Cingulate fasciculus integrity disruption in schizophrenia: a magnetic resonance diffusion tensor imaging study

https://doi.org/10.1016/S0006-3223(03)00419-0Get rights and content

Abstract

Background

Evidence suggests that a disruption in limbic system network integrity and, in particular, the cingulate gyrus (CG), may play a role in the pathophysiology of schizophrenia; however, the cingulum bundle (CB), the white matter tract furnishing both input and output to CG, and the most prominent white matter fiber tract in the limbic system, has not been evaluated in schizophrenia using the new technology of diffusion tensor imaging (DTI).

Methods

We used line scan DTI to evaluate diffusion in the CB in 16 male schizophrenia patients and 18 male control subjects, group-matched for age, parental socioeconomic status, and handedness. We acquired 4-mm-thick coronal slices through the entire brain. Maps of fractional anisotropy (FA) were generated to quantify diffusion within the left and right CB on eight slices that included the central portion of the CB.

Results

Results showed group differences, bilaterally, in area and mean FA for CB, where patients showed smaller area and less anisotropy than controls. For patients, decreased left CB correlated significantly with attention and working memory measures as assessed by the Wisconsin Card Sorting Test.

Conclusions

These data provide strong evidence for CB disruptions in schizophrenia, which may be related to disease-related attention and working memory abnormalities.

Introduction

The cingulum bundle (CB) is the white matter tract that underlies, and provides, the cingulate cortex with connections to and from other components of Broca’s “grand limbic lobe.” Of note, cingulate gyrus abnormalities have been reported in morphometric studies of schizophrenia and include bilateral decrease of cingulate gyrus gray matter volume and decreased gray matter density in voxel-based morphometric studies Crespo-Facorro et al 2000, Goldstein et al 1999, Sigmudsson et al 2001. Moreover, histopathologic studies of schizophrenia have provided evidence for decreased cortical thickness, decreased pyramidal neuron size, and a decrease in density in both pyramidal and nonpyramidal neurons as well as deficits in small interneurons within the cingulate gyrus Benes et al 1992, Benes et al 2001, Weinberger et al 1992, Bouras et al 2001.

The anatomy and the connections of the cingulate gyrus have been described in detail Goldman-Rakic 1988, Pandya and Seltzer 1982, Vogt et al 1979. In cytoarchitectonics, connectivity, and function, there appear to be distinct differences between the anterior and posterior portions. The anterior–agranular, motor-related cortex is strongly interconnected with amygdala, nucleus accumbens, medial dorsal thalamus, and dorsolateral prefrontal cortex, whereas the posterior–granular, sensory-related cortex is interconnected with temporal association cortex, medial temporal cortex, and parietal and orbitofrontal cortex. The anterior division is, in fact, implicated more often in schizophrenia-related dysfunction than is the posterior division, and neuroimaging data suggest this region is integral to the processing of error detection and decision monitoring. Such functions have variously been interpreted as monitoring conflict Carter et al 1998, Kiehl et al 2000a and as a comparator making use of corollary discharge or efference copy Coles et al 1995, Dehaene and Cohen 1994, Ghering et al 1993.

There are now many studies from several neuroimaging domains (including positron emission tomography (PET), functional magnetic resonance [MR] imaging, and event-related potential [ERP]) that indicate functional cingulate abnormalities in schizophrenia. These include reduced activation in the cingulate region during error-related ERP negativity (Kiehl et al 2000b), reduced activation in an error detection-related Stroop paradigm Carter et al 1997, Nordahl et al 2001, impaired self-monitoring performance during a continuous performance task (Carter et al 2001), and impaired sustained attention detected during an auditory discrimination test (Cohen et al 1998). Moreover, this evidence for a cingulate-based deficiency in self-monitoring has been related to an inability to distinguish one’s own internal thoughts from external events, thus furnishing a possible basis for hallucinations Ford et al 2001, Frith et al 1995. Of particular note, cingulate volume deficits in structural MRI studies have been reported to be associated with hallucinations, reduced executive functions, psychomotor poverty, and negative symptoms Ashton et al 2000, Liddle et al 1992, Noga et al 1995, Paillere-Martinot et al 2001, Szeszko et al 2000. Taken together, these findings support the hypothesis that abnormalities in the cingulate region may play an important role in the pathophysiology of schizophrenia.

Of further note, all of the neuroimaging and anatomic studies suggest that proper function of the cingulate gyrus critically depends on connections with other parts of the neuronal network, rather than simply an sich (e.g., Benes 1993). In this article, we test the hypothesis that at least part of the abnormal activation and symptom association of the cingulate gyrus observed in patients with schizophrenia may, in fact, be attributed to disrupted white matter connections of this region with other limbic structures.

To date, white matter findings in schizophrenia have been equivocal. Most of the studies investigating volumetric differences between schizophrenia and control subjects have detected gray but not white matter volume reductions (see review by Shenton et al 2001). Two recent studies, however, both report white matter volume deficits, within the temporal and frontal regions on the left side (Sigmudsson et al 2001), and within the frontal lobes bilaterally (Paillere-Martinot et al 2001). Lack of compelling evidence for white matter abnormalities in schizophrenia is not surprising, given that white matter appears fairly uniform and homogeneous on conventional MR scans, where the orientation, density, and asymmetry of the fiber tracts cannot be visualized or quantified.

In contrast to structural MRI studies, diffusion tensor imaging (DTI; Basser 1995) represents an MRI technique that can detect subtle white matter abnormalities in vivo by assessing the degree to which directionally organized tissues have lost their normal integrity.1 This method has recently been used to discern the directionality of white matter tracts in the normal human brain Mamata et al, Pierpaoli and Basser 1996 and to evaluate white matter fiber integrity in multiple sclerosis (Filippi et al 2001), stroke (Zelaya et al 1999), and Alzheimer’s disease (Rose et al 2000). Of note, the first three studies in schizophrenia to quantify anisotropic diffusion showed lower anisotropy within prefrontal white matter (Buchsbaum et al 1998), as well as in whole white matter (Lim et al 1999) and in the splenium of the corpus callosum (Foong et al 2000b) relative to control subjects. A more recent study by our group (Kubicki et al 2002) showed a difference in asymmetry in the uncinate fasciculus, the white matter tract connecting the frontal and temporal lobe. Here, patients with schizophrenia did not show a left > right asymmetry as was observed in normal control subjects. None of these studies, however, focused on the CB, as proposed here.

In this study, we apply line scan diffusion imaging (LSDI; Gudbartsson et al 1996) to obtain fractional anisotropy (FA) maps in 16 schizophrenia and 18 control comparison subjects to measure the integrity of fibers within the CB, the most prominent fiber tract within the limbic system. We also examined neuropsychologic correlates of FA of the CB in patients with schizophrenia. Based on prior studies that have linked CB to deficits in executive functions of performance monitoring in patients with schizophrenia, we examined correlations between our DTI measures and performance indices of the Wisconsin Card Sorting Test (WCST), a well-known neuropsychologic measure of executive functions.

Section snippets

Subjects

Sixteen patients with chronic schizophrenia (all men with a mean duration of illness of 22 years) were recruited from inpatient, day treatment, outpatient, and foster care programs at the Veteran’s Administration (VA) Boston Healthcare System, Brockton, MA. The Structured Clinical Interview for DSM-IV (SCID)—Patient Edition was used for diagnoses and the SCID-Nonpatient Edition (First 2001) interviews were completed for the 18 normal comparison subjects (also all men). The patient interviews

Demographic data

There were no group differences in age, handedness, or gender (Table 1). Groups did differ, however, in education and socioeconomic status, likely reflecting a decline in functioning in schizophrenia. Importantly, groups did not differ in parental socioeconomic status. Also, whereas verbal IQ showed differences between groups, a proxy measure of verbal IQ, oral reading of the Wide Range Achievement Test, version III (WRAT-III) (Wilkinson 1993), which is often considered a valid measure of

Discussion

Our study revealed decreased diffusion anisotropy within the CB in male patients diagnosed with chronic schizophrenia compared with male normal comparison subjects. There are many studies suggesting a disruption in connectivity in schizophrenia (e.g., Fletcher et al 1999, Friston and Frith 1995, McGuire and Frith 1996, Weinberger et al 1992. Most of these studies point to a frontotemporal or temporolimbic network as the most likely pathway for these disruptions Weinberger et al 1992,

Acknowledgements

This study was supported by the National Alliance for Research on Schizophrenia and Depression (MK, MF), the National Institute of Health (Grant Nos. K02 MH 01110 and R01 MH 50747 to MES, R01 MH 40799 to RWM, and R01 NS 39335 to SEM), the Department of Veterans Affairs Merit Awards (MES, PGN, RWM), the National Center for Research Resources (11747 to RK and P41 1321 to FAJ and CFW), and a VA Psychiatry/Neuroscience Research Fellowship Award (MF).

We thank Marie Fairbanks for her administrative

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