Diffusion tractography of the fornix in schizophrenia

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Abstract

Background

White matter fiber tracts, especially those interconnecting the frontal and temporal lobes, are likely implicated in pathophysiology of schizophrenia. Very few studies, however, have focused on the fornix, a compact bundle of white matter fibers, projecting from the hippocampus to the septum, anterior nucleus of the thalamus and the mamillary bodies. Diffusion Tensor Imaging (DTI), and a new post-processing method, fiber tractography, provides a unique opportunity to visualize and to quantify entire trajectories of fiber bundles, such as the fornix, in vivo. We applied these techniques to quantify fornix diffusion anisotropy in schizophrenia.

Methods

DTI images were used to evaluate the left and the right fornix in 36 male patients diagnosed with chronic schizophrenia and 35 male healthy individuals, group matched on age, parental socioeconomic status, and handedness. Regions of interest were drawn manually, blind to group membership, to guide tractography, and fractional anisotropy (FA), a measure of fiber integrity, was calculated and averaged over the entire tract for each subject. The Doors and People test (DPT) was used to evaluate visual and verbal memory, combined recall and combined recognition.

Results

Analysis of variance was performed and findings demonstrated a difference between patients with schizophrenia and controls for fornix FA (p = 0.006). Protected post-hoc independent sample t-tests demonstrated a bilateral FA decrease in schizophrenia, compared with control subjects (left side: p = 0.048; right side p = 0.006). Higher fornix FA was statistically significantly correlated with DPT and measures of combined visual memory (r = 0.554, p = 0.026), combined verbal memory (r = 0.647, p = 0.007), combined recall (r = 0.516, p = 0.041), and combined recognition (r = 0.710, p = 0.002) for the control group. No such statistically significant correlations were found in the patient group.

Conclusions

Our findings show the utility of applying DTI and tractography to study white matter fiber tracts in vivo in schizophrenia. Specifically, we observed a bilateral disruption in fornix integrity in schizophrenia, thus broadening our understanding of the pathophysiology of this disease.

Introduction

Prior to the advent of Diffusion Tensor Imaging (DTI), most magnetic resonance imaging studies of schizophrenia focused on gray matter (see review in Shenton et al., 2001). With the advent of DTI, however, we are now able to focus more closely on white matter integrity in schizophrenia. This technique is relatively recent and it depends upon the motion of water molecules to provide structural information in vivo (Basser et al., 1994, Pierpaoli et al., 1996). More specifically, DTI is dependent upon the structural environment of the brain, which modifies water according to the type of tissue involved. For example, myelin sheaths and nerve fibers restrict the motion of water in directions that are perpendicular to the fiber tracts. Other tissue properties such as the density of axons and dendrites, axon diameter, thickness of myelin tissue, as well as the organization and orientation of fibers, all affect the diffusion of water in the brain and thus provide important information about tissue integrity. Moreover, DTI is particularly useful for evaluating brain tissue where water diffusion is anisotropic, or unevenly restricted in direction (e.g., white matter), as opposed to isotropic or non-restricted, or evenly restricted diffusion (e.g., cerebral spinal fluid, gray matter).

DTI studies of white matter in schizophrenia have focused on large white matter regions (e.g., Buchsbaum et al., 1998, Lim et al., 1999, Kumra et al., 2004), as well as on smaller brain regions of interest (e.g., Burns et al., 2003, Kubicki et al., 2003, Wang et al., 2004b) (See also reviews in Kubicki et al., 2005, Kubicki et al., 2007, Kanaan et al., 2005). Most of these studies have used rotationally invariant indices of diffusion anisotropy, most commonly fractional anisotropy (FA), a measure of the fraction of the magnitude of the tensor that constitutes the anisotropic diffusion (Basser, 1995). Most have also focused on region of interest (ROI) or voxel based morphology (VBM) analyses, and it is only more recently that tractography measures have been used to evaluate white matter fiber tracts in the brain (e.g., Jones et al., 2006, Kanaan et al., 2006).

Of further note, white matter fiber tracts, especially those interconnecting the frontal and temporal lobes, have long been thought to be involved in schizophrenia (e.g., Wernicke 1906, and more recently Weinberger et al., 1992, McGuire and Frith, 1996). Recently, DTI studies in schizophrenia have focused on individual association fiber bundles and have reported abnormalities in the cingulum bundle (Kubicki et al., 2003, Sun et al., 2003, Wang et al., 2004a, Wang et al., 2004b, Mori et al., 2007, Fujiwara et al., 2007), uncinate fasciculus (Kubicki et al., 2002, Burns et al., 2003), and arcuate fasciculus (Burns et al., 2003, Hubl et al., 2004). The corpus callosum has also been evaluated where abnormalities have also been reported in schizophrenia (Foong et al., 2000, Agartz et al., 2001, Ardekani et al., 2003, Kanaan et al., 2006, Mori et al., 2007).

The current study focuses on the fornix, a compact bundle of white matter fibers projecting from the hippocampus to the septum, anterior nucleus of the thalamus and the mamillary bodies. This structure is involved in important brain functions such as spatial memory (e.g., Gaffan, 1994, Parker and Gaffan, 1997), memory retrieval (e.g., Calabrese et al., 1995), and verbal memory (e.g., Calabrese et al., 1995, McMackin et al., 1995). These are also all functions disturbed in schizophrenia, including spatial memory (e.g., Park and Holzman, 1992, Carter et al., 1996, Park et al., 1999) memory retrieval (e.g., Anderson and Spellman, 1995) and verbal memory (e.g., Park and Holzman, 1992, Carter et al., 1998, Cohen et al., 1997, Callicott et al., 2000, Perlstein et al., 2001). Thus characterizing disruptions in fornix integrity might further our understanding of this disorder. It is nonetheless important to emphasize that the fornix is an integral part of both verbal and spatial memory networks, which also involves various other interconnected brain structures that we did not investigate here, including prefrontal cortex, temporal and limbic structures, as well as the parieto-occipital association cortex. Of further note, the hippocampus is one of the most frequently implicated brain structures that has been consistently reported to be abnormal in schizophrenia (e.g., Bogerts et al., 1985, Jeste and Lohr, 1989, Nelson et al., 1998, McCarley et al., 1999, Wright et al., 2000, Shenton et al., 2001, Heckers, 2001, Weiss et al., 2004), with volume reductions more prominent on the left side (see review in Shenton et al., 2001).

One of the main reasons for studying the fornix is because it is the main hippocampal output. Few studies have investigated the fornix in schizophrenia. Of those that have, Zahajszky et al. (2001), from our laboratory, found no MRI volumetric differences between healthy controls and patients with chronic schizophrenia. In contrast, Davies et al. (2001) showed an increase of cross-sectional area of the fornix in early onset schizophrenia. In the only post-mortem study evaluating the fornix, Chance et al. (1999) found increased fiber density in the left fornix in male subjects with schizophrenia.

To our knowledge there is only one DTI study of the fornix in schizophrenia (Kuroki et al., 2006). In this study, from our laboratory, the authors investigated a small, cross-sectional portion of the fiber tract, and found a decrease in fiber integrity in chronic schizophrenia subjects compared with controls. Recent advances in DTI post-processing-DT tractography, however, as proposed here, enable us to follow, and to quantify the entire tract, thus making it more reliable and more powerful, compared with region of interest or voxel-based analyses (Kanaan et al., 2005, Jones et al., 2005a, Jones et al., 2005b).

The main objective of the current study is to identify, separate and evaluate left and right fornix integrity in patients with chronic schizophrenia compared with healthy controls. Because previous work has demonstrated the relationship between verbal and spatial memory and fornix integrity (Nestor et al., 2007), we will also evaluate this relationship in schizophrenia.

Section snippets

Subjects

DTI-MRI data was acquired to evaluate the right and the left fornix in 36 male patients diagnosed with chronic schizophrenia and 35 male healthy individuals. The population consisted of schizophrenic patients from the Brockton Veterans Administration Medical Center. Patients were diagnosed with schizophrenia based on the (DSM-IV) criteria. Normal controls were recruited through newspaper advertisement. The study was approved by the local IRB at both the VA and Brigham and Women's Hospital.

Results

There were no group differences in gender (all males) or handedness (all right), and mean age did not differ either between normal subjects and schizophrenics (39.5, SD = +/− 9.3, versus 39.8, SD = +/− 9.06). Parental socioeconomic status also showed no significant difference (2.75, SD = +/− 1.34 versus 3.06, SD = +/− 0.983) and there was no difference between groups on IQ (109.38, SD +/– 11.11 versus 97.29, SD +/– 13.03) (Table 1).

There was a group effect for Fornix FA in both left (F = 4.049; df = 1.69; p = 0.048)

Fornix integrity and schizophrenia

In this study, fiber integrity of the fornix was measured in patients with chronic schizophrenia and in normal controls. Our results showed bilateral reduction of FA (indicative of white matter integrity) in the fornix of patients with schizophrenia compared to normal control subjects. Although we did not find neuropsychological correlations with measures of FA for the fornix in schizophrenic patients, we did find statistically significant correlations between fornix integrity and combined

Conclusion

We used DTI and a tractographic approach to make measurements of fractional anisotropy in a specific white matter tract and found this to be a useful tool. Our results point to bilateral disruption in the fornix integrity in schizophrenia. Considering the role of the fornix in connecting key brain structures involved in superior cognitive functions, this study can help broaden our understanding of the pathophysiology of schizophrenia.

Role of funding source

This study was supported, in part, by grants from the National Institute of Health (K05 MH070047 and R01 MH 50740 to MES, R01 MH 40799 to RWM and ROI MH 074794 to CFW, P50 MH 080272 to RWM, MES), the Department of Veterans Affairs Merit Awards (MES, RWM), and the VA Schizophrenia Center Grant (RWM/MES). This work is also part of the National Alliance for Medical Image Computing (NAMIC), funded by the National Institutes of Health through the NIH Roadmap for Medical Research, Grant U54 EB005149

Contributors

Jennifer Fitzsimmons, M.D., and Marek Kubicki, M.D., Ph.D. designed the study and wrote the protocol. Jennifer Fitzsimmons, M.D also wrote the first draft of the manuscript. Marek Kubicki, M.D, Ph.D. and Carl-Fredrik Westin, Ph.D. supervised the MRI data acquisition and processing, and provided guidance on technical aspects of diffusion tensor imaging. Paul Nestor, Ph.D., Margaret Niznikiewicz, Ph.D., and Robert W. McCarley, M.D managed the recruitment and collected clinical information of

Conflict of interest

None of the authors have any conflicts of interest that require disclosure.

Acknowledgements

The authors would like to thank Nancy Maxwell and Jennifer Goodrich for administrative support; Marek Kubicki, M.D., Ph.D., and Martha Shenton, Ph.D. for personal support; and Georgia Bushell, B.A., Kate Smith, B.A. and Usman Khan, B.A. for their support as research assistants. Additionally, we gratefully acknowledge the support of the National Institute of Health (K05 MH070047 and R01 MH 50740 to MES, R01 MH 40799 to RWM and R01 MH 074794 to CFW, P50 MH 080272 to RWM, MES), the Department of

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