We here report an asymmetry (left greater than right) in uncinate fasciculus anisotropic diffusion in normal male subjects, which was not evident in male patients with chronic schizophrenia. This result was obtained by measuring fractional anisotropy within the uncinate fasciculus, and it was confirmed by measures of the area of the uncinate fasciculus and by the sum of fractional anisotropy for the entire area, derived from an automated segmentation. To our knowledge, this result has not been previously reported in the literature.
The asymmetry of uncinate fasciculus diffusion anisotropy in the comparison subjects may reflect structural and functional differences between the two hemispheres that are neurodevelopmental in origin. Such asymmetries have been documented in several brain regions, including the Sylvian fissure (37
), planum temporale (38
), and frontal operculum (37
), during the second and third trimesters of gestation. Many of these asymmetry differences may be relevant to specialized functions of the brain, which are lateralized in humans, such as language (e.g., references 39
). The greater anisotropy found in the left than in the right uncinate fasciculus in normal subjects in our study may indicate a higher number and/or density of fibers in the left uncinate fasciculus than in that on the right.
The uncinate fasciculus is the largest of the three big fiber bundles connecting the frontal and temporal lobes; the other two are the cingulate and the superior longitudinal fasciculus. The absence of asymmetry in schizophrenia suggests a significant abnormality in the integrity of the fiber tracts connecting the frontal and temporal lobes. Not known, however, is how this lack of normal asymmetry might be understood vis-à-vis the pathophysiology of schizophrenia. For example, abnormalities in anisotropy within white matter might be explained by abnormalities in the number and/or density of the interconnecting fiber tracts or by abnormalities in myelination (41
). In addition, differences in anisotropy between schizophrenia patients and comparison subjects might be explained by alack of, or a loss of, coherence of white matter fiber bundles traveling between two distinct brain regions, affecting the connectivity between these regions. Thus, an abnormality in one or in a combination of these features might be manifest in a loss of asymmetry, as we report here in schizophrenia.
There are several candidate pathological processes that might influence the integrity of white matter fiber connections between frontal and temporal regions. For example, Akbarian et al. (42
) reported an abnormal distribution of interstitial neurons in prefrontal and temporal regions in schizophrenia, which they attributed to the disruption of fetal brain development and failure of neuron migration during the second trimester of pregnancy, thereby affecting the ingrowth of connections to the cortex. The higher number of neurons in schizophrenia might therefore adversely affect the number and organization of their possible axonal projections and, consequently, water diffusion within the white matter tracts, as measured by diffusion tensor imaging.
In addition, Deakin and Simpson (2
) suggested that neurochemical, histological, and functional abnormalities in schizophrenia most likely reflect progressive degeneration of projections from the ventral frontal to the anterior temporal lobe. They suggested that dysplastic cellular architecture in the ventral frontal cortex gives rise to projections to the temporal cortex, which are vulnerable, as a consequence of their dysplastic origins, to some extrinsic and intrinsic pathological processes. These speculations, in conjunction with their report of left-lateralized glutamate uptake sites in the polar temporal cortex of patients with schizophrenia (43
), are consistent with our finding of changes in uncinate fasciculus diffusion anisotropy in schizophrenia.
The results reported here are also consonant with MRI (44
) and postmortem (45
) findings suggesting an absence of normal brain asymmetry in schizophrenia. According to Crow et al. (46
), who posited a “lateralization hypothesis of schizophrenia,” abnormal neural development of brain lateralization is critical to the etiology of schizophrenia. They stated that the left hemisphere may be more vulnerable to insult or damage because it develops later than the right hemisphere (see also reference 39
) and that this damage might occur in schizophrenia. If such damage occurs in white matter, it might affect white matter fiber tracts as measured by diffusion tensor imaging.
Differences in brain development are also the focal point of work by Benes and co-workers (47
), who suggested that myelination in specific brain regions (especially the frontal and temporal lobes, where myelination still occurs in the second decade of life) might play a neuroprotective role, particularly with respect to the timing of the appearance of symptoms in individuals at risk for schizophrenia. In addition, in a study using magnetization transfer contrast imaging, which measures the myelin component of white matter (48
), the myelin component of fibers in the temporal lobe was lower in patients with schizophrenia. Thus, it is possible that schizophrenia patients have an abnormality of myelin. As myelin sheaths form linear structures surrounding and insulating axons, their integrity and thickness influence the water diffusion within the brain, and measures of diffusion might reflect such alterations (41
Other diffusion tensor imaging studies have also shown anisotropy abnormalities in schizophrenia. Lim and coworkers (26
), for example, using a measure of fractional anisotropy averaged over large regions of interest, reported widespread lower anisotropy in patients with schizophrenia than in normal subjects. Buchsbaum et al. (25
), using methods based on statistical probability maps, reported lower relative anisotropy (another index of anisotropy with a slightly different scaling parameter) within the left prefrontal white matter region in schizophrenia. Finally, Foong et al. (27
) reported lower anisotropy within the splenium but not genu of the corpus callosum in schizophrenia patients than in comparison subjects, determined by using small region-of-interest averaging techniques and fractional anisotropy.
These findings, taken together, provide strong evidence for loss of integrity within the white matter fiber tracts in schizophrenia. The question remains, however, as to whether it is the same widespread pathological process affecting the whole white matter or whether the process is more localized, affecting several white matter fiber tracts. A further question is whether the anomaly is primary and due to loss of gray matter volume or secondary to the regional abnormalities within gray matter areas interconnected by the fiber tract, as several MR structural studies have shown abnormalities of orbitofrontal and temporal pole volume in schizophrenia, specifically reduced volume in patients with chronic schizophrenia (49
) and increased volume on the right side in subjects with first-episode schizophrenia (50
) in the orbital frontal region and volume reduction within the temporal pole in schizophrenia subjects (7
) when compared with normal comparison subjects.
With respect to correlations with clinical measures, the diffusion tensor imaging measures correlated in expected ways with neuropsychological measures in the patients with schizophrenia. That is, poor performance on a measure of visual attention correlated with right-sided white matter abnormalities, whereas poor verbal associative memory correlated with left-sided white matter abnormalities. These correlations between neuropsychological performance and measures of connectivity suggest the presence of a disruption in frontal-temporal functional connectivity.
A possible limitation of our study is the small number of subjects, although, to date, most diffusion studies in schizophrenia have been based on relatively small study groups. In addition, our study suggests that motion artifact in diffusion tensor imaging studies may be an issue. Although line-scan diffusion tensor imaging is less sensitive to movement artifacts than is echo-planar imaging (28
), one might still want to examine motion artifacts as a potential confound.
While the expected direction of the fiber tracts in the uncinate fasciculus is anterior-posterior, fibers traveling in other directions might decrease the diffusion anisotropy within our region of interest. Hanyu et al. (24
), who calculated anisotropy diffusion within the temporal stem in patients with Alzheimer’s disease, noted that fiber bundles crossing the anterior commissure might be an additional source of alterations in diffusion anisotropy within the anterior temporal region. Analogously, it is possible that other fibers crossing the uncinate fasciculus within our region of interest could decrease anisotropy findings (19
), although we would expect to find this effect in both groups equally.
In summary, we believe that this study presents new findings relevant to the status of white matter tracts in schizophrenia. We were able to evaluate directly in vivo fiber tracts of the uncinate fasciculus, a bundle of fibers that might play an important role in the pathology of this disorder. Our study revealed disruptions in connectivity between the frontal and temporal lobes that were marked by a significant loss of normal left-greater-than-right asymmetry in patients with schizophrenia. Further studies are needed to determine the exact functional role of the uncinate fasciculus and the implications of abnormalities in this white matter fiber tract in schizophrenia.