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.     

精神分裂症首次发病患者的脑扩散张量成像研究

目的 利用磁共振扩散张量成像(DTI)技术研究未经药物治疗的精神分裂症首次发病(以下简称首发)患者主要脑区白质纤维束的异常.方法 选取26例首发精神分裂症患者(患者组)和20名健康志愿者(对照组)行脑DTI扫描(两组均为右利手),测量胼胝体膝部、压部、双侧额叶白质、扣带束前部及海马头的部分各向异性(FA)值.结果 (1)对照组左侧扣带束FA值(0.428±0.067)大于右侧(0.375±0.079;P＜0.05).(2)患者组两侧相对应感兴趣区FA值差异均无统计学意义(P＞0.05).(3)患者组左右侧胼胝体压部FA值(均为0.734±0.085)、左右侧扣带束前部FA值(0.300±0.068和0.306 4±0.062)均低于对照组(0.785±0.045,0.428±0.067,0.375±0.079;均P＜0.05).结论 首发精神分裂症患者存在双侧扣带束、胼胝体压部白质纤维束的受损,支持脑内连接异常假说.     

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.     

Alterations of white matter integrity related to motor activity in schizophrenia

Altered structural connectivity is a key finding in schizophrenia, but the meaning of white matter alterations for behavior is rarely studied. In healthy subjects, motor activity correlated with white matter integrity in motor tracts. To explore the relation of motor activity and fractional anisotropy (FA) in schizophrenia, we investigated 19 schizophrenia patients and 24 healthy control subjects using Diffusion Tensor Imaging (DTI) and actigraphy on the same day. Schizophrenia patients had lower activity levels (AL). In both groups linear relations of AL and FA were detected in several brain regions. Schizophrenia patients had lower FA values in prefrontal and left temporal clusters. Furthermore, using a general linear model, we found linear negative associations of FA and AL underneath the right supplemental motor area (SMA), the right precentral gyrus and posterior cingulum in patients. This effect within the SMA was not seen in controls. This association in schizophrenia patients may contribute to the well known dysfunctions of motor control. Thus, structural disconnectivity could lead to disturbed motor behavior in schizophrenia.     

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.     

Age-related deficits in fronto-temporal connections in schizophrenia: a diffusion tensor imaging study

OBJECTIVE: Impairment of white matter connecting frontal and temporal cortices has been reported in schizophrenia. Yet, not much is known about the effects of age on fibers connecting these brain regions. Using diffusion tensor imaging tractography, we investigated the relationship between age and fiber integrity in patients with schizophrenia vs. healthy adults. METHODS: DTI tractography was used to create 3D reconstructions of the cingulum, uncinate and inferior occipito-frontal fasciculi in 27 patients with schizophrenia and 34 healthy volunteers (23-56 years of age, group-matched on age). Fractional anisotropy (FA), describing fiber integrity, was then calculated along the entire length of these tracts, and correlated with subjects' age. RESULTS: Patients revealed a significant decline in FA with age in both the cingulum and uncinate, but not in the inferior occipito-frontal fasciculi. No statistically significant correlations were found in these fiber bundles in controls. CONCLUSIONS: These results suggest an age-associated reduction of frontal-temporal connectivity in schizophrenia, but not in healthy controls.     

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.     

Diffusion tensor imaging in schizophrenia: relationship to symptoms

In this diffusion tensor imaging (DTI) study, the authors investigated white matter integrity in schizophrenia and the relationships between white matter alterations and specific symptoms of the disorder. We compared DTI images of 25 schizophrenia patients and 25 matched healthy controls and performed voxel-wise correlational analyses using the patient's DTI data and their severity scores of positive and negative symptoms. We found diffuse deficits in multiple types of white matter tracts in schizophrenia, and an inverse relationship of DTI fractional anisotropy (FA) values with positive symptom scores in association fibers, supporting a "disconnection" hypothesis of positive symptoms in schizophrenia.     

White matter organization and neurocognitive performance variability in schizophrenia

BackgroundWhite matter alterations in schizophrenia are associated with deficits in neurocognitive performance. Recently, across task within-individual variability (WIV) has emerged as a useful construct for assessing the profile in cognitive performance in schizophrenia. However, the neural basis of WIV has not been studied in patients with schizophrenia.MethodsTwenty-five patients with schizophrenia (SZ) and 27 healthy comparison subjects (HC) performed a computerized neurocognitive battery (CNB) and underwent diffusion tensor imaging (DTI). WIV for performance accuracy and speed on the CNB was calculated across-tasks. Voxel-wise group comparisons of white matter fractional anisotropy (FA) were performed using tract-based spatial statistics (TBSS). The relationship between accuracy and speed WIV on the CNB and white matter FA was examined within the regions that differentiated patients and healthy comparison subjects.ResultsSZ had higher WIV for performance accuracy and speed as compared to HC. FA in SZ compared to HC was reduced in bilateral frontal, temporal and occipital white matter including a large portion of the corpus callosum. In white matter regions that differed between patients and comparison subjects, higher FA in the left cingulum bundle and left fronto-occipital fasciculus were associated with lower CNB speed WIV for HC, but not SZ. Accuracy WIV was not associated with differences in white matter FA between SZ and HC.ConclusionsWe provide evidence that WIV is greater in patients with SZ and that this greater within-individual variability in performance in patients is associated with disruptions of WM integrity in specific brain regions.     

White Matter Abnormalities in Schizophrenia and Schizotypal Personality Disorder

Prior diffusion tensor imaging (DTI) studies examining schizotypal personality disorder (SPD) and schizophrenia, separately have shown that compared with healthy controls (HCs), patients show frontotemporal white matter (WM) abnormalities. This is the first DTI study to directly compare WM tract coherence with tractography and fractional anisotropy (FA) across the schizophrenia spectrum in a large sample of demographically matched HCs (n = 55), medication-naive SPD patients (n = 49), and unmedicated/never-medicated schizophrenia patients (n = 22) to determine whether (a) frontal-striatal-temporal WM tract abnormalities in schizophrenia are similar to, or distinct from those observed in SPD; and (b) WM tract abnormalities are associated with clinical symptom severity indicating a common underlying pathology across the spectrum. Compared with both the HC and SPD groups, schizophrenia patients showed WM abnormalities, as indexed by lower FA in the temporal lobe (inferior longitudinal fasciculus) and cingulum regions. SPD patients showed lower FA in the corpus callosum genu compared with the HC group, but this regional abnormality was more widespread in schizophrenia patients. Across the schizophrenia spectrum, greater WM disruptions were associated with greater symptom severity. Overall, frontal-striatal-temporal WM dysconnectivity is attenuated in SPD compared with schizophrenia patients and may mitigate the emergence of psychosis.Key words: DTI, MRI, schizotypal personality disorder, schizophrenia, psychosis, white matter, genu, cingulum, inferior longitudinal fasciculus     

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.     

Diffusion tensor imaging measures of normal appearing white matter in patients who are aging,or have amnestic mild cognitive impairment,or Alzheimer’s disease

To evaluate whether cerebral white matter integrity is related to cognitive function, and whether diffusion tensor imaging (DTI) could differentiate amnestic mild cognitive impairment (aMCI) from Alzheimer’s disease (AD), 12 patients with AD, 12 with aMCI, and 12 controls were recruited for this study. Cognitive functions of all subjects were assessed using the Mini-Mental State Examination (MMSE) and AD Assessment Scale – Cognitive Subscale (ADAS-Cog). DTI studies were acquired, and fractional anisotropy (FA) and mean diffusivity (MD) values of normal-appearing white matter (NAWM) in multiple brain regions were obtained. Results showed that MMSE and ADAS-Cog subscores were significantly associated with white matter integrity of the temporal-parietal lobes. A decrease in FA values and an increase in MD values in multiple cortical regions were confirmed in patients with AD compared to controls. MD values in the posterior region of the corpus callosum in aMCI differed from those of early AD. Significant reductions of FA values in the NAWM of the parietal lobe was observed in aMCI compared to controls. Our data indicate that the microstructural white matter integrity in the temporal-parietal lobes is gradually impaired in the progressive process of AD, and that splenium MD values could be used as a biomarker differentiating aMCI from AD.     

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.     

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.     

精神分裂症患者全脑白质纤维弥散张量成像的初步研究

目的运用能够提示白质纤维(white matter,WM)完整性的弥散张量成像(diffusion tensor imaging,DTI)技术,探讨精神分裂症患者全脑白质纤维是否受到损害。方法对21例精神分裂症患者(患者组)和21名健康人(对照组)进行全脑DTI扫描,用SPM2(Statistical Parametric Maps,SPM)软件对图像进行处理,采用以像素为基础的分析方法(voxel-based analysis,VBA)对两组的分数各向异性(fractional anisotropy,FA)值进行组间比较。结果患者组下列脑区的FA值显著低于对照组(P<0·001):左侧额眶区和右侧额中回的白质、双侧颞下回白质、双侧顶叶内侧白质、右侧前扣带、双侧海马、双侧大脑脚、双侧岛叶、右侧放射冠和右侧小脑上脚。结论精神分裂症多个部位脑白质纤维的完整性受到破坏。     

Cingulate fasciculus integrity disruption in schizophrenia: a magnetic resonance diffusion tensor imaging study.

Evidence suggests that a disruption in limbic system network integrity and, in particular, the cingulate gyrus (CG), may play a role in the pathophysiology of schizophrenia; however, the cingulum bundle (CB), the white matter tract furnishing both input and output to CG, and the most prominent white matter fiber tract in the limbic system, has not been evaluated in schizophrenia using the new technology of diffusion tensor imaging (DTI).We used line scan DTI to evaluate diffusion in the CB in 16 male schizophrenia patients and 18 male control subjects, group-matched for age, parental socioeconomic status, and handedness. We acquired 4-mm-thick coronal slices through the entire brain. Maps of fractional anisotropy (FA) were generated to quantify diffusion within the left and right CB on eight slices that included the central portion of the CB.Results showed group differences, bilaterally, in area and mean FA for CB, where patients showed smaller area and less anisotropy than controls. For patients, decreased left CB correlated significantly with attention and working memory measures as assessed by the Wisconsin Card Sorting Test.These data provide strong evidence for CB disruptions in schizophrenia, which may be related to disease-related attention and working memory abnormalities.     

A DTI study of white matter microstructure in individuals at high genetic risk for schizophrenia

Structural brain developmental anomalies, particularly those in frontotemporal white matter pathways, may have a genetic component and place people at increased risk for schizophrenia. The current study employed Diffusion Tensor Imaging (DTI) to measure fractional anisotropy (FA) as a quantitative indicator of white matter integrity. We examined twenty-two participants at high genetic risk for schizophrenia (HR), 23 people with schizophrenia (most of whom were family members of those at HR) and 37 non-psychiatric controls for comparison. In those at HR, reduced FA was observed in the cingulate and angular gyri bilaterally. In a few regions, FA was higher in HR participants than in comparison participants. These regional variations in FA might reflect differences in white matter development from comparison participants. Our data provide some evidence that abnormal white matter integrity may be detectable before the onset of a psychotic illness, although longitudinal studies are necessary to determine whether these individuals at genetic risk with abnormal FA will develop illness and whether these changes are associated with the genetic risk for the disorder.     

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.     

首发未服药精神分裂症患者脑弥散张量成像的基于体素分析

目的分析首发未服药精神分裂症患者脑白质完整性的变化。 方法对40例首发未服药精神分裂症患者和68例健康对照者进行脑弥散张量磁共振成像检查,以DTI-studio软件和统计参数图(SPM)软件对所得图像进行预处理,得到的各向异性分数(FA)图像在SPM软件中进行两样本t检验,获得两组患者FA值差异统计参数图。 结果在P值小于0.001（未校正）水平下,首发未服药精神分裂症患者右侧杏仁核区(MNI：24,2,-14,cluster=347 voxels)、双侧前扣带区(MNI:6,42,2,cluster=586 voxels)、右侧前额叶眶上回区域(MNI：20,18,-10,cluster= 166 voxels)白质FA值较健康对照者下降,且未发现前者有脑区白质FA值较后者增高。 结论精神分裂症患者皮层一边缘系统环路存在结构连接障碍,这可能是精神分裂症的神经机制。