In the present study, we investigated UF and CB using DTI in patients with recent-onset schizophrenia, in patients with recent-onset affective psychosis, and in psychiatrically healthy control subjects to determine whether or not UF and CB white matter integrity were altered at the early stage of illness and were specific to schizophrenia. To our knowledge, no previous study has evaluated the DTI measures directly compared schizophrenia with affective psychosis. Our results suggest that bilateral UF, but not CB white matter integrity is altered at the early stage of illness in schizophrenia. Left hemisphere UF integrity also appears to be abnormal in affective psychosis early in the disease, though this finding was not significantly different from healthy controls, suggesting the sample size was not sufficient, as the effect size was 0.89. This is interesting in light of the putative role of frontal lobe control of mood state stabilization, although manic mood is generally associated more with right frontal lesions, but been reported following left frontal lesions and surgical resections (Pang and Lewis, 1996
). Recently our laboratory found that the patients with affective psychosis as well as schizophrenia showed smaller overall neocortical grey matter volumes at the time of their first hospitalization than healthy controls using a semi-automated tissue segmentation of MRI (Nakamura et al., 2007
). Taken together, the patients with affective psychosis as well as those with schizophrenia have some structural abnormalities in brains at first hospitalization.
Previous DTI studies have reported UF abnormalities in chronic schizophrenia. Our previous study (Kubicki et al., 2002
), for example, showed reduced FA in left UF using the same methods as the present study. Two other studies using voxel-based morphometry analyses have also reported a trend level reduction in left UF FA (Burns et al., 2003
) and another study reported significant reduction in bilateral UF FA (Mori et al., 2007
) in chronic schizophrenia. Negative correlations between FA values and positive symptom scores of the Positive and Negative Syndrome Scale were also observed in chronic schizophrenia, further supporting a disconnection hypothesis of positive symptoms in schizophrenia (Skelly et al., 2008
). In addition, a recent study by Price et al. has reported reduced FA in left UF in patients with first-episode schizophrenia using a probabilistic tractography algorithm (Price et al., 2008
). Of further note, FA reduction in UF has been observed in patients with chronic bipolar disorder (McIntosh et al., 2008
). Our present findings suggest that UF white matter integrity is altered at an early stage of illness in schizophrenia, bilaterally, and, to a lesser degree, in the early-stage of illness in affective psychosis. Finally, given that some studies report left lateralized findings for UF, as noted above, while other studies report bilateral findings for UF in schizophrenia, further studies are needed to clarify the laterality of abnormal UF in schizophrenia.
Of note, a significant age-related reduction of FA has also been reported in UF, which was more pronounced in patients with chronic schizophrenia than in healthy control subjects (Mori et al., 2007
). We also note that a recent study by our group revealed a significant association, bilaterally, in patients with chronic schizophrenia between age at scan and reduced FA in both the uncinate fasciculus and in the cingulum bundle, which was not evident in healthy control subjects (Rosenberger et al., 2008
). In addition, a recent volumetric MRI study reported that the individuals with prodromal symptoms who were at ultra high-risk of developing schizophrenia showed significantly lower white matter volume in the right temporal cortex compared to healthy controls (Witthaus et al., 2008
). Taken together with these previous findings, our present results suggest that there may be some abnormalities in pathological aging of schizophrenia in right UF which progress following onset of the disease.
Importantly, however, there were no significant group differences in mean FA for CB among schizophrenia or affective psychosis in the early stage of illness, compared with healthy controls. We previously reported CB integrity disruption in chronic schizophrenia (Kubicki et al., 2005
; Kubicki et al., 2003
; Park et al., 2004a
), and several other studies have also reported CB abnormalities in chronic schizophrenia using DTI (Mitelman et al., 2007
; Mori et al., 2007
; Sun et al., 2003
; Wang et al., 2004
). Of further note, other studies of first-episode patients with schizophrenia using voxel-based analysis of DTI data have not shown significant differences of FA in CB compared with healthy controls (Cheung et al., 2007
; Szeszko et al., 2005
). A deteriorating course in schizophrenia (e.g. Salisbury et al., 2007
), or perhaps medication effects following the early stage of illness may account for the discrepancy between DTI findings in CB in recent onset versus chronic schizophrenia. In this study, we found that FA in UF but not in CB is decreased in patients with recent-onset schizophrenia using healthy controls as well as affective psychosis. To our knowledge this is the first report demonstrating UF abnormalities in recent-onset schizophrenia using affective psychosis as a comparison group. In addition, our findings suggest that there may be some brain regions, such as UF, that are present at early onset of illness, or even before onset, and thus driven more by neurodevelopmental influences, while some brain regions, such as CB, are not abnormal at early onset of illness but evolve over time and may thus be more associated with progressive aspects of schizophrenia. Longitudinal follow-up DTI studies of a large sample of first-episode patients, however, are needed to determine whether CB abnormalities occur during the chronic course of illness, as suggested by the current cross-sectional study.
The advantage of our method over voxel-based methods is that it is based on directional information obtained only from the diffusion tensor, whereas exploratory voxel-based approaches discard this important information. Nonetheless, because our method works only for the unidirectional portion of fiber bundles and not for their dispersive portions or for fiber crossings, we excluded CB portions outside of the anterior and posterior boundaries defined by the genu and splenium of corpus callosum. However, since we focused on the most frequently investigated regions in DTI studies in chronic schizophrenia, where differences between controls and patients were reported, we believe that this same directional threshold technique, employed here, would have detected differences between first-episode patients and controls if they were present.
In contrast, we have found only a single DTI study by Hao et al. (Hao et al., 2006
) that showed lower FA only in the subgenual part of right CB, but not in the whole CB, in patients with first-episode schizophrenia using a voxel-based analysis. However, a voxel-based analysis needs smoothing process to reduce the effect of normalization errors on the statistical analysis. Larger smoothing kernel sacrifices spatial resolution resulting in failure to detect fiber bundles such as CB, while smaller smoothing kernel increases the probabilities of a type I error. The discrepancy for CB findings between the study by Hao et al. and other DTI studies might therefore be due to an error in registration or a type I error.
Of particular interest, the present result in recent onset schizophrenia was consistent with our previous DTI study in antipsychotic-naïve subjects with schizotypal personality disorder, which showed bilateral UF FA reduction but intact CB integrity using the identical methodology as in the present study (Nakamura et al., 2005
). Reduced UF FA in schizotypal personality disorder was also significantly correlated with clinical features of ideas of reference, suspiciousness, restricted affect, and social anxiety. Nakamura et al. concluded that the UF but not CB abnormality in schizotypal personality disordered individuals suggested disturbed ventral aspects of fronto-temporal disconnectivity, with more intact frontal lobe function. It may be that in early psychosis more ventral aspects of fronto-temporal disconnectivity are evident, with more frontal lobe regions such as CB being affected later in the course of the illness. Only a longitudinal study, however, of early psychosis patients can address this issue.
In an exploratory analysis of correlations between UF FA and psychopathologic measures, we did not find statistically significant correlations between UF FA reduction and factors or items of the Positive and Negative Syndrome Scale in schizophrenia or in affective psychosis. Although our subjects included some non-first-episode patients, we performed clinical ratings of subjects within 2–3 weeks time of scanning. The fluctuation of clinical stability and the inclusion of some non-first-episode patients in our sample (schizophrenia n=3, affective psychosis n=3), may have contributed to this lack of correlation, although when we evaluated the non-first-episode patients separately, we note that we also found no statistically significant correlations between FA and clinical measures.
A possible limitation of our study is the small number of subjects, although, to date, most diffusion studies in schizophrenia, especially with first-episode patients, have been based on relatively small study groups.
In conclusion, our study found that patients with schizophrenia within 4 years of first hospitalization showed significantly lower mean FA bilaterally for UF compared with healthy controls. Our results suggest that bilateral UF, but not CB white matter integrity, is altered at the early stage of illness in schizophrenia, although the patients with affective psychosis did not differ significantly from either patients with schizophrenia or healthy controls on this measure. Further studies with larger samples within a short interval from first hospitalization are necessary to address the issue of specificity more definitively. Changes in FA and Dm longitudinally, and possible medication effects remain to be determined.