Diffusion tensor imaging in schizophrenia: Relationship to symptoms

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Abstract

In this diffusion tensor imaging (DTI) study, the authors investigated white matter integrity in schizophrenia and the relationships between white matter alterations and specific symptoms of the disorder. We compared DTI images of 25 schizophrenia patients and 25 matched healthy controls and performed voxel-wise correlational analyses using the patient's DTI data and their severity scores of positive and negative symptoms. We found diffuse deficits in multiple types of white matter tracts in schizophrenia, and an inverse relationship of DTI fractional anisotropy (FA) values with positive symptom scores in association fibers, supporting a “disconnection” hypothesis of positive symptoms in schizophrenia.

Introduction

Increasing evidence suggests the presence of white matter abnormalities in schizophrenia at the molecular (Davis et al., 2003), structural magnetic resonance imaging (MRI) (Takase et al., 2004) and neuropathologic levels (Zai et al., 2005). These observations “underscore the importance of evaluating white matter fiber tract abnormalities in schizophrenia” (Kubicki et al., 2005) which may contribute to the hypothesized disordered connectivity between brain regions in schizophrenia (Friston, 1998). A number of recent studies have applied diffusion tensor imaging (DTI), a magnetic resonance imaging method sensitive to white matter integrity, to the study of schizophrenia; using the apparent diffusion coefficient (ADC) or fractional anisotropy (FA) measures, the majority of these find white matter deficits associated with the disease (Kubicki et al., 2007, Mori et al., 2007, Shergill et al., 2007, Buchsbaum et al., 2006, Rose et al., 2006, Jones et al., 2005b, Kitamura et al., 2005, Kubicki et al., 2005, Kanaan et al., 2005, Kumra et al., 2005, Szeszko et al., 2005).

Symptom profiles in schizophrenia vary considerably between different individuals (Kirkpatrick et al., 2001). Thus, in order to address possible heterogeneity in the underlying pathophysiology, recent studies have examined correlations between different aspects of the disease and DTI data, through examination of specific symptoms and symptom groups (Shin et al., 2006, Hubl et al., 2004, Wolkin et al., 2003,), or via performance on tests of cognitive ability (Lim et al., 2006, Nestor et al., 2004). Recent studies have also looked at the relationship between structural data (including DTI) and the Positive and Negative Symptom Scales (PANSS) scores (Mitelman et al., 2006, Okugawa et al., 2006, Shin et al., 2006, Minami et al., 2003, Foong et al., 2000, Paillere-Martinot et al., 2001). Shin et al. reported that a small area of white matter near the right insula showed a positive correlation between the PANSS negative symptoms and ADC. In this study, we compared FA between patients with schizophrenia and matched healthy controls, and performed a voxel-wise correlational analysis with the patients' PANSS scores.

Section snippets

Subjects

Participants were 25 outpatients with chronic schizophrenia (mean age 34.2 (sd = 11.7), range 19–58, seven female, two non-right handed) and 25 healthy controls (mean age 34.7 (sd = 13.6), range 21–64, nine female, three non-right handed). All subjects provided written informed consent to participate after the procedures were fully explained to them, and all procedures were approved by Yale University and Hartford Hospital institutional review boards. Diagnoses were confirmed using the Structured

Full-brain voxel-based analysis

There was no significant between-group difference in age, sex, or handedness. PANSS scores were unavailable for two patients, leaving n = 23 for this analysis. The mean values of the PANSS positive, negative, and general scores were 16.2(SD = 6.1), 18.3(7.1), and 34.6(10.7), respectively.

In the whole brain comparison between schizophrenic patients and healthy controls, there were no voxels in which FA was significantly lower in controls. Significant reductions in the FA of the patient group at a

Discussion

We report diffuse differences in white matter integrity between schizophrenia patients and matched healthy controls. Using robust normalization methods and carefully matching results to specific white matter tracts, our findings both support disconnection hypothesis-based expectations in association and callosal fibers and detect unanticipated deficits in projection fibers. Projection fibers are not typically the target of white matter studies of schizophrenia, but in their review of white

Role of the funding source

Funding for this study was provided by the following sources: NIMH, 2 RO1 MH43775 (MERIT Award) and 5 RO1 MH52886; NIDA, 1 R01 DA020709; by NIAAA, 1 RO1 AA015615 and a NARSAD Distinguished Investigator Award, all awarded to Dr. Pearlson; and through NIBIB 1 R01 EB 000840 and 1 R01 EB 005846, awarded to Dr. Calhoun. No funding source had any further role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the paper

Contributors

Drs. Calhoun, Mathalon, and Pearlson designed the study. Ms. Skelly wrote the protocol and managed the literature searches and analyses. Ms. Skelly, Mr. Meda and Drs. Kim and Calhoun undertook the statistical analysis, and Ms. Skelly and Dr. Pearlson wrote the first draft of the manuscript. All authors contributed to and have approved the final manuscript.

Conflict of interest

No author has any conflict of interest to report.

Acknowledgements

The authors would like to thank Drs. Michal Assaf M.D., Michael Stevens Ph.D. and Pawel Skudlarski Ph.D. at the Olin Center.

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