Progressive changes of white matter integrity in schizophrenia revealed by diffusion tensor imaging

Recent magnetic resonance imaging (MRI) studies using diffusion tensor imaging (DTI) have suggested reduced fractional anisotropy (FA) in the white matter (WM) of the brain in patients with schizophrenia. We tried to examine whether such reduction in FA exists and whether such changes in FA progress in an age-dependent manner in a Japanese sample of chronic schizophrenia. FA values were compared between 42 patients with chronic schizophrenia and 42 controls matched for age and gender, by using DTI with voxel-by-voxel and region-of-interest analyses. Correlations of FA values with age and duration of illness were examined. Patients with schizophrenia showed lower FA values, compared to controls, in the widespread WM areas including the uncinate fasciculi and cingulum bundles. A significant group-by-age interaction was found for FA in the WM, i.e., age-related reduction of FA was more pronounced in schizophrenics than in controls. A significant negative correlation between FA and duration of illness was also found in the WM. Our data confirmed decreased FA in schizophrenics, compared to controls in the widespread WM areas. Such decreased FA values in schizophrenia might be attributable, at least in part, to progressive changes after the onset of the illness.     

Alterations in White Matter Evident Before the Onset of Psychosis

Background

Psychotic disorders are associated with widespread reductions in white matter (WM) integrity. However, the stage at which these abnormalities first appear and whether they are correlates of psychotic illness, as opposed to an increased vulnerability to psychosis, is unclear. We addressed these issues by using diffusion tensor imaging (DTI) to study subjects at ultra high risk (UHR) of psychosis before and after the onset of illness.

Methods

Thirty-two individuals at UHR for psychosis, 32 controls, and 15 patients with first-episode schizophrenia were studied using DTI. The UHR subjects and controls were re-scanned after 28 months. During this period, 8 UHR subjects had developed schizophrenia. Between-group differences in fractional anisotropy (FA) and diffusivity were evaluated cross sectionally and longitudinally using a nonparametric voxel-based analysis.

Results

At baseline, WM DTI properties were significantly different between the 3 groups (P < .001). Relative to controls, first-episode patients showed widespread reductions in FA and increases in diffusivity. DTI indices in the UHR group were intermediate relative to those in the other 2 groups. Longitudinal analysis revealed a significant group by time interaction in the left frontal WM (P < .001). In this region, there was a progressive reduction in FA in UHR subjects who developed psychosis that was not evident in UHR subjects who did not make a transition.

Conclusions

People at UHR for psychosis show alterations in WM qualitatively similar to, but less severe than, those in patients with schizophrenia. The onset of schizophrenia may be associated with a progressive reduction in the integrity of the frontal WM.     

A comparative diffusion tensor imaging study of corpus callosum subregion integrity in bipolar disorder and schizophrenia

Structural magnetic resonance imaging (MRI) studies have provided evidence for corpus callosum (CC) white matter abnormalities in bipolar disorder (BD) and schizophrenia (SZ). These findings include alterations in shape, volume, white matter intensity and structural integrity compared to healthy control populations. Although CC alterations are implicated in both SZ and BD, no study of which we are aware has investigated callosal subregion differences between these two patient populations. We used diffusion tensor imaging (DTI) to assess CC integrity in patients with BD (n=16), SZ (n=19) and healthy controls (HC) (n=24). Fractional anisotropy (FA) of CC subregions was measured using region of interest (ROI) analysis and compared in the three groups. Significant group differences of FA values were revealed in five CC subregions, including the anterior genu, middle genu, posterior genu, posterior body and anterior splenium. FA values of the same subregions were significantly reduced in patients with SZ compared with HC. FA values were also significantly reduced in patients with BD compared to the HC group in the same subregions, excepting the middle genu. No significant difference was found between patient groups in any region. Most of the alterations in CC subregions were present in both the BD and SZ groups. These results imply an overlap in potential pathology, possibly relating to risk factors common to both disorders. The one region that differed between patient groups, the middle genu area, may serve as an illness marker and is perhaps involved in the different cognitive impairments observed in BD and SZ.     

Anatomical brain connectivity and positive symptoms of schizophrenia: A diffusion tensor imaging study

Structural brain changes in schizophrenia are well documented in the neuroimaging literature. The classical morphometric analyses of magnetic resonance imaging (MRI) data have recently been supplemented by diffusion tensor imaging (DTI), which mainly assesses changes in white matter (WM). DTI increasingly provides evidence for abnormal anatomical connectivity in schizophrenia, most often using fractional anisotropy (FA) as an indicator of the integrity of WM tracts. To better understand the clinical significance of such anatomical changes, we studied FA values in a whole-brain analysis comparing paranoid schizophrenic patients with a history of auditory hallucinations and matched healthy controls. The relationship of WM changes to psychopathology was assessed by correlating FA values with PANSS scores (positive symptoms and severity of auditory hallucinations) and with illness duration. Schizophrenic patients showed FA reductions indicating WM integrity disturbance in the prefrontal regions, external capsule, pyramidal tract, occipitofrontal fasciculus, superior and inferior longitudinal fasciculi, and corpus callosum. The arcuate fasciculus was the only tract which showed increased FA values in patients. Increased FA values in this region correlated with increased severity of auditory hallucinations and length of illness. Our results suggest that local changes in anatomical integrity of WM tracts in schizophrenia may be related to patients' clinical presentation.     

Abnormal anterior cingulum in patients with schizophrenia: a diffusion tensor imaging study

Diffusion tensor imaging (DTI) can non-invasively examine the molecular diffusion of water in vivo and directly reflects the anatomical integrity of neural fibers in white matter. Fractional anisotropy (FA) can be calculated from DTI data, and utilized to evaluate white matter integrity. DTI was performed on 30 patients with schizophrenia and 19 healthy controls, and their FA values were subsequently measured in multiple brain regions. Statistical analyses revealed that FA values were decreased in the anterior cingulum of schizophrenia subjects. There were no significant differences between patients and controls in any other regions. This study supports the hypothesis that schizophrenia is associated with abnormal white matter integrity of the anterior cingulum.     

Disrupted integrity of the fornix is associated with impaired memory organization in schizophrenia

BACKGROUND: The fornix is a major projection of the hippocampus to and from other brain regions. A previous diffusion tensor imaging (DTI) study has reported disrupted integrity of the fornix in patients with schizophrenia. However, functional significance of the DTI abnormalities of the fornix in schizophrenia has not been fully studied yet. We investigated an association between DTI abnormalities of the fornix and impairment of memory organization in schizophrenia. METHODS: Thirty-one patients with schizophrenia and 65 age- and gender-matched healthy controls underwent DTI, and fractional anisotropy (FA) and mean diffusivity (MD) were measured in cross-sections of fornix tractography. In addition, all of the patients and 32 controls performed a verbal learning task specialized for evaluating memory organization, the verbal memory subscale of the Wechsler Memory Scale-Revised, the category- and letter fluency tests, and the Japanese version of National Adult Reading Test. RESULTS: Statistically significant reduction of FA and increase of MD were found in the fornix of patients with schizophrenia compared with controls with no significant lateralization. A significant patients-specific correlation was found between increased MD in the left fornix and lower scores on utilization of semantic organization in the verbal learning task. In addition, increased MD in the right fornix showed a patients-specific association with poorer performance on the category fluency test, which indexes organization of long-term semantic memory. These patients-specific correlations, however, were not statistically lateralized to either hemisphere. CONCLUSIONS: These results indicate that disrupted integrity of the fornix contributes to impaired memory organization in schizophrenia.     

Increased white matter integrity in the corpus callosum in subjects with high genetic loading for schizophrenia

Objective

White matter abnormalities in the corpus callosum (CC) of schizophrenia have been reported to predate the illness onset. This study aimed to investigate the effect of genetic predisposition on the white matter integrity of the CC, in subjects at genetically high risk for schizophrenia (GHR) and schizophrenia patients.

Method

Fractional anisotropy (FA) of the mid-sagittal CC in 22 young GHR, 15 schizophrenia, and 26 control subjects were examined. GHR subjects were defined as non-prodromal individuals who had more than two relatives with schizophrenia within third-degree relatives, one of whom must be a first-degree relative.

Results

ANCOVA with age and gender as covariates revealed overall difference of FA in the genu and splenium among the three groups. Post-hoc analysis found significantly increased FA in the genu of GHR subjects compared to controls (corrected p < 0.01), whereas schizophrenia patients showed significantly decreased FA in the splenium.

Conclusion

The white matter change of the CC in young GHR subjects was the opposite of that in schizophrenia. To consider previous reports on FA decrease in the CC in schizophrenia and the impaired frontal functioning in GHR group, the increased FA may be an indicator of compensatory alteration in white matter integrity in young GHR people.     

Anterior and posterior cingulum abnormalities and their association with psychopathology in schizophrenia: a diffusion tensor imaging study

Evidence suggests that a disruption in limbic system network integrity and, in particular, the cingulate gyrus may play a role in the pathophysiology of schizophrenia. The cingulum bundles (CBs; posterior and anterior) are the most prominent white matter tracts in the limbic system, furnishing both input and output to the cingulate gyrus . In previous diffusion tensor imaging (DTI) studies, abnormal integrity has been demonstrated in the anterior CB portion, but not the posterior, in schizophrenia. As well, the relationships between the abnormalities of CB integrity and the psychopathology of schizophrenia remain to be elucidated. Using DTI acquired on a 3 T MRI machine, we examined fractional anisotropy (FA) in the anterior and posterior CBs of 42 patients with schizophrenia and 24 group-matched controls. Moreover, we investigated the relationships between CB abnormalities and the psychopathology of schizophrenia. Bilaterally reduced FA was demonstrated in both anterior and posterior CBs in schizophrenia patients. However, the pattern of FA reduction was different between anterior and posterior CBs: the reduction in FA was left-accentuated in anterior CBs, while no such lateralized abnormality was found in posterior ones. Finally, FA in posterior CBs correlated with positive symptom scores in patients with schizophrenia. These findings suggest that CB abnormalities in schizophrenia are not restricted to the anterior CB, but include the posterior as well. Pathology in the posterior CB would be one of the possible neural underpinnings of positive symptoms in schizophrenia.     

Comparing Fractional Anisotropy in Patients With Childhood-Onset Schizophrenia,Their Healthy Siblings,and Normal Volunteers Through DTI

Background:

Diffusion tensor imaging is a neuroimaging method that quantifies white matter (WM) integrity and brain connectivity based on the diffusion of water in the brain. White matter has been hypothesized to be of great importance in the development of schizophrenia as part of the dysconnectivity model. Childhood-onset schizophrenia (COS), is a rare, severe form of the illness that resembles poor outcome adult-onset schizophrenia. We hypothesized that COS would be associated with WM abnormalities relative to a sample of controls.

Methods:

To evaluate WM integrity in this population 39 patients diagnosed with COS, 39 of their healthy (nonpsychotic) siblings, and 50 unrelated healthy volunteers were scanned using a diffusion tensor imaging (DTI) sequence during a 1.5 T MRI acquisition. Each DTI scan was processed via atlas-based analysis using a WM parcellation map, and diffeomorphic mapping that shapes a template atlas to each individual subject space. Fractional anisotropy (FA), a measure of WM integrity was averaged over each of the 46 regions of the atlas. Eleven WM regions were examined based on previous reports of WM growth abnormalities in COS.

Results:

Of those regions, patients with COS, and their healthy siblings had significantly lower mean FA in the left and right cuneus as compared to the healthy volunteers (P < .005). Together, these findings represent the largest DTI study in COS to date, and provide evidence that WM integrity is significantly impaired in COS. Shared deficits in their healthy siblings might result from increased genetic risk.Key words: DTI, COS, siblings, cuneus, FA     

Fornix integrity and hippocampal volume in male schizophrenic patients.

BACKGROUND: The hippocampus has been shown to be abnormal in schizophrenia. The fornix is one of the main fiber tracts connecting the hippocampus with other brain regions. Few studies have evaluated the fornix in schizophrenia, however. A focus on fornix abnormalities and their association with hippocampal abnormalities might figure importantly in our understanding of the pathophysiology of schizophrenia. METHODS: Line-scan diffusion tensor imaging (DTI) was used to evaluate diffusion in the fornix in 24 male patients with chronic schizophrenia and 31 male control subjects. Maps of fractional anisotropy (FA) and mean diffusivity (D(m)), which are indices sensitive to white-matter integrity, were generated to quantify diffusion within the fornix. We used high spatial resolution magnetic resonance imaging (MRI) to measure hippocampal volume. RESULTS: FA and cross-sectional area of the fornix were significantly reduced in patients compared with control subjects. D(m) was significantly increased, whereas hippocampal volume was bilaterally reduced in patients. Reduced hippocampal volume was correlated with increased mean D(m) and reduced cross-sectional area of the fornix for patients. Patients also showed a significant correlation between reduced scores on neuropsychologic measures of declarative-episodic memory and reduced hippocampal volumes. CONCLUSIONS: These findings demonstrate a disruption in fornix integrity in patients with schizophrenia.     

White matter abnormalities in bipolar disorder and schizophrenia detected using diffusion tensor magnetic resonance imaging

Objectives:  Strong qualitative and quantitative evidence exists of white matter abnormalities in both schizophrenia and bipolar disorder (BD). Diffusion tensor imaging (DTI) studies suggest altered connectivity in both disorders. We aim to address the diagnostic specificity of white matter abnormalities in these disorders.
Methods:  DTI was used to assess white matter integrity in clinically stable patients with familial BD (n = 42) and familial schizophrenia (n = 28), and in controls (n = 38). Differences in fractional anisotropy (FA) were measured using voxel-based morphometry and automated region of interest analysis.
Results:  Reduced FA was found in the anterior limb of the internal capsule (ALIC), anterior thalamic radiation (ATR), and in the region of the uncinate fasciculus in patients with BD and those with schizophrenia compared with controls. A direct comparison between patient groups found no significant differences in these regions. None of the findings were associated with psychotropic medication.
Conclusions:  Reduced integrity of the ALIC, uncinate fasciculus, and ATR regions is common to both schizophrenia and BD. These results imply an overlap in white matter pathology, possibly relating to risk factors common to both disorders.     

High-resolution diffusion tensor imaging of the hippocampus in temporal lobe epilepsy

PURPOSE: To assess the quantitative diffusion characteristics of the hippocampus with high-resolution diffusion tensor imaging (DTI) in temporal lobe epilepsy (TLE). METHODS: Thirteen controls and seven unilateral TLE patients (six with hippocampal sclerosis, one with normal magnetic resonance imaging (MRI)) were scanned with DTI using a zonally magnified oblique multislice echo planar imaging (ZOOM-EPI) acquisition. Fractional anisotropy (FA) and mean diffusivity (MD) were measured in the hippocampi. RESULTS: The mean hippocampal MD ipsilateral to the seizure focus was higher than the contralateral MD in patients (p<0.05) and the mean MD in controls (p<0.001). Hippocampal FA ipsilateral to the seizure focus was lower than the mean FA in controls (p<0.05). MD asymmetry indexes were significantly different between the patient and control groups (p<0.01). All six individual HS patients had ipsilateral hippocampal MD >or=2 standard deviations (S.D.) above the control mean. The patient with normal structural MRI had bilaterally low hippocampal FA and high MD. DISCUSSION: High-resolution DTI identifies lateralizing abnormalities of MD and FA in TLE patients. This quantitative data on hippocampal integrity may assist in evaluating TLE patients with normal MRI, and in longitudinal studies.     

抑郁症患者脑白质变化初步研究

目的：利用能够提示脑白质纤维完整性的磁共振弥散张量成像（DTI）探讨首发和复发重性抑郁症患者脑白质纤维的变化及其差异。方法：20例重性抑郁症患者（首发9例，复发11例）和20名正常对照者均经常规磁共振成像（MRI）平扫，未发现异常者继续进行DTI和结构MRI（3D）扫描，基于像素的全脑分析技术对DTI数据进行分析。结果：与对照组相比较，抑郁症组白质纤维结构在双侧额中回、右顶下小叶及双侧脑岛等区域白质的各向异性值（FA）显著降低（各脑区P均〈0.001，cluster〉30像素）;与首发抑郁症患者相比较，复发抑郁症患者右侧额上回、右顶叶、中央前回、中央后回及右顶下小叶等区域FA值降低更为显著（各脑区P均〈0.001，cluster〉10像素）。结论：重性抑郁症患者存在脑白质异常，抑郁反复发作会导致脑白质损害进一步加重。     

Uncinate fasciculus abnormalities in recent onset schizophrenia and affective psychosis: A diffusion tensor imaging study

Two of the most frequently investigated regions in diffusion tensor imaging studies in chronic schizophrenia are the uncinate fasciculus (UF) and cingulum bundle (CB). The purpose of the present study was to determine whether UF and CB white matter integrity were altered at the early stage of illness and specific to schizophrenia. Fifteen schizophrenia subjects and 15 affective psychosis within 4 years of first hospitalization (12 patients with schizophrenia and 12 patients with affective psychosis during their first hospitalization), and 15 psychiatrically healthy controls underwent line-scan diffusion tensor imaging. Fractional anisotropy (FA) and mean diffusivity (D_m) were used to quantify water diffusion, and cross-sectional area was defined with a directional threshold method. Bilaterally reduced FA, but not D_m, was present in the UF of schizophrenia compared with healthy controls. Affective psychosis was intermediate between schizophrenia subjects and healthy controls, but not significantly different from either. For CB, there was no significant group difference for FA or D_m. These findings suggest that UF, but not CB, white matter integrity is altered at the early stage of illness in schizophrenia although it may not be specific to schizophrenia. The CB abnormalities reported in chronic schizophrenia may develop during the later course of the disease.     

Tract-specific analysis of white matter integrity disruption in schizophrenia

Several studies have suggested that white matter integrity is disrupted in some brain regions in patients with schizophrenia. The purpose of this study was to assess the white matter integrity of the cingulum, uncinate fasciculus, fornix, and corpus callosum using diffusion tensor imaging (DTI). Participants comprised 39 patients with schizophrenia (19 males and 20 females) and 40 age-matched normal controls (20 males and 20 females). We quantitatively assessed the fractional anisotropy (FA) and apparent diffusion coefficient (ADC) of the anterior cingulum, body of the cingulum, uncinate fasciculus, fornix, and corpus callosum on a tract-specific basis using diffusion tensor tractography (DTT). Group differences in FA and ADC between the patients and normal controls were sought. Additional exploratory analyses of the relationship between the FA or ADC and four clinical parameters (i.e., illness duration, positive symptom scores, negative symptom scores, and medication dosage) were performed. Results were analyzed in gender-combined and gender-separated group comparisons. FA was significantly lower on both sides of the anterior cingulum, uncinate fasciculus, and fornix in the schizophrenia patients irrespective of gender group separation. In the gender-combined analyses, significantly higher ADC values were demonstrated in the schizophrenia patients in both sides of the anterior cingulum, body of the cingulum and uncinate fasciculus, the left fornix, and the corpus callosum, compared with those of the normal controls. In the gender-separated analyses, the male patients showed higher ADC in the left anterior cingulum, the bilateral cingulum bodies, and the bilateral uncinate fasciculi. The female patients showed higher ADC in the right anterior cingulum, the left fornix, and the bilateral uncinate fasciculus. In correlation analyses, a significant negative correlation was found between illness duration and ADC in the right anterior cingulum in the gender-combined analyses. The gender-separated analyses found that the male patients had a significant negative correlation between negative symptom scores and FA in the right fornix, a positive correlation between illness duration and FA in the right anterior cingulum, and a negative correlation between illness duration and FA in the left uncinate fasciculus. Our DTI study showed that the integrity of white matter is disrupted in patients with schizophrenia. The results of our sub-analyses suggest that changes in FA and ADC may be related to negative symptom scores or illness duration.     

Altered white matter integrity in temporal lobe epilepsy: Association with cognitive and clinical profiles

Purpose: Diffusion tensor imaging (DTI) studies have reported substantial white matter abnormalities in patients with temporal lobe epilepsy (TLE). However, limited data exist regarding the extent of white matter tract abnormalities, cognitive effects of these abnormalities, and relationship to clinical factors. The current study examined these issues in subjects with chronic TLE. Methods: DTI data were obtained in 12 TLE subjects and 10 age‐matched healthy controls. Voxel‐wise statistical analysis of fractional anisotropy (FA) was carried out using tract‐based spatial statistics (TBSS). White matter integrity was correlated with cognitive performance and epilepsy‐related clinical parameters. Results: Subjects with TLE, as compared to healthy controls, demonstrated four clusters of reduced FA, in anterior temporal lobe, mesial temporal lobe, and cerebellum ipsilateral, as well as frontoparietal lobe contralateral to the side of seizure onset. Mean FA was positively correlated with delayed memory, in anterior temporal lobe; and immediate memory, in mesial temporal lobe. Lower FA values in the posterior region of corpus callosum were related to earlier age of seizure onset. Conclusion: TLE is associated with widespread disturbances in white matter tracts and these changes have important cognitive and clinical consequences.     

A diffusion tensor MRI study of white matter integrity in subjects at high genetic risk of schizophrenia

Diffusion tensor imaging (DTI) has previously shown compromised white matter integrity in frontotemporal white matter fibers in patients with schizophrenia, as indicated by reduced fractional anisotropy (FA). In the present study we investigated whether reduced white matter FA is also present in relatives of individuals with schizophrenia who are at high risk (HR) for genetic reasons. Twenty-two HR subjects, 31 patients with schizophrenia and 51 control subjects underwent DTI. We compared FA between the three groups in the cingulum cingulate gyri, the uncinate and the arcuate fasciculi and the anterior limb of the internal capsules (ALIC). A voxel-based analysis showed lower FA in patients with schizophrenia compared to controls in left and right uncinate (p<0.03), the left arcuate (p<0.03) and left and right ALIC (p<0.01). Using an automatic region-of-interest analysis, less sensitive to potential misregistration errors, produced essentially the same results, as well as reduced FA of the ALIC in the HR group compared to controls (p<0.05). This study replicates previous findings showing lower FA in frontotemporal white matter fibers of schizophrenia patients. We also found reduced FA in the ALIC of both patients and subjects at high risk of schizophrenia when compared to controls. This may be a possible indicator of the higher vulnerability of relatives to develop the disorder.     

Reduced white matter fractional anisotropy and clinical symptoms in schizophrenia: a voxel-based diffusion tensor imaging study

Although not consistently replicated, diffusion tensor imaging (DTI) studies in schizophrenia have revealed lower fractional anisotropy (FA) in various white matter regions, a finding consistent with the disruption of white matter integrity. In this study, we used voxel-based DTI to investigate possible whole-brain differences in the white matter FA values between 58 schizophrenia patients and 58 healthy controls. We also explored the association between FA values and clinical symptoms in schizophrenia. Compared with the controls, the schizophrenia patients showed significant FA reductions in bilateral superior longitudinal fasciculus, bilateral inferior fronto-occipital fasciculus, and genu of right internal capsule. Furthermore, in the patient group, the FA value of the anterior part of the corpus callosum was negatively correlated with the avolition score on the Scale for the Assessment of Negative Symptoms. These findings suggest widespread disruption of white matter integrity in schizophrenia, which could partly explain the severity of negative symptomatology.     

Voxel-based morphometry (VBM) studies in schizophrenia-can white matter changes be reliably detected with VBM?

Voxel-based morphometry (VBM) is a hypothesis-free, whole-brain, voxel-by-voxel analytic method that attempts to compare imaging data between populations. Schizophrenia studies have utilized this method to localize differences in diffusion tensor imaging (DTI) derived fractional anisotropy (FA), a measure of white matter integrity, between patients and healthy controls. The number of publications has grown, although it is unclear how reliable and reproducible this method is, given the subtle white matter abnormalities expected in schizophrenia. Here we analyze and combine results from 23 studies published to date that use VBM to study schizophrenia in order to evaluate the reproducibility of this method in DTI analysis. Coordinates of each region reported in DTI VBM studies published thus far in schizophrenia were plotted onto a Montreal Neurological Institute atlas, and their anatomical locations were recorded. Results indicated that the reductions of FA in patients with schizophrenia were scattered across the brain. Moreover, even the most consistently reported regions were reported independently in less than 35% of the articles studied. Other instances of reduced FA were replicated at an even lower rate. Our findings demonstrate striking inconsistency, with none of the regions reported in much more than a third of the published articles. This poor replication rate suggests that the application of VBM to DTI data may not be the optimal way for finding the subtle microstructural abnormalities suggested in schizophrenia.     

Voxel-based morphometry (VBM) studies in schizophrenia—can white matter changes be reliably detected with VBM?

Voxel-based morphometry (VBM) is a hypothesis-free, whole-brain, voxel-by-voxel analytic method that attempts to compare imaging data between populations. Schizophrenia studies have utilized this method to localize differences in diffusion tensor imaging (DTI) derived fractional anisotropy (FA), a measure of white matter integrity, between patients and healthy controls. The number of publications has grown, although it is unclear how reliable and reproducible this method is, given the subtle white matter abnormalities expected in schizophrenia. Here we analyze and combine results from 23 studies published to date that use VBM to study schizophrenia in order to evaluate the reproducibility of this method in DTI analysis. Coordinates of each region reported in DTI VBM studies published thus far in schizophrenia were plotted onto a Montreal Neurological Institute atlas, and their anatomical locations were recorded. Results indicated that the reductions of FA in patients with schizophrenia were scattered across the brain. Moreover, even the most consistently reported regions were reported independently in less than 35% of the articles studied. Other instances of reduced FA were replicated at an even lower rate. Our findings demonstrate striking inconsistency, with none of the regions reported in much more than a third of the published articles. This poor replication rate suggests that the application of VBM to DTI data may not be the optimal way for finding the subtle microstructural abnormalities suggested in schizophrenia.