White matter integrity of the whole brain is Yihui Haoa, Zhening Liua, Tianzi Jiangc, Gaolang Gongc, Haihong Liua, Lihua Tanb, Fan Kuangb, Lin Xua,d, aThe Institute of Mental Health, bDepartment of Radiology, Second Xiangya Hospital,Central South University, Changsha, Hunan, cNational Laboratory ofPattern Recognition, Institute of Automation,Chinese Academy of Sciences, Beijing and dLaboratory of Learning and Memory, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming,Yunnan, PR China Correspondence and requests for reprints to Dr Zhening Liu, Institute of Mental Health, Second Xiangya Hospital, Central South University, No.139 Renmin Zhong Road, Changsha 410011, Hunan, China Tel: + 8613508489006; fax: + 07315554052; e-mail: zheningl@hotmail.com and ProfessorTianzi Jiang, Tel: + 8610 82614469; fax: + 8610 62551993; email: jiangtz@nlpr.ia.ac.cn Sponsorship: The National Basic Research Program of China (2006CB500800) supported this work.
Received17 October 2005; revised 8 November 2005; accepted 9 November 2005 Di¡usion tensor imaging studies in schizophrenia have demon- fractional anisotropy in white matter of the patients was lower than strated lower di¡usion anisotropy within white matter that provides that in controls at the cerebral peduncle, frontal regions, inferior information about brain white matter integrity. We have examined temporal gyrus, medial parietal lobes, hippocampal gyrus, insula, whether white matter is abnormal in ¢rst-episode schizophrenia by right anterior cingulum bundle and right corona radiata. These using di¡usion tensor imaging. Twenty-one schizophrenic patients results suggested that white matter integrity of the whole brain and healthy controls underwent di¡usion tensor imaging scans that was disrupted in early illness onset of schizophrenia. NeuroReport analyzed by using a rigorous voxel-based approach. We found that c 2006 Lippincott Williams & Wilkins.
Keywords: di¡usion tensor imaging, ¢rst-episode schizophrenia, fractional anisotropy, white matter studies, but the placement of ROI is subjective and manual Growing evidences from diffusion tensor imaging (DTI) errors may occur while defining the anatomical area. In the studies have supported the view that a disturbance in case of schizophrenia, however, voxel-based analysis in- connectivity between different brain regions is responsible stead of ROI may be useful in detecting the abnormal for the clinical symptoms and cognitive dysfunctions regions in the whole brain. Furthermore, antipsychotic observed in schizophrenia [1]. Buchsbaum et al. [2] report drugs may be related to the changes of anisotropy in the a DTI study on the first time that white matter diffusion left frontal white matter and in the middle cerebellar anisotropy was reduced in schizophrenic patients compared peduncle [4]. These studies suggest that there is a need to with that in normal controls. Since then, DTI study has carefully differentiate the effects of medication/unmedica- attracted much attention because it may provide important tion and chronic/first-episodic patients [1,3].
new information about the anatomical connectivity of the To our knowledge, the participants in previous DTI studies were mainly medicated chronic schizophrenia Kanaan et al. [3] and Kubicki et al. [1] systematically patients. Only two studies involved the first-episode reviewed DTI studies on schizophrenia. The most consistent schizophrenic patients who showed no fractional anisotropy finding is impairment of white matter integrity within the (FA) changes in the hippocampus and the corpus callosum prefrontal and temporal lobes, and splenium of the corpus by using the ROI approach [5,6]. Using voxel-based callosum, internal capsule, cingulum bundle, uncinate and analysis, we have studied whether the white matter arcuate fasciculus. Meanwhile, some reports suggest that integrity is disrupted in the whole brain of first-episode white matter integrity in the whole brain is disrupted in Not all of previous DTI studies report a reduced diffusion anisotropy in patients with schizophrenia [3]. This discre- pancy may be because of different conditions including the data analysis. The two major methods in anisotropy analysis Twenty-one first-episodic patients (12 men, 9 women) and are region of interest (ROI) and whole brain voxel-based 21 normal controls (10 men, 11 women) were involved in analysis. ROI has been used in a majority of previous this study. The patients were recruited from the Institute of Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Mental Health, Second Xiangya Hospital of Central South University, China, from February 2005 to July 2005.
ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi Psychiatrists administered a clinical interview using the 3½ðl1 À hliÞ2 þ ðl2 À hliÞ2 þ ðl3 À hliÞ2Š ; Positive and Negative Syndrome Scale (PANSS) [7]. The ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi total score of PANSS was between 43 and 113 (72.16721.92).
All patients met the following inclusion criteria: (1) DSM-IV criteria for schizophrenia; (2) duration of illness must be less than 2 years and the maximum allowed exposure to For each participant, the b¼0 image was first normalized to antipsychiatric treatment is 2 weeks in the year preceding the standard Montreal Neurological Institute (MNI) space study entry or 6 weeks lifetime exposure [8]; (3) age between using statistical parameters maps (SPM2) (Wellcome De- 18 and 45 years; (4) absence of neurological or significant partment of Cognitive Neurology, London, UK), and then physical disorders; (5) absence of dependence on alcohol or the transformation matrix was applied to the FA map in illicit drugs; (6) no history of receiving electroconvulsive order to normalize the FA map to the standard MNI space.
therapy (ECT). Normal controls were recruited from All images were re-sampled with a final voxel size of 2 Â2 Â the community and had no history of psychiatric disorder.
2 mm3. Further, each FA map was spatially smoothed by an They also met the inclusion criteria (3), (4), (5) and (6).
8-mm full-width at half the maximum Gaussian kernel in Approval was obtained from the ethical committee of order to decrease spatial noise and compensate for the the hospital. Informed consents were obtained from all The ages of the patients were between 18 and 42 years (23.7175.47 years) and length of illness was between 6 and Intergroup comparisons (controls vs. patients) were carried 24 months (10.3376.22 months). The education level was out using a two-sample t-test analysis in a voxel-by-voxel between 9 and 16 years (13.1472.12 years). All the patients manner. Voxels with Z43.47 (Po0.001 uncorrected for were receiving antipsychotic medication during the time of multiple comparisons) and clusters of size 430 voxels were imaging. Four patients were receiving typical antipsychotics considered as significant differences between the patients (sulpiride), and 17 patients were receiving atypical anti- and controls. For visualization of the regions showing psychotics (clozapine, risperidone, olanzapine, seroquel, significantly different FA values between the two groups, and aripiprazole). All medication doses were converted to the significant clusters were superimposed onto SPM2’s chlorpromazine equivalence (364.067143.75 mg/day). The spatially normalized template brain.
ages of control individuals were between 19 and 33 years(25.0574.58 years). The education level of the controls wasbetween 7 and 18 years (15.1472.57 years). All participants were right-handed. No significant differences in age, as well In a voxel-by-voxel contrast, several regions showed as sex, were observed between the patient group and the significantly lower FA values in the patients than in the controls (uncorrected Po0.001, cluster size 430 voxels).
The coordinates and Z scores of peak voxels for theseregions are briefly listed in Table 1. The white matter areas that showed lower FA values are the bilateral cerebral Magnetic resonance imaging was performed on 1.5-T peduncle (Fig. 1A), bilateral hippocampal gyrus (Fig. 1B), magnetic resonance scanner (GE signal 1.5 T Twinspeed, right corona radiate (Fig. 1C), bilateral precuneus (Fig. 1D), Milwaukee, Wisconsin, USA). The standard head coil was right (Fig. 1E) and left (Fig. 1F) cuneus, left frontoorbital used for radio frequency transmission and reception of the area (Fig. 1G) and right middle frontal lobe (Fig. 1H), left nuclear magnetic resonance signal. Head motion was (Fig. 1I) and right (Fig. 1J) inferior temporal gyrus, right minimized with restraining foam pads provided by the superior cerebellar peduncle (Fig. 1K), bilateral insular (Fig. 1L), right anterior cingulum (Fig. 1M). No FA value Diffusion weighted imaging was acquired with single- was significantly higher in the patients than those in shot echo planar imaging sequence in alignment with the anterior–posterior commissure plane. The diffusion sensi-tizing gradients were applied along 13 non-collineardirections (b¼1000 s/mm2), together with an acquisition without diffusion weighting (b¼0). Thirty contiguous axial The present DTI studies have strongly suggested that the slices were acquired with a slice thickness of 4 mm and reduced FA is not regional but distributed in the whole no gap. The acquisition parameters were as follows: brain of a schizophrenic patient, extending from the frontal TR¼12 000 ms; TE¼105 ms; matrix¼128 Â 128; FOV¼24 Â to occipital brain regions. These findings of DTI studies in first-episode schizophrenia are consistent with previousreports on chronic schizophrenia.
DTI studies have documented that the integrity of the cingulum bundle is disrupted in patients with schizophre- The diffusion tensor matrix was calculated according to the nia compared with normal controls [11–13]. Wang et al. [14] Stejskal and Tanner equation [9]. Three pairs of eigenvalues and Ardekani et al. [15] report a reduced FA in the bilateral (l1, l2, l3) and eigenvectors can be obtained by diagona- anterior cingulum bundle in schizophrenia patients. In the lization of the tensor matrix. The principal direction at each present study, we detected a significant reduction of FA point was given by the eigenvector that corresponds to the value in the right anterior cingulum bundle of first-episode largest eigenvalue, and FAs [10] were calculated according schizophrenic patients compared with that of normal Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
WHITE MATTER INTEGRITY DISRUPTION IN SCHIZOPHRENIA Table 1 Regions with reduced fractional anisotropy values in schizophrenia patients compared with those in normal controls (uncorrected Po0.001) aCluster size is in the unit of voxel.
L/R; left/right; MNI, Montreal Neurological Institute.
Significant reduction in diffusion anisotropy has been found in the white matter of the frontal, temporal and parietal areas in schizophrenic patients [16,18,19]. Similarly,in the present study, we observed that the FA was significantly reduced in the white matter areas of the frontal lobes, inferior temporal gyrus and parietal lobes in bothhemispheres in schizophrenic patients compared with that of controls. Large-scale disruption of white matter integrity in our present study further illuminated that those changesin patients with schizophrenia should be sought at thesupra-regional rather than regional level. Both struc- tural and functional abnormalities of frontoparietal and frontotemporal networks have been described in schizo-phrenia [20,21], which may constitute a basis for the impairment of cognitive functions, such as selective attention, language processing and the execution of work- ing memory. Deficits in these cognitive functions arebelieved to be a cardinal feature of the pathophysiology of The fact that there are similar findings in first-episode and chronic schizophrenia suggested that white matter diffusionabnormalities are present at early illness onset. The present findings of reduced FA in the bilateral hippocampus are not consistent with a previous report by Begre et al. [5], who has examined FA of the hippocampus by using ROI analysis in seven first-episode schizophrenic patients and normal Fig. 1 Transverse slices through regions with reduced fractional aniso- controls. This discrepancy may be relevant to a different tropy values in white matter in schizophrenic patients compared with approach of data analysis or other conditions.
those in controls. (A) Bilateral cerebral peduncle, (B) bilateral hippocam- Most DTI studies in schizophrenia find positive results, pus, (C) right corona radiata, (D) bilateral precuneus, (E) right cuneus, although there are many negative results compared with (F) left cuneus, (G) left frontoorbital area, (H) right middle frontal lobe, controls. A positive result was obtained for some regions by (I) left inferior temporal gyrus, ( J) right inferior temporal, (K) superiorcerebellar peduncle, (L) bilateral insular, (M) right anterior cingulum.
some groups but this result was not obtained by othergroups in the same region. A long history of antipsychoticsmedication and the length of illness are possible confound- controls. The anterior cingulum bundle is central to limbic ing factors in the studies of DTI. Therefore, all the patients circuitry [16] and its dysfunction links to attention deficits in we recruited were first-episode schizophrenic patients schizophrenia. The most common interpretation for reduced whose exposure to medication was limited and length of FA is that it reflects lower white matter ‘integrity’. Reduced illness was short. Taken together, the similar distribution FA in white matter is consistent with the idea that regions of the reduced FA between patients with chronic or schizophrenia involves the disruption of cortical regions, first-episode schizophrenia and normal controls suggested which is supported by studies in other modalities. Con- that white matter integrity of the whole brain may not be sistent with our finding of the anterior cingulum bundle, a caused by the effect of antipsychotics and the length of previous report has found that cingulotomy patients with illness. Consistent with this notion, Foong et al. [23], Kubicki small bilateral lesions in the anterior cingulate gyrus show et al. [11,13], and Minami et al. [18] find that the FA is not deficits of attention and executive dysfunction, which are correlated with the medication dose or length of illness of prominent features of schizophrenia [17].
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