Diffusion tensor imaging in schizophrenia

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European Psychiatry 23 (2008) 255e273 http://france.elsevier.com/direct/EURPSY/

Original article

Diffusion tensor imaging in schizophrenia Marinos Kyriakopoulos a,*, Theodoros Bargiotas a, Gareth J. Barker b, Sophia Frangou a b

a Section of Neurobiology of Psychosis Institute of Psychiatry, King’s College London, London, UK Department of Clinical Neuroscience, Centre for Neuroimaging Sciences, Institute of Psychiatry, King’s College London, London, UK

Received 30 July 2007; received in revised form 19 November 2007; accepted 3 December 2007 Available online 4 June 2008

Abstract Diffusion tensor imaging (DTI) is a magnetic resonance imaging technique that is increasingly being used for the non-invasive evaluation of brain white matter abnormalities. In this review, we discuss the basic principles of DTI, its roots and the contribution of European centres in its development, and we review the findings from DTI studies in schizophrenia. We searched EMBASE, PubMed, PsychInfo, and Medline from February 1998 to December 2006 using as keywords ‘schizophrenia’, ‘diffusion’, ‘tensor’, and ‘DTI’. Forty studies fulfilling the inclusion criteria of this review were included and systematically reviewed. White matter abnormalities in many diverse brain regions were identified in schizophrenia. Although the findings are not completely consistent, frontal and temporal white matter seems to be more commonly affected. Limitations and future directions of this method are discussed. Ó 2008 Published by Elsevier Masson SAS. Keywords: Schizophrenia; Diffusion tensor imaging; White matter; Anisotropy; Tractography

1. Introduction Diffusion Tensor Imaging (DTI) is a magnetic resonance imaging (MRI) technique which has become established in the last two decades as a valuable research tool. It is based on a modification of conventional MRI in a way that allows the non-invasive and in vivo quantification of the diffusion characteristics of water molecules [7,67,117]. Diffusion is isotropic when this motion is the same in all directions. In the brain, however, as in all tissues containing a large number of fibers, the movement of water molecules is restricted by various tissue components (for example myelin sheaths, cell membranes, microfilaments), so that they diffuse more freely along neural fiber tracts than across them [59]. This anisotropic diffusion can be described mathematically by a tensor (diffusion tensor D) which is often represented as an ellipsoid. The directions of the main axes of the ellipsoid (in the MR scanner’s coordinate system) are given by the eigenvectors (e1, e2, e3) with their lengths representing the eigenvalues (l1, l2, l3) of the diffusion tensor. The largest * Corresponding author. Tel.: þ44 20 78480425. E-mail address: [email protected] (M. Kyriakopoulos). 0924-9338/$ - see front matter Ó 2008 Published by Elsevier Masson SAS. doi:10.1016/j.eurpsy.2007.12.004

eigenvalue (l1) corresponds to the principal eigenvector e1 which demonstrates the main diffusion direction within the voxel [7]. Commonly used measures of diffusion include fractional anisotropy (FA) which is an estimate of the fraction of the diffusion attributed to anisotropy and can take values between 0 (no anisotropy) and 1 (diffusion hypothetically allowed only in a single direction), and relative anisotropy (RA) which uses the ratio of the anisotropic part of the diffusion tensor to its isotropic part. Both FA and RA are quantitative and dimensionless [9]. Another measure that has been used to compare different voxels in terms of diffusion is intervoxel coherence (IC) which quantifies the degree of diffusion collinearity between adjacent voxels [87]. Measures of diffusivity like mean diffusivity (MD) or apparent diffusion coefficient (ADC) and trace of the diffusion tensor (Tr) (all closely related to each other) can also be used to quantify the overall diffusion in a particular voxel or region, whilst avoiding anisotropic diffusion effects [90]. Different approaches have been applied to study differences in regional brain anisotropy between subjects. Some studies have used voxel based approaches (VBA), where data sets from subjects belonging to a group with specific characteristics (e.g. specific diagnosis) have been processed with reference to

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a measure of anisotropy (e.g. FA), normalized to a standard anatomical template, combined and averaged, before being compared to similarly processed data sets from another group (Fig. 1). Other studies have used a region of interest (ROI) approach, where ROIs are placed in regions of the brain thought to be implicated to a particular condition, and are compared in terms of an averaged measure of anisotropy (e.g. FA) between different groups of subjects [59]. Finally, although not yet widely used, tractography [46,48,73] is a method which allows segmentations and visualization of putative fiber tracts crossing one or more brain regions (Fig. 2), along with measurement of various characteristics over the tract so defined, such as average FA, or average length of the tract. This facilitates a more direct comparison of specific neuronal circuits. 2. DTI: A European perspective European researchers have been among those at the forefront of DTI techniques development, and have also been involved in their application to Schizophrenia and other diseases. Denis Le Bihan, a French radiologist and doctor of Medicine and Physics, was the pioneer of diffusion MRI. He published the first paper introducing diffusion measurements in a neurological context in 1986, shortly before his move to the United States in 1987. There he held senior academic posts in NIH and Georgetown University, and in 1994 his group was the first to publish on the new MRI modality of DTI [7,8], based on the estimation of the effective diffusion tensor Deff within the voxel. Le Bihan returned to France that same year to work at the Service Hospitalier Fre´de´ric Joliot of the CEA, in Orsay. This is among several centres in Europe to have contributed in the further development of DTI methodology. Some of the recent European advances have been in analysis techniques [3,101] including probabilistic tractography [12,85,86,107], in optimization and standardization of diffusion measurements [2,28,47,46] and in the use of DTI in neurological [14,22e24,26,78,98,106,112,113], neuropsychiatric [6,51,91] and other medical applications [30,93,96]. There have been in total 50 papers examining DTI in schizophrenia of which 17 are by European researchers. To these, the University of London (Institute of Psychiatry and Institute of Neurology), UK, with 6 studies, and the University Hospital of Clinical Psychiatry in Bern, Switzerland, with 5 studies, have had the largest contribution. 3. DTI as applied to schizophrenia Structural brain abnormalities in cortical and subcortical structures have been described in both neuroimaging [99] and neuropathological studies [37] of schizophrenia. With the normal integration of cerebral function being compromised [27], evidence for functional disconnectivity [33,34], abnormalities in neuronal arborisation [37] and myelin function and distribution [118,35,39], it is not surprising that white matter (WM) network deficits have been suggested to be a key component of the disorder [4,13]. Therefore, brain imaging methods that allow the direct study of WM connections in

vivo would be expected to contribute substantially in the evaluation of potential structural disconnectivity in schizophrenia. Several MRI methods have been used in the investigation of brain WM. WM is difficult to study in detail with conventional MRI approaches such as Voxel Based Morphometry because of its high degree of homogeneity. Conventional MRI techniques also do not allow for the evaluation of its directionality and organization. As a result, it had not been possible until recently for WM tracts to be individually identified and visualized in vivo, so diffusion MRI has been a significant development. From the time of the first paper on its clinical implications by Le Bihan and colleagues in 1986 [66], and the subsequent introduction of diffusion tensor MRI (DTI) by Basser and colleagues in 1994, diffusion imaging has become one of the most important methods in brain WM studies [42,72]. DTI is becoming increasingly important in the field of schizophrenia research. The number of DTI studies in schizophrenia is increasing and optimal variations of methodology are continuously tested. There have also been 3 published reviews of the DTI findings specific to schizophrenia [53,56,57]. In the current article we review all published studies to date in an attempt to evaluate the WM abnormalities identified in schizophrenia with the use of this method. 4. Methods 4.1. Literature search and inclusion criteria Studies were identified by searching the major databases (EMBASE, PubMed, PsychInfo, and Medline) from February 1998 to December 2006. The search strategy used was based on the Cochrane review technique. The keywords used in the search were: ‘schizophrenia’, ‘diffusion’, ‘tensor’, and ‘DTI’. The articles were included if they met the following criteria: (a) used Diffusion Tensor Imaging, (b) included patients with schizophrenia, schizophreniform or schizoaffective disorder, (c) included a psychiatric and a normal comparison group and compared the groups in terms of diffusion measures, (d) used well-established diagnostic criteria [Research Diagnostic Criteria (RDC, [119]); Diagnostic and Statistical Manual of Mental Disorders (DSM), 3rd edition, 3rd edition revised and 4th edition (American Psychiatric Association 1980, 1987, 1994); International Statistical Classification of Diseases and Related Health Problems, 9th and 10th revision (WHO 1977, 1992)], (e) were written in English. 5. Results We identified 40 studies that fulfilled the inclusion criteria. We also found 4 studies that did not include a comparison group [40,41,70,115], 2 studies that did not compare the groups in terms of the chosen measure of FA [79,80] and 4 that did not mention explicit diagnostic criteria [18,32,45,84]. Table 1 summarizes the studies discussed in detail in this review while Table 2 outlines the 10 studies that did not fulfill the inclusion criteria.

Table 1 DTI studies fulfilling inclusion criteria Sample

Mean age (years)  SD

DTI method

Abnormalities in SZ patients compared to controls

Correlations

Comments/limitations

Lim et al. [71]

10 DSM-IV SZ 10 NC

47.7  7.8 41.9  8.3

8 Slice ROI; Measured WM FA

Reduced WM FA BL in prefrontal, temporal-parietal and parietal-occipital regions.

None examined.

e Diagnoses based on SCID. e All patients were on atypical antipsychotics. e Male subjects only. e 7 of 10 patients had lifetime diagnoses of substance abuse/ dependence. e Patients had reduced GM but not WM volumes.

Foong et al. [31]

20 DSM-IV SZ 25 NC

37.65* 33.84

Single slice ROI approach (28.1 mm2); CC e measured FA, D

Increased D and reduced FA in the genu but not the splenium

None examined.

e No diagnostic instrument. e All patients were on antipsychotics.

Agartz et al. [1]

20 DSM-IV SZ 24 NC

38.4  7.9 42.2  6.7

VBA; measured WM FA and MD.

Reduced FA in the splenium of corpus callosum and in forceps major BL. Widespread increase in MD.

None examined.

e Diagnoses based on SCID. e All but one patient were on antipsychotic medication.

Steel et al. [102]

10 DSM-IV SZ 10 NC

34  14 35  7

ROI approach; frontal and occipital lobes (15 mm3) e measured WM FA

No group differences between SZ patients and controls; post hoc analysis showed increased R occipital WM FA in female patients only (n ¼ 5).

R prefrontal NAA levels correlated with R and L prefrontal WM FA in patients only. FA did not correlate with illness duration.

e Diagnoses based on SADS-L. e Proton MRS spectra obtained from the prefrontal cortex. e All patients were on antipsychotics.

Kubicki et al. [58,59]

15 DSM-IV SZ 18 NC

43  7 43  6

ROI approach; single slice through the UF e measured WM FA and total anisotropy.

No group differences between patients and controls. L > R FA within the UF in controls e absent in patients.

In patients only: e Lower R FA correlated significantly with worse performance on the Trail Making Test and on the similarities subtest of the WAIS-III; e Lower L FA correlated significantly with worse immediate recall in the verbal paired associate subtest of the WMS e No correlation between FA and medication dose

e Diagnoses based on SCID. e Male subjects only. e All subjects assessed with verbal paired associate learning subtest of WMS-III, WCST, Trail Making Test and similarities subtest of the WAIS-III. e All patients were on antipsychotics.

Ardekani et al. [5]

7 DSM-IV SZ 7 DSM-IV Schizoaffective Disorder (SZAF) 14 NC

30.8  8.5 33.5  10.8

VBA; measured WM FA

Reduced FA in inferior parietal lobule BL, cingulate gyrus BL, forceps occipitalis BL, middle temporal gyri BL, L superior temporal gyrus and in the body and splenium of CC.

None examined.

e Diagnoses based on SCID. e The majority of patients were on antipsychotics. e Patients with SZAF were not examined separately.

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Table 1 (continued) Sample

Mean age (years)  SD

DTI method

Abnormalities in SZ patients compared to controls

Correlations

Comments/limitations

Begre et al. [11]

7 DSM-IV SZ 7 NC

22.6 22.8

ROI approach; 16  16 voxels e measured WM FA in hippocampus.

No group differences between patients and controls in FA

None examined.

Burns et al. [19]

30 DSM-IV SZ 30 NC

36.4  11.2 35.7  12.4

VBA with small volume correction; 3 regions centrered on UF, arcuate fascisculus (AF) and anterior cingulum e measured FA.

Reduced FA in L AF. Trend towards WM FA reduction on L UF.

None examined.

e No diagnostic interview e Sample of FE patients; 6 out of 7 patients male e All but one patient were on antipsychotics. e Study also acquired EEG data. e No diagnostic instrument. e Most patients were on antipsychotic medication.

Kubicki et al. [61]

16 DSM-IV SZ 18 NC

43  6.8 43  5.9

8 slices ROI through the CB; measured FA and diffusivity.

Reduced FA in the CB BL. No group differences in diffusivity

No correlation between FA and antipsychotic dose. Reduced FA in L CB correlated with increased number of incorrect responses and non-perseverative errors on the WCST.

e Diagnoses based on SCID. e Neuropsychological assessment with WCST. e Male subjects only e Same sample as in Kubucki et al.’s study [58,59].

Minami et al. [75]

12 DSM-IV SZ 11 NC

30.8  6 29  4

ROI approach; 4 regions 2  2 mm2 in the frontal, temporal, parietal and occipital lobes e measured FA.

Reduced WM FA in frontal, temporal, parietal and occipital regions BL.

Antipsychotic dose correlated with higher FA values in the left frontal lobe. No correlations with PANSS scores.

e No diagnostic instrument. e Symptoms rated with PANSS. e All but 2 patients were on antipsychotics.

Sun et al. [104]

30 ICD-10 SZ 19 NC

27.4  8.2 25.7  8.2

ROI approach; frontal, temporal, parietal, occipital regions, and regions in the genu and splenium of the CC, the anterior CB and the anterior and posterior limb of internal capsule e measured FA.

Reduced FA in the anterior CB.

None examined.

e No diagnostic instrument e All patients were on antipsychotics.

Wang et al. [109]

29 ICD-10 SZ 20 NC

28.45  7.01 24.21  5.92

ROI approach; 4 regions in the R and L superior and middle cerebellar penduncles e measured FA and ADC.

No group differences

None examined.

e No diagnostic interview. e Male subjects only. e All patients were on atypical antipsychotics.

Hubl et al. [43]

13 ICD-10 SZ with auditory hallucinations (AH) 13 ICD-10 SZ without AH 13 NC

33.3  8.5 31.0  9.3 32.0  8.4

VBA; measured WM FA. ROI analysis of medial and lateral AF.

Reductions in FA in BL AF, UF, CC and ILF. AH patients had higher FA mostly in the L AF and CC compared to controls. AH patients had higher FA values in the L CB compared to non-AH patients.

None examined.

e No diagnostic interview. e Symptoms rated with PANSS, CGI. e All patients but 2 received antipsychotic medication.

Kalus et al. [49]

15 ICD-10 SZ 15 NC

32.27  10.67 30.27  6.69

ROI approach; 2 regions in the anterior and posterior hippocampus e measured GM intervoxel coherence.

Reduced intervoxel coherence in the R and L posterior hippocampus.

None examined.

e No diagnostic interview. e Symptoms rated with PANSS. e All patients were on antipsychotics. e No effects of age, gender, duration of illness, or PANSS scores when used as covariates.

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Kumra et al. [63]

12 DSM-IV SZ 9 NC

16.5  1.8 15.5  1.7

ROI approach; measured FA in frontal WM of seven consecutive images, ranging from 25 mm above to 5 mm below the AC-PC plane; genu and splenium and occipital lobe at the AC-PC plane.

Reduced frontal FA BL at AC-PC level. Reduced FA in the R occipital lobe at AC-PC level.

Okugawa et al. [82]

25 DSM-IV SZ 21 NC

29.8  6.7 29.4  3.8

ROI approach; 2 regions 2 mm2 in L and R middle cerebellar peduncles e measured FA and ADC.

Reduced FA but not ADC on the L and R middle cerebellar peduncles.

Wang et al. [108]

21 ICD-10 SZ 20 NC

29.24  5.58 26  5.99

ROI approach; 2 regions in the anterior and posterior CB e measured FA.

Reduced FA in the anterior CB in patients particularly on the L.

None examined.

e No diagnostic interview. e Male subjects only. e All patients on atypical antipsychotics.

Kalus et al. [50]

14 ICD-10 SZ 14 NC

27.93  6.37 31.37  5.97

ROI approach; amygdala e measured Intervoxel Coherence.

Reduced Intervoxel Coherence in amygdala BL.

No correlations between amygdala Intervoxel Coherence and volume, PANSS scores, duration of illness and antipsychotic dose.

e No diagnostic interview. e Symptoms were assessed with PANSS. e All patients were on antipsychotics. e Structural and quantitative Magnetization Transfer Imaging data (qMTI) also obtained. e No group differences in the volume of the amygdala.

Kalus et al. [52]

15 ICD-10 SZ 15 NC

32.27  10.67 30.27  6.69

ROI approach; Entorhinal cortex (EC) e measured Intervoxel Coherence.

Reduced Intervoxel Coherence in EC BL.

No correlations between EC Intervoxel Coherence and volume, PANSS scores, duration of illness and antipsychotic dose.

e Symptoms were assessed with PANSS. e All patients on antipsychotic medication. e High-resolution volumetry of EC also obtained. e No group differences in the volume of the EC.

Kanaan et al. [54]

33 DSM-IV SZ 40 NC

32  10 34  9

Tractography; 4 sequential slices of the genu of CC e measured FA.

No group differences.

None examined.

e No diagnostic interview. e All patients were on antipsychotic medication.

Kitamura et al. [55]

6 DSM-IV SZ 6 NC

31  5.4 32  4.3

Data acquired in a 3.0 T system ROI approach; 4-voxel (6.25  6.25  5 mm3) ROIs in frontal and parietal WM bilaterally on a single slice passing through the body of CC e l longitudinal and l transverse (LCA), FA.

Increased l longitudinal and l transverse but decreased FA in frontal WM.

No correlations between diffusion measures, symptoms, antipsychotic dose and duration of illness.

e Evaluation of patients with the use of Comprehensive Assessment of Symptoms and History (CASH) and BPRS e Male subjects only. e All patients were on antipsychotics.

No significant correlations between IQ, age, age of onset of psychotic symptoms, length of antipsychotic treatment, premorbid adjustment, clinical ratings of psychotic symptoms and the FA measures of the frontal WM at the AC-PC plane. No correlation between FA and PANSS. FA in the R correlated with current antipsychotic dose.

e Diagnoses based on SADS School Age Children version. e Symptoms were assessed with the BPRS and SANS. e Patients on atypical antipsychotics.

e Diagnoses based on SCID. e All patients were on antipsychotics. e Symptoms rated with PANSS. M. Kyriakopoulos et al. / European Psychiatry 23 (2008) 255e273

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Table 1 (continued) Sample

Mean age (years)  SD

DTI method

Abnormalities in SZ patients compared to controls

Correlations

Comments/limitations

Kubicki et al. [57,60]

21 DSM-IV SZ 26 NC

Group matched but not explicitly stated.

VBA; measured WM FA.

Reduced FA in anterior and middle CB BL, anterior and posterior superior occipitofrontal fasciculus BL, internal capsule BL, CC, fornix, R inferior occipitofrontal fasciculus and L AF.

e Diagnosis based on SCID-P. e SCID-NP completed for NC. e Not clear how many patients were on medication. e Magnetization Transfer Imaging and WCST data also obtained. e Multiple correlations which would not survive Bonferroni correction.

Kumra et al. [62]

26 EOS 34 NC

15.2  2.2 15.4  2.8

VBA; measured WM FA.

Reduced FA in the L anterior CB.

Correlations between FA and MTR in L CB, CC, fornix, R internal capsule and superior longitudinal fasciculus BL. No correlations between FA or MTR and age or medication. Correlations between L CB FA and WCST total incorrect, perseverative responses and perseverative errors. No significant correlations between FA and premorbid IQ, parental SAS, number of antipsychotic trials in the past, length of antipsychotic treatment, duration of illness, dose when scanned, total lifetime exposure to CPZ equivalent doses.

Price et al. [92]

20 DSM-IV SZ 29 NC

24.95 28.06

ROI approach; 2 regions 28 mm2 in genu and splenium of CC e measured FA and D.

No group differences between patients and controls in FA and D.

None examined.

e No diagnostic interview. e First Episode Schizophrenia. e All patients on atypical antipsychotics. e The gender distribution was different between the two groups (38% of controls male vs. 70% of patients). e Gender effect in genu of CC with females having lower FA.

Shin et al. [100]

19 DSM-IV SZ 21 NC

27.84  4.78 27.09  5.51

VBA; measured ADC.

Increased ADC in L inferior frontal gyrus adjacent WM (AWM), insular AWM BL, R parahippocampal gyrus AWM, R parahippocampal gyrus, R middle frontal gyrus, L middle frontal gyrus AWM, R medial frontal gyrus, middle temporal gyrus AWM BL, L cingulate gyrus and L superior temporal gyrus.

ADC values in R lnsular AWM positively correlated with negative symptoms scores in PANSS. No correlation between ADC and illness duration, dose-years medication, PANSS positive and general symptoms subscales.

e Diagnosis based on SCID e Symptoms were rated with PANSS. e All patients on atypical antipsychotics. e Correlations would not survive Bonferonni correction.

e Patient diagnoses based on KSADS-PL. e All patients were on antipsychotics. e 8 Patients had SZAF and 1 had schizophreniform disorder. e Trend towards reduced FA in schizophrenia patients in comparison to the rest of the patient group. e Non-significant increase of FA with age in healthy subjects; nonsignificant decrease of FA with age in patients.

M. Kyriakopoulos et al. / European Psychiatry 23 (2008) 255e273

Authors

10 DSM-IV SZ/ SZAF 13 NC

26.9  4.6 28.9  6.0

VBA; measured WM FA.

FA was reduced in the middle frontal, posterior superior temporal gyri and in the internal capsule extending into the globus pallidus.

None examined.

e Diagnosis based on SCID. e SCID-NP completed for NC. e First episode patients; all minimally medicated. e 4 Patients were antipsychoticna€ıve at the time of the scan. e Half the patient sample had SZAF.

Buchsbaum et al. [17]

63 DSM-IV SZ 55 NC

41.7  12.5 42.4  19.7

VBA; measured FA.

Widespread areas of reduced FA in frontal white matter, CC, cingulate gyrus, anterior internal capsule and SLF.

None examined.

Buchsbaum et al. [16]

92 DSM-IV SZ 11 DSM-IV SZAF 41 NC

43.0  12.4 44.1  14.7

Tractography; FA and length of tracts between ROIs in the anterior limb of the internal capsule and the prefrontal cortex.

Reduced length of tracts at ventrodorsal level. Reduced FA in the ventral part of the tracts.

Negative correlations between size of the internal capsule and tract length in patients at the most ventral level L.

e Diagnosis based on CASH. e Symptoms were assessed with PANSS. e NC group better educated, more likely to be married. e All but three patients were on antipsychotics. e Diagnosis based on CASH. e Symptoms were rated with PANSS. e All but 11 patients were on antipsychotics, some of who were also on additional medication. Some of the patients had poor recent medication history recorded. e Patients were also divided into good and poor-outcome subgroups and had separate analyses of tract length. e Same sample with Mitelman et al. [76].

Buttler et al. [20]

17 DSM-IV SZ 21 NC

36.6  1.0 34.9  10.6

ROI approach; ROIs placed in optic radiation, striate cortex, inferior parietal lobule and fusiform gyrus e measured FA along the visual pathways.

Reduced FA in the optic radiations BL.

None examined.

e e e e

Caan et al. [21]

34 DSM-IV SZ or related disorder. 24 NC

22.3  2.6 22.5  3.2

Principal component analysis (PCA) combined with linear discriminant analysis (LDA) followed by shaving; Measured WM FA.

Decreased FA in the genu of CC and increased FA in the posterior limb of the internal capsule and R UF.

None examined.

e No diagnostic interview. e All patients were on antipsychotics. e Comparison of the new method to VBA findings from previous studies. e The paper is oriented in presenting a new method, and has no clinical conclusions.

Diagnosis based on SCID Symptoms were rated with BPRS. 2 Patients had SZAF. All patients were on antipsychotics.

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Szeszko et al. [105]

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Table 1 (continued) Sample

Mean age (years)  SD

DTI method

Abnormalities in SZ patients compared to controls

Correlations

Comments/limitations

Federspiel et al. [29]

12 ICD-10 SZ 12 NC

23.4  3.0 23.2  3.1

VBA; measured WM Intervoxel Coherence.

Reduced Intervoxel Coherence in frontal areas near BA 10 BL, R temporal areas near BA 42 and 22, R external capsule, R SLF, R anterior occipito-frontal fasciculus, L posterior cingulate, L internal capsule and L corpus callosum. Increased Intervoxel Coherence in R anterior thalamic peduncle, R optic radiation and L external capsule.

None examined.

e No diagnostic interview. e All but one patient were on antipsychotics. e No differences in WM volumes between groups or hemispheres.

Hao et al. [36]

21 DSM-IV SZ 21 NC

23.715.47 25.054.58

VBA; measured WM FA.

None examined.

e No diagnostic interview e All patients were on antipsychotics. e Symptoms were rated with PANSS.

Jones et al. [44]

14 DSM-IV SZ 14 NC

34 (median) SD ¼ 9.3 Range 22e53 34 (median) SD ¼ 9.8 Range 19e57

Tractography; measured average FA and MD of UF, SLF, IFOF and the CB BL.

Reduced FA in cerebral peduncle BL, hippocampal gyrus BL, R corona radiate, precuneous BL, cuneus BL, L fronto-orbital area, R middle frontal lobe, inferior temporal gyrus BL, R superior cerebellar peduncle, insular BL and R anterior cingulum. Reduced FA in L SLF. Reduced average FA from all 8 tracts combined. Increased MD from all 8 tracts combined.

Age was negatively correlated with average FA from all 8 tracts combined in NC but not in patients. When tracts were examined separately this correlations was found to be significant only in L SLF.

e No diagnostic interview. e All patients were on antipsychotics. e Male subjects only. e Multiple comparisons; Only correlation between L SLF and FA would survive Bonferroni correction.

Kuroki et al. [64]

24 DSM-IV SZ 31 NC

40.3  8.5 40.6  8.7

3 slice ROI; Fornix e measured FA and Dm.

Reduced FA and increased Dm in fornix.

Mean Dm of fornix negatively correlated with hippocampal volume BL in patients. Cross sectional area of the fornix positively correlated with hippocampal volume BL in patients. No correlation between FA and hippocampal volumes. Age was positively correlated with mean Dm of the fornix in control group. Cross sectional area of the fornix negatively correlated with SANS score for global attention but did not remain significant when controlling for medication dosage. WMS scores in patients correlated positively with hippocampal volumes. Medication dose

e Diagnosis based on SCID. e SCID-NP and SCID II completed for NC. e Male subjects only. e Symptoms assessed with SAPS and SANS. e Neuropsychological assessment with WMS-III. e Measurements of hippocampal volume and volume of cross sectional area of fornix were also obtained. e Hippocampal volume was reduced BL in patients. Cross sectional area of fornix was smaller in patients. e Differences between groups in IQ and SES.

M. Kyriakopoulos et al. / European Psychiatry 23 (2008) 255e273

Authors

was negatively correlated with mean FA ( p < 0.001) and cross sectional are of the fornix and positively correlated with Dm. Typicals vs atypicals, IQ, age, age of onset, duration of illness were not correlated with any MRI measure. Negative correlations between positive and negative PANSS subscale scores and whole brain pixel percentage of WM displacement peak.

e All patients were on antipsychotic medication. e Multiple correlations which would not survive Bonferroni correction.

26  6 29  3

b-value DWP. ROIs in prefrontal and temporal areas e measurement of q-space displacement and FA.

No differences in FA between the groups.

Mitelman et al. [76]

93 DSM-IV SZ 11 DSM-IV SZAF 41 NC

Good outcome 40.6  12.6 Poor outcome 44.8  11.4 44.1(14.7

ROI approach; measured WM FA from each Brodmann area (BA).

Total WM FA reduction in patients especially R. Lower WM FA in patients in parietal and temporal lobes BL, R posterior cingulate and occipital areas, R lateral and L polar, medial and orbital prefrontal areas. FA values higher in patients in L dorsolateral prefrontal, L medial temporal, L ventral anterior, L retrosplenial cingulate, R frontopolar and R ventral anterior WM.

Intercorrelations among regional FA were predominantly positive and the total number of all intercorrelations was higher in patients with poor outcome. The number of correlations between WM FA and WM volume was higher in patients with good outcomes in comparison to those with poor outcomes. The number of correlations between WM FA and GM volume was higher in patients with good outcome than controls and those patients with poor outcome.

e Diagnosis based on CASH. e Symptoms were rated with PANSS. e Not clear how many patients were on antipsychotics.

Okugawa et al. [81]

21 DSM-IV SZ 21 NC

31.1  6.7 30.4  4.9

ROI approach; 2 mm  2 mm in the superior cerebellar peduncles e measured ADC, FA.

Reduced FA in superior cerebellar peduncle BL.

Positive correlation between L superior cerebellar peduncle FA and PANSS cognitive cluster scores. No correlations with ADC, positive and negative symptoms score or medication dosage.

e No diagnostic interview. e Symptoms were rated with PANSS. Cognitive function assessed by extrapolating cognitive cluster scores. e All but 2 patients were on antipsychotic medication.

Rose et al. [94]

12 DSM-IV SZ 12 NC

31.4  10.7 32.2  11.7

VBA; measured MD.

Significantly increased MD in temporal and frontal areas, caudate body and thalamus.

None examined.

e Patient diagnosis based on Diagnostic Interview for Genetic Studies, medical records and informants. e One patient had SZAF. e All patients were on antipsychotic medication.

e Diagnosis based on SCID. e All patients on medication for less than 1 month. e Symptoms were rated with PANSS and CGI. e Overall decrease of mean peak displacement values corresponding to WM In patients. Decrease in mean displacement in L prefrontal cortex ROIs.

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9 DSM-IV SZ 5 NC

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Mendelsohn et al. [120]

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Table 1 (continued) Sample

Mean age (years)  SD

DTI method

Abnormalities in SZ patients compared to controls

Correlations

Comments/limitations

Schlosser et al. [95]

18 DSM-IV 18 HC

29.6  7.0 29.0  10.0

VBA; measured FA.

Reduced FA in R medial temporal lobe and R dorsolateral prefrontal area.

Positive correlation between prefrontal FA extracted from the area of difference between patients and controls and fMRI activation in the already identified hypoactivated prefrontal areas in patients.

White et al. [114]

14 DSM-IV SZ 15 NC

15.2  2.6 14.5  2.7

VBA; measured average diffusivity (AD) and FA.

Decreased FA and increased AD in L posterior hippocampus and L posterior limbic regions involved in connections with the posterior cingulate. These areas of difference disappeared after controlling for IQ.

None examined.

e Diagnosis based on abbreviated SCID interview. e Symptoms were rated with PANSS. e All patients were on antipsychotics and some in additional mood stabilizers. e fMRI using a modified Sternberg task to examine working memory. e Increased activation in NC relative to patients in lateral prefrontal, superior parietal and occipital areas. e In fMRI analysis an uncorrected threshold for multiple comparisons ( p < 0.001) was used. e Diagnosis based on K-SADS-PL. e Symptoms rated with SAPS and SANS. e Patients and controls not matched for IQ and SES. e One patient had SZAF. e Not clear how many patients were on antipsychotics.

ROI, region of interest; VBA, voxel based approach; FE, first episode patients; BA, Broadman area; FA, fractional anisotropy; ADC, apparent diffusion coefficient; Dm, D, MD, mean diffusivity; AD, average diffusivity; IQ, intelligence quotient; MRS, magnetic resonance spectroscopy; qMRT, quantitative magnetization transfer imaging; MRT, magnetization transfer imaging; L, left; R, right; BL, bilateral;; SZ, schizophrenia; SZAF, schizoaffective disorder; NC, normal controls; WM, white matter; GM, gray matter; CB, cingulum bundle; AF (SLF), arcuate fasciculus (superior longitudinal fasciculus); ILF, inferior longitudinal fasciculus; IFOF, inferior fronto-occipital fasciculus; EC, entorhinal cortex; SES, socioeconomic status; SCID, Structured Clinical Interview for DSM-IV; SADS-L, Schedule for Affective Disorders and Schizophrenia, Lifetime version; K-SADS-PL, Schedule for Affective Disorders and Schizophrenia for school-aged children, Present and Lifetime version; CASH, Comprehensive Assessment of Symptoms and History; SCID NP, SCID for non-patients; PANSS, Positive and Negative Symptoms Scale; CGI, Clinical Global Impression scale; BPRS, Brief Psychiatric Rating Scale; SANS, Scale for Assessment of Negative Symptoms; SAPS, Scale for Assessment of Positive Symptoms, WMS, Weshler Memory Scale; WAIS, Weshler Adult Intelligence scale; WCST, Wisconsin Card Sorting Test.

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Authors

Table 2 Studies on DTI not fulfilling inclusion criteria for current review Sample

Mean age (years)  SD

DTI method

Abnormalities in SZ patients compared to controls

Correlations

Comments/limitations

Buchsbaum et al. [18]

5 SZ 6 NC

34  7.3 45.5  13.3

VBA; measured WM RA.

Reduced WM RA in R frontal lobe and R internal and external capsule

No correlation between FA and memory performance.

e Diagnoses based on CASH. e All patients were on conventional antipsychotics.

Foong et al. [32]

14 SZ 19 NC

38.6 34.6

VBA; measured FA and D.

No significant difference in FA or D between patients and controls.

None examined.

e No diagnostic interview. e All patients were on antipsychotics.

Hoptman et al. [41]

14 DSM-IV SZ No NC

40.5  7.8

ROI approach; 24 and 12 voxel ROIs in 4 regions: 5 mm below, at the level of, 5 and 15 mm above the AC-PC line e measured FA and Tr.

No NC.

BIS Motor Impulsiveness score was inversely correlated with R fontal WM FA in a region 5 mm below the AC-PC line. Tr in the same region was positively correlated with BDHI and LHA.

Diagnoses based on SCID-CV. Male subjects only. Symptoms were rated with PANSS. Impulsivity was assessed with the Barratt Impulsiveness Scale e Version 11 (BIS); Aggressiveness with the Buss Durkee Hostility Inventory; Aggressive behaviour with the Life History of Aggression. e All patients were on antipsychotics.

Wolkin et al. [115]

10 DSM-IV SZ No NC

41  9

ROI approach; 5 frontal regions (superior, middle, inferior) e measured WM FA.

No NC.

Inferior frontal FA negatively correlated with negative symptoms.

e No diagnostic interview e Male subjects only. e Symptoms rated with the BPRS and SANS. e All patients were on antipsychotics. e FA values not given.

Hoptman et al. [40]

25 DSM-IV SZ or SZAF No NC

38.6  7.4

VBA; measured FA.

No NC.

Negative correlations between motor impulsivity and age corrected FA in R ventromedial prefrontal WM, L putamen, L lingual gyrus, L posterior cingulate, anterior cingulate WM BL, caudate BL, insula BL, inferior parietal lobule BL and middle temporal gyrus BL. Positive correlations with L postcentral gyrus, L supplementary motor area, L superior frontal and fusiform gyri and L superior and middle temporal gyri.

e e e e

Nestor et al. [79]

14 DSM-IV SZ 14 NC

40.73  7.17 41.94  6.58

ROI approach; Single slice through the UF e measured FA. 8 Slices through the CB Measured FA.

Not examined.

In the patient group, L UF FA positively correlated with Immediate and Delayed Memory scores. FA in L cingulate fasciculus negatively correlated with Non-perseverative Errors score in WCST.

e Diagnoses based on SCID-P. Patients’ gender not specified. Neuropsychological assessment included WMS-III and WCST. e All patients were on antipsychotics. e Multiple correlations which would not survive Bonferroni correction. e Same sample as Kubicki [58,59,61].

e e e e

Diagnoses based on SCID-P Male subjects only Medication not mentioned Impulsivity assessed with BIS.

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Table 2 (continued) Sample

Mean age (years)  SD

DTI method

Abnormalities in SZ patients compared to controls

Correlations

Comments/limitations

Park et al. [84]

23 SZ 32 NC

43  7.2 44  6.2

VBA; measured WM FA.

None examined.

Jones et al. [45]

12 SZ 12 NC

78.1  7.4 82.3  9.7

Tractography; measured average FA and MD of UF, SLF, IFOF and CB BL.

No asymmetry in FA in the UF, in the anterior limb of the internal capsule and in the superior cerebellar peduncle. Reduced asymmetry in CB and anterior CC. No group differences between patients and controls in FA and MD.

e No diagnostic interview e Male subjects only. e Neuropsychological assessment included WMS-III, WCST, Trail Making Test and the similarities subtest of WAIS-III. e Diagnosis based on international consensus criteria of Very-Late-Onset Schizophrenia. e Nine patients were on antipsychotics.

Lim et al. [70]

25 DSM-IV SZ or SZAF No NC

36.4  10.0

VBA approach; measured WM FA.

None examined.

Positive correlations of story A from logical memory subtest score of WMS-III with FA in hippocampus and posterior cingulate BL, L parahippocampal gyrus, L fusiform gyrus, L cingulate gyrus, L BA 31, L BA 0, L posterior cingulate, L WM adjacent to the caudate tail, the insula and the claustrum, R middle frontal gyrus and R middle occipital gyrus. Negative correlations with R inferior frontal gyrus and R putamen. Positive correlations of digit symbol subtest score of WAIS-III with FA in anterior cingulate BL, fimbria-fornix BL, L cingulate gyrus, L mediale frontal gyrus, L BA 32, 9, 44, R claustrum, WM adjacent to R caudate. Negative correlations with the R cuneus. Positive correlations of digit spanbackward subtest score of WAIS-III with anterior cingulate BL, insula BL, body of corpus callosum BL, L cingulate gyrus, L BA 24,31,32, L thalamic WM, L precentral and postcentral gyrus, WM adjacent to L globus pallidus and caudate, R BA 13, R parahippocampal middle occipital and posterior cingulate gyri.

e Diagnosis based on SCID. e Verbal declarative memory assessed with immediate recall for story A from logical memory subtest of WMS-III., attention with digit span score from WAIS-III and executive function with the digit-span-backward subtest of WAIS-III. e No information on medication.

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Authors

ROI, region of interest; VBA, voxel based approach; BA, Broadman area; FA, fractional anisotropy; RA, relative anisotropy; ADC, apparent diffusion coefficient; D, MD, mean diffusivity; IQ, intelligence quotient; L, left ; R, right; BL, bilateral; SZ, schizophrenia; SZAF, schizoaffective disorder; NC, normal controls; WM, white matter; CB, cingulum bundle; SLF, superior longitudinal fasciculus; ILF, inferior longitudinal fasciculus; IFOF, inferior fronto-occipital fasciculus; SES, socioeconomic status; SCID, Structured Clinical Interview for DSM-IV; CASH, Comprehensive Assessment of Symptoms and History; SCID CV, SCID Clinician version; PANSS, Positive and Negative Symptoms Scale; WMS, Weshler Memory Scale; WAIS, Weshler Adult Intelligence scale; WCST, Wisconsin Card Sorting Test; ANT, Ayyention Network Test; BIS, Barratt Impulsiveness Scale.

Nestor et al. [80]

30 DSM-IV SZ 30 NC

39.11  10.3 41.27  8.59

8 Slices ROI; measured CB FA.

In the patient group, ANT alertness negatively correlated with illness duration and medication exposure. Reaction time of ANT in patients positively correlated with medication exposure and negatively with volume of R CB. Orienting measure of ANT positively correlated with L CB FA.

e Diagnosis based on SCID. e All patients were on antipsychotics. e Eighteen of the 30 subjects were previously scanned for another study [57,60]. e Volume of CB was also calculated. e Attention Network Test (ANT) was used to assess alerting, orienting and executive control. e Multiple correlations would not survive Bonferroni correction.

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5.1. Negative studies Of the included 40 studies, 6 did not report group differences in anisotropy measures between patients and controls [11,53,58,59,92,109,120]. All the negative studies examined FA focusing on specific areas of the brain using either ROI approach [11,58,59,92,109,120] or tractography [53]. These areas were the uncinate fasciculus (UF; [58,59]), the hippocampus [11], the superior and middle cerebellar peduncles [109], the corpus callosum (CC; [53,92]) and prefrontal and temporal areas [120]. No VBA studies with negative results have been published to date. 5.2. Positive studies 5.2.1. Studies using VBA Fifteen studies used voxel-based group mapping analysis. Twelve of these studies used FA as an anisotropy measure either on its own [5,16,17,19,21,36,43,57,60,62,95,105] or in combination with a measure of diffusivity [1,114]. Federspiel et al. [29] used intervoxel coherence (IC) as measure of anisotropy, while two studies only used measures of diffusivity [94,100]. These studies reported white matter abnormalities in a number of different regions ranging from lobar white matter (prefrontal, parietal, temporal and occipital) to tracts in the brainstem and the cerebellum. White matter tracts that were reported to be affected in more than one study include the corpus callosum (CC), the arcuate fasciculus (AF), the cingulum bundle (CB) and the internal capsule (ICP). In addition, taking a more general view of the studies’ findings (focusing on anatomical area rather than specific coordinates of the regions reported), then 12 studies found abnormalities in white matter in prefrontal regions [5,16,21,29,36,43,57,60,62,94,95,100,105], 12 studies in temporal regions [5,16,19,29,36,43,57,60,94,95,100,105,114], 5 studies in occipital regions [1,5,43,57,60,36] and 4 studies in parietal regions [5,36,43,57,60]. Finally, cerebellar white matter FA was reported to be decreased in Hao et al.’s study [36]. As far as specific tracts are concerned, the CC was reported to have decreased FA in patients in 5 VBA studies [1,5,16,21,57,60]. In addition, Federspiel et al. [29], who measured IC, also reported reductions of this in the CC. Hubl et al. [43] , whose study differentiated between patients with and without auditory hallucinations, reported increased FA in the CC in patients with hallucinations compared to healthy controls, but also increased FA in healthy controls in comparison to patients as a whole. The AF (also know as the superior longitudinal fasciculus, SLF) was also shown to be affected in 5 VBA studies. The first study to find AF abnormalities was that of Burns et al. [19]. This group used a combination of ROI and VBA approaches to identify a small area of reduced FA within the left AF. Three more VBA studies have since identified AF as having reduced FA in patients. These were Hubl et al.’s [43] and Buchsbaum et al.’s [16] studies e showing bilateral FA reductions e and the Kubicki et al. [57,60] study, showing reductions on the left alone. Federspiel et al. [29] also

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Fig. 1. Voxel-based approach: comparison of white matter fractional anisotropy between two groups reveals areas of microstructural changes.

reported reduced IC in the right AF. Three VBA studies found reduced FA in the CB. Kubicki et al. [57,60] reported the anterior and middle part of CB bilaterally, among other regions, to have reduced FA. Hao et al. [36] found the right anterior CB to be affected while Kumra et al. [62], who studied adolescents with schizophrenia, reported the left anterior CB to have reduction in FA. Finally, the ICP was reported to be affected in patients in 4 studies. Kubicki et al. [57,60] found bilateral reductions in ICP FA, Szeszko et al. [105] reported reduced FA in the left ICP extending into globus pallidus, while Buchsbaum et al. [16] in the anterior part of the tract. Federspiel et al. [29] identified IC reductions in the ICP on the left alone.

Fig. 2. 3D representation of the left cingulum bundle using tractography.

5.2.2. Studies using ROI approach Seventeen DTI studies have used a ROI approach. Fourteen of these studies used FA as the main anisotropy measure [20,31,55,61,63,64,71,75,76,81,82,102,104,108] while 3 used IC [49,50,52]. ROI studies are hypothesis driven; therefore the findings depend on the regions chosen by the researchers. Of the regions identified as affected with VBA studies, the CC is also reported in ROI studies to have reduced FA in the splenium [31]. In addition, the CB was examined in 3 ROI studies. Kubicki et al. [61] used ROI approach to show bilateral reductions in CB FA and Sun et al. [104] and Wang et al. [108] reported reductions in FA in the anterior part of the tract. Three ROI studies from the Kansai Medical University in Japan also showed evidence of cerebellar WM abnormalities. Okugawa et al.’s [82,83] studies suggested that middle CP are affected in schizophrenia while the Okugawa et al. [81] study showed reduced FA in the superior CP bilaterally. As with the VBA studies, it is also of interest to take a more general approach of the ROI studies’ findings, in an attempt to identify the parts of the brain most commonly affected. Of the 10 studies [31,55,61,63,71,75,76,102,104,108] that examined anterior regions (including frontal lobe WM, genu and anterior areas of CC and anterior CB) 9 reported positive findings [31,55,61,63,71,75,76,104,108]. Similarly, of the 10 studies [20,31,61,63,71,75,76,102,104,108] examining posterior brain regions (including occipital WM, splenium and posterior areas of CC and posterior cingulum) 7 reported positive findings [20,61,63,71,75,76,102]. Temporal structures (including hippocampus, entorhinal cortex, fusiform gyrus, amygdala and

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temporal WM) were found to be affected in 6 [49,50,52,71,75,76] of 8 studies [20,49,50,52,71,75,76,104]. Parietal WM seems to be less commonly affected; only 3 [71,75,76] of 6 studies [20,55,71,75,76,104] reported parietal WM abnormalities in FA measures. 5.2.3. Studies using tractography Two studies using tractography reported positive findings [17,44]. In the Buchsbaum et al. study, tracts connecting the anterior limb of the internal capsule with the prefrontal cortex were identified by setting ROI across their length. FA was found to be reduced in patients in the ventral part of the tracts. Jones et al. measured average FA and MD of UF, AF, CB and inferior fronto-occipital fasciculus (IFOF) after reconstructing the tracts using fiber tracking. Left AF was found to have reduced FA in patients. 5.3. Correlations 5.3.1. Clinical variables Eight of the included studies examined correlations between duration of illness and the used measures [50,52,55,57,60,62,64,100,102] and reported negative findings. Of the 8 studies examining correlations between symptom rating scales scores and anisotropy measures, 7 reported negative findings [49,50,52,55,63,75,83] while Shin et al. [100] study reported positive correlation of right insular WM ADC with negative symptoms subscore in PANSS (r ¼ 0.747, p < 0.0001). Age of the subjects was examined in 5 studies [44,57,60,62e64]. In 4 of these studies [57,60,62e64] age did not correlate with FA values. However, in the Jones et al. study [44], age was negatively correlated with the average FA from all the tracts examined and also of the AF alone. A non-significant increase of FA with age in healthy subjects and a non-significant decrease of FA with age in patients were also reported for the anterior CB in the Kumra et al. study [62]. 5.3.2. Medication Of the 12 studies to examine effects of medications on anisotropy measures, 9 reported negative findings [50,52,55,57e 60,62,63,100] while 3 reported positive findings. More specifically, Minami et al. [75] found positive correlation of left frontal FA with antipsychotic medication dose (r ¼ 0.64, p ¼ 0.047), Okugawa et al. [82] reported positive correlation of middle cerebellar peduncle FA with medication dose (r ¼ 0.56, p ¼ 0.004), while Kuroki et al. [64] reported negative correlation between fornix FA and medication (r ¼ 0.679, p < 0.001). 5.3.3. Cognitive variables Four of the included studies ran correlations with cognitive assessment variables. Three of these studies come from the same group. Kubicki et al. [58,59] evaluated all subjects with the verbal paired associate learning subtest of Weschler Memory Scale 3rd edition (WMS; [110]), the Wisconsin Card Sorting Test (WCST; [38]), the Trail Making Test [69],

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and the similarities subtest of Weschler Adult Intelligence Scale 3rd Edition (WAIS III; [111]), and examined correlations between UF WM FA and scores on these tests. In patients, lower right FA correlated significantly with worse performance on the Trail Making Test (r ¼ 0.71, p  0.01) and on the similarities subtest of the WAIS-III (r ¼ 0.55, p < 0.05); and lower left UF FA correlated significantly with worse immediate recall in the verbal paired associate subtest of the WMS (r ¼ 0.79, p < 0.01). In their second study, Kubicki et al. [61] used only WCST and found reduced that FA in left CB correlated with increased number of incorrect responses (r ¼ 0.546, p ¼ 0.04) and non-perseverative errors (r ¼ 0.658, p ¼ 0.01). In their 2005 study Kubicki et al. again used the WCST and reported correlations between left CB FA and WCST total incorrect (r ¼ 0.471, p ¼ 0.042), perseverative responses (r ¼ 0.478, p ¼ 0.038) and perseverative errors (r ¼ 0.517, p ¼ 0.023). Finally, Okugawa et al. [81] assessed cognitive function by extrapolating cognitive cluster scores of PANSS and reported positive correlation between this score and left superior cerebellar peduncle FA (r ¼ 0.72, p ¼ 0.002).

6. Discussion DTI is a relatively new and developing MRI technique which is increasingly used in the evaluation of possible WM abnormalities in schizophrenia. The published studies have more than doubled in the last 2 years, and increasingly sensitive optimised techniques and combinations of different imaging modalities are being used to increase the validity of the findings. Newer studies using larger samples also increase the power to detect genuine differences between patients with schizophrenia and health subjects. However, one of the things that still remains elusive is an in-depth understanding and accurate interpretation of the findings. DTI studies have detected WM changes as measured by anisotropy measures in many areas of the brain. These changes are mostly in keeping with a simple interpretation of what anisotropy measures represent (i.e. some form of ‘disruption’ of the structure of the tissue), and the values of these measures in patients with schizophrenia do indeed indicate WM abnormalities. So, the vast majority of studies report reductions of FA in schizophrenia which are in keeping with compromised WM tract integrity or WM microstructural disorganisation. However, there are many reasons why these changes might emerge so that WM FA decreases do not necessarily mean structural abnormalities. For example, voxels corresponding to regions of crossing fibers might also give reduced values of FA without the individual tracts lacking in integrity [117]. However, the fact that almost all studies (with the exception of Mitelman et al.’s study [76], which although finding overall WM FA reductions, also identified regions of increased FA) point towards a reduction in FA in schizophrenia may suggest that a common underlying WM pathology affecting the anisotropy measures, rather than factors unrelated to the illness, might account for these differences. Regardless, given the difficulties in

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determining accurately what these anisotropy reductions represent, we need to interpret the findings with caution. Another important question to be answered is whether WM of specific regions might emerge as particularly important for the pathophysiology of schizophrenia. So far there is a general agreement from cytoarchitectural studies [37] and brain imaging studies [65,99,116] that the disorder has widespread and subtle effects in numerous brain regions, many of which are most probably functionally related. Decreased total volume, gray matter (GM) and WM volume, as well as increased volume of the lateral ventricles, seem to be the most replicated findings. Regions also very likely to be affected include the frontal lobes, middle temporal lobe structures (amygdala, hippocampus), superior temporal gyrus, as well as subcortical regions like the CC, and the cerebellum [99]. Given the difficulty in determining the nature of the underlying neurobiological deficit of the disorder, the likelihood that WM abnormalities as quantified by anisotropy measures are also subtle, along with the immaturity of the DTI technique and the differences in methodology between DTI studies, it is not surprising that the findings from the WM investigations with DTI are not always consistent and also indicate widespread pathology. There have been a number of WM tracts identified as deficient (in terms of anisotropy) in schizophrenia subjects in more than one study. These tracts include the CC, the AF, the CB and the cerebellar peduncles, and are all known to connect into functional networks regions already linked with schizophrenia in port-mortem and other MRI studies. In addition, frontal and temporal WM are more commonly reported to be affected than parietal and occipital WM, which point towards increased significance of frontal and temporal regions in the disorder. The vast majority of patients participating in DTI studies to date have been on antipsychotic medication treatment. Ten studies also included very few unmedicated patients [1,11,16,17,19,29,75,76,81,105] and 2 studies included minimally medicated patients [105.120]. Although medication dose or cumulative exposure do not correlate with measures of anisotropy in most studies, 3 studies reported positive findings. One additional MRI volumetric study [25] has reported decrease in white matter volume in those patients with schizophrenia successfully treated with antipsychotic medication. As cross-sectional studies on medicated patients do not allow for the adequate investigation of medication effects on FA, antipsychotic treatment remains a potential confounder. Age effects in WM of patients with schizophrenia also require additional attention. It is well known that FA changes with age and this has been attributed to changes in myelination of fiber tracts, water concentration in the brain and overall integrity of the tracts [10,15,74,87,88,97,103]. However, tract morphological characteristics affect how changes in integrity will translate into brain anisotropy values. In regions with crossing fibers, illness related compromise of WM tracts might lead to increased FA, as the remaining tracts might be more uniformly oriented [89]. The studies that examined correlations with age generally failed to identify a significant effect. Only the Jones et al. [44] study has reported positive findings to date. It might be that the studies lack the power to detect age

effects due to relatively small sample sizes. In any case, there is a need to examine in more detail the effect of age in this group of patients in future studies. Only one of the included studies [100] reported positive correlations between psychopathology (negative symptom sub-score of PANSS) and a measure of diffusivity (right insular ADC) and this correlation is robust. There have been few studies reporting correlations between neuropsychological measures and FA. Left CB, left UF and left superior cerebellar peduncle are areas that have emerged as probably interesting in this respect [57,58,59,60,61,81]. However, many of the DTI studies assessing correlations with neuropsychological measures are not included in this review as they did not fulfill the inclusion criteria (Table 2), and in most of the included studies the correlations reported would not survive Bonferroni correction for multiple comparisons. Finally, there are a number of additional limitations that must be considered when DTI finding are interpreted. Eddy currents, motion artifacts, gradient distortions, partial volume effects, and relatively coarse resolution, can all affect the quality and accuracy of the images [57,60,68]. Crossing tracts, as already discussed, and inability to determine anatomical boundaries between tracts that run very close to each other [77] can also be problematic. Finally, tractography, while generally a promising method, at present lacks a reference standard. 7. Future research DTI, despite its current limitations, offers significant additional information on whether WM tract integrity is compromised in the brain in schizophrenia. It currently is the only method that can do this in vivo, and has the potential to assist our understanding of how WM networks connect brain regions into functional entities and whether microstructural abnormalities in these networks can partly account for the emergence of the disorder. The combination of DTI with other imaging modalities will enhance our ability to investigate functional and structural mediating factors that might provide a better framework in which to explore underlying pathophysiology. Better acquisition methods, more sophisticated analysis techniques, and well conducted studies taking into account subjects‘ developmental stage and clinical parameters are likely to provide more consistent findings. Particularly important in this regard would be studies of medication-na€ıve patients. Further evolution of methods of tractography may also allow for more direct and valid comparisons, with more meaningful results. Finally, combination of DTI with genetic studies may also lead to identification of more specific WM abnormalities associated with genotypically or endophenotypically defined subgroups of patients with schizophrenia. References [1] Agartz I, Andersson JL, Skare S. Abnormal brain white matter in schizophrenia: a diffusion tensor imaging study. Neuroreport 2001;12: 2251e4.

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