White matter damage is associated with memory decline in chronic alcoholics: A quantitative diffusion tensor tractography study

Back to table of contents Previous article Next article EditorialFull AccessNeural Networks in SchizophreniaJohn G. Csernansky M.D.Will J. Cronenwett M.D.John G. Csernansky M.D.Search for more papers by this authorWill J. Cronenwett M.D.Search for more papers by this authorPublished Online:1 Aug 2008https://doi.org/10.1176/appi.ajp.2008.08050700AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail As methods for high-resolution MRI continue to develop, our understanding of changes in brain structure in patients with psychiatric disorders improves. In patients with schizophrenia, decreases in the gray matter volume of a variety of cortical and subcortical brain regions have been repeatedly observed (1) . Two articles in this issue of the Journal add to this literature and go further by strengthening the hypothesis that schizophrenia involves abnormalities in specific cortical-subcortical networks. Ellison-Wright et al. (2) present a meta-analysis of MRI studies that reveals different patterns of structural changes in first-episode and chronic schizophrenia. Adapting a technique developed to combine data from functional MRI studies (3) , the authors evaluated group differences in specific brain regions in reference to a three-dimensional coordinate system. The result of this adaptation, called anatomical likelihood estimation, adds to a growing literature on probabilistic approaches to neuroanatomical computation (4) . In patients with first-episode schizophrenia, Ellison-Wright et al. found evidence for decreased gray matter volume in the hippocampus, the caudate nucleus, the thalamus (mediodorsal nucleus), the insula, the anterior cingulate gyrus, the inferior frontal gyrus, and the cerebellum. Subcortical changes were similar in patients with chronic schizophrenia, but cortical changes were even more extensive. As Ellison-Wright et al. note, this pattern of abnormality implicates a neural circuit originating with limbic input to the striatum, then the thalamus, and finally to the prefrontal and cingulate cortex ( Figure 1 ). Abnormalities of thalamocortical circuitry have previously been implicated in schizophrenia, particularly in reference to the pathophysiological concept of cognitive dysmetria (5) . Figure 1. Gray Matter Deficits and Thalamocorticostriatal Circuit Dysfunction in Schizophrenia aa The diagram on the left illustrates the circuit pathways. On the right is a diagrammatic representation of thalamocorticostriatal circuits superimposed on regions of gray matter showing signal decrease in both first-episode schizophrenia (yellow) and chronic schizophrenia (red). The thalamus (blue triangle) sends thalamocortical projections to the cortex (blue arrow). Cortical regions project (green arrow) to the caudate (pink circle) and then back to the thalamus (orange arrow). Components of these circuits show anatomical changes in schizophrenia, with the caudate head showing gray matter deficits in first-episode schizophrenia and more widespread cortical changes in chronic schizophrenia. The thalamus shows gray matter deficits in both first-episode and chronic schizophrenia. Also in this issue, Friedman et al. (6) report on their use of diffusion tensor imaging to examine the pattern of white matter changes in patients with first-episode and chronic schizophrenia. Using fractional anisotropy (FA) to assess the integrity of white matter connections (7) , they found evidence in first-episode patients for decreased connectivity only in the inferior longitudinal fasciculus (at the trend level), while chronic patients showed a broader pattern of white matter disturbances ( Figure 2 ). Figure 2. Regions of Fractional Anisotropy (FA) Reductions in Schizophrenia aa Relative to healthy comparison subjects, patients with first-episode schizophrenia showed trend-level FA reductions in the left and right inferior longitudinal fasciculus. Patients with chronic schizophrenia showed significant FA reductions in the right forceps minor and the left inferior longitudinal fasciculus. ILF=inferior longitudinal fasciculus; GCC=genu of corpus callosum; SCC=splenium of corpus callosum. The results of Friedman’s study, to date the largest to directly examine FA in first-episode and chronic schizophrenia patients, suggest a number of intriguing interpretations. As they note, one explanation may be that pathological white matter abnormalities may be present but too subtle to detect with current imaging methods in first-episode schizophrenia. Alternatively, white matter changes may develop as the disease process of schizophrenia progresses.Taken together, the results of these two studies provide strong support for the hypothesis that schizophrenia involves abnormalities in networks of brain regions. They further suggest that such abnormalities may be progressive in at least some patients. If the “progression” hypothesis is confirmed in future studies, we must redouble our efforts at early and effective intervention for this potentially disabling disorder.Address correspondence and reprint requests to Dr. Csernansky, Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, 446 E. Ontario, Suite 7-200, Chicago, IL 60611; [email protected] (e-mail). Editorial accepted for publication May 2008 (doi: 10.1176/appi.ajp.2008.08050700).Dr. Csernansky has consulted for Eli Lilly, Sanofi-Aventis, and HoustonPharma. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships. Dr. Cronenwett reports no competing interests.

Objectives: We aim to investigate whether multi-dimensional diffusion tensor imaging (DTI) measures can sensitively identify different cognitive status of cerebral small vessel disease (CSVD) and to explore the underlying pattern of white matter disruption in CSVD.Methods: Two hundred and two participants were recruited, composed of 99 CSVD patients with mild cognitive impairment (VaMCI) and 60 with no cognitive impairment (NCI) and 43 healthy subjects as normal controls (NC). Full domain neuropsychological tests and diffusion-weighted imaging were performed on each subject. DTI metrics such as fractional anisotropy (FA), mean diffusivity (MD), the skeletonized mean diffusivity (PSMD), and structural brain network measures including network strength, global efficiency (EGlobal), and local efficiency (ELocal) were calculated. Region of interest (ROI) analysis of 42 white matter tracts was performed to examine the regional anatomical white matter disruption for each group.Results: Significant differences of multiple cognitive test scores across all cognitive domains especially processing and executive function existed among the three groups. DTI measures (FA, MD, and PSMD) showed significant group difference with the cognitive status changing. FA and EGlobal showed significant correlation with processing speed, executive function, and memory. ROI analysis found that white matter integrity impairment occurred from the preclinical stage of vascular cognitive impairment (VCI) due to CSVD. These lesions in the NCI group mainly involved some longitudinal fibers such as right superior longitudinal fasciculus (SLF-R), right superior fronto-occipital fasciculus (SFO-R), and right uncinate fasciculus (UNC-R), which might be more vulnerable to the cerebrovascular aging and disease process.Conclusions: DTI measures are sensitive neuroimaging markers in detecting the early cognitive impairment and able to differentiate the different cognitive status due to CSVD. Subtle changes of some vulnerable white matter tracts may be observed from the preclinical stage of VCI and have a local to general spreading pattern during the disease progression.

Psychotic symptoms are core clinical features of schizophrenia. We tested recent hypotheses proposing that psychotic, or positive, symptoms stem from irregularities in long-range white matter tracts projecting into the frontal cortex, and we predicted that selective dopamine D2/3 receptor blockade would restore white matter. Between December 2008 and July 2011, antipsychotic-naive patients with first-episode schizophrenia and matched healthy controls underwent baseline examination with 3 T MRI diffusion tensor imaging and clinical assessments. We assessed group differences of fractional anisotropy (FA) using voxelwise tract-based spatial statistics (TBSS) and anatomic region of interest (ROI)-based analyses. Subsequently, patients underwent 6 weeks of antipsychotic monotherapy with amisulpride. We repeated the examinations after 6 weeks. We included 38 patients with first-episode schizophrenia and 38 controls in our analysis, and 28 individuals in each group completed the study. At baseline, whole brain TBSS analyses revealed lower FA in patients in the right anterior thalamic radiation (ATR), right cingulum, right inferior longitudinal fasciculus and right corticospinal tract (CT). Fractional anisotropy in the right ATR correlated with positive symptoms (z = 2.64, p= 0.008). The ROI analyses showed significant associations between positive symptoms and FA of the frontal fasciculi, specifically the right arcuate fasciculus (z = 2.83, p= 0.005) and right superior longitudinal fasciculus (z = -3.31, p= 0.001). At re-examination, all correlations between positive symptoms and frontal fasciculi had resolved. Fractional anisotropy in the ATR increased more in patients than in controls (z = -4.92, p< 0.001). The amisulpride dose correlated positively with FA changes in the right CT (t= 2.52, p= 0.019). Smoking and a previous diagnosis of substance abuse were potential confounders. Long-term effects of amisulpride on white matter were not evaluated. Antipsychotic-naive patients with schizophrenia displayed subtle deficits in white matter, and psychotic symptoms appeared specifically associated with frontal fasciculi integrity. Six weeks of amisulpride treatment normalized white matter. Potential remyelinating effects of dopamine D2/3 receptor antagonism warrant further clarification.

Reduced white matter integrity and facial emotion perception in never-medicated patients with first-episode schizophrenia: A diffusion tensor imaging study

Network specific change in white matter integrity in mesial temporal lobe epilepsy

Patients with type 2 diabetes mellitus (T2DM) have usually been found cognitive impairment associated with brain white matter (WM) abnormalities. However, findings have varied across studies, and any potential relationship with Alzheimer's disease (AD) remains unclear. The aim of this study was to assess the whole-brain WM integrity of T2DM patients and to compare our findings with those of published AD cases. In this study, we used diffusion tensor imaging (DTI) combined with tract-based spatial statistics (TBSS) to investigate whole-brain WM abnormalities in 48 T2DM patients and 48 healthy controls. The effects of age and gender were also evaluated. In our study, significantly decreasing FA and increasing MD and DA values (P<0.05) were found in some WM regions closely related to the default mode network (DMN), including cingulum, the right frontal lobe involving the right uncinate fasciculus (UF), bilateral parietal lobes involving the superior longitudinal fasciculus (SLF) and the inferior longitudinal fasciculus (ILF), and the right middle temporal gyrus (MTG) involving the UF and the ILF. We also found abnormalities in the thalamus involving the fornix (FX), anterior thalamic radiation (ATR), and posterior thalamic radiation (PTR). The damaged regions above are similar to those found in patients with AD, as reported in previous studies. The present study not only provides useful information about the WM regions and tracts affected by T2DM but also offers insight into the underlying neuropathological process in T2DM patients and the relationship between T2DM and AD.

The functional organization of white matter (WM) tracts is not well characterized, especially in patients with intrinsic brain tumors where complex patterns of tissue injury, compression, and neuroplasticity may be present. This study uses diffusion tensor imaging (DTI) to investigate the relationships between WM tract disruption and cognitive deficits in glioma patients. Seventy-nine patients with glioma underwent preoperative DTI and neuropsychological testing. Thirteen WM tracts were reconstructed bilaterally. Fractional anisotropy and streamline number were obtained for each tract as indices of connectivity. Univariate regression models were used to model the association between WM tract connectivity and neuropsychological outcomes. Glioma patients exhibited variable injury to WM tracts and variable cognitive deficits on validated neuropsychological tests. We identified 16 age-adjusted associations between WM tract integrity and neuropsychological function. The left inferior frontal-occipital fasciculus (IFOF) predicted list learning and dominant-hand fine motor dexterity. The right IFOF predicted non-dominant-hand fine motor dexterity and visuospatial index scores. The left inferior longitudinal fasciculus (ILF) predicted immediate memory list learning and index scores. The right ILF predicted non-dominant-hand fine motor dexterity and backward digit span scores. The left superior longitudinal fasciculus (SLF) I predicted processing speed. The left SLF III predicted list learning, immediate memory index scores, phonemic fluency, and verbal abstract reasoning. The left cingulum predicted processing speed. The right anterior AF predicted verbal abstract reasoning. WM tract disruption predicts cognitive dysfunction in glioma patients. By improving knowledge of WM tract organization, this analysis may guide maximum surgical resection and functional preservation in glioma patients.

Diffusion tensor imaging with tractography to predict memory deficits in patient groups with temporal lobe lesions.

BackgroundNew daily persistent headache (NDPH) is a rare primary headache disorder characterized by daily and persistent sudden onset headaches. The pathogenesis of NDPH remains unclear, and there are few white matter imaging studies related to NDPH. The purpose of this study was to investigate the micro-structural abnormalities of white matter in NDPH and provided insights into the pathogenesis of this disease based on tract-based spatial statistics (TBSS).MethodsTwenty-one patients with NDPH and 25 healthy controls (HCs) were included in this study. T1 structural and diffusion magnetic resonance imaging (MRI) were acquired from all participants. Differences in the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) between patients with NDPH and HCs were investigated using TBSS analysis.ResultsSignificantly decreased FA, increased MD and RD were found in patients with NDPH compared to HCs. White matter regions overlaid with decreased FA, increased MD and RD were found in 16 white matter tracts from the Johns Hopkins University ICBM-DTI-81 White-Matter Atlas and Johns Hopkins University White-Matter Tractography Atlas. Specifically, these white matter regions included the right anterior thalamic radiation (ATR), body of the corpus callosum (BCC), bilateral cingulum, left hippocampal cingulum (CGH), left corticospinal tract (CST), forceps major, fornix, left inferior fronto-occipital fasciculus (IFOF), bilateral inferior longitudinal fasciculus (ILF), left posterior limb of the internal capsule (PLIC), right retrolenticular part of the internal capsule (RPIC), splenium of the corpus callosum (SCC), right superior longitudinal fasciculus (SLF) and left uncinate fasciculus (UF). After Bonferroni correction, there were no correlations between the FA, MD, AD and RD values and the clinical characteristics of patients with NDPH (p > 0.05/96).ConclusionThe results of our research indicated that patients with NDPH might have widespread abnormalities in the white matter of the brain.

BackgroundRecent Magnetic Resonance Imaging (MRI) studies on schizophrenia suggest that auditory verbal hallucinations (AVH) might be caused by alterations in connectivity of frontal and temporoparietal language-related areas.3 as well as in connectivity of the default mode network (DMN).1 Therefore, diffusion tensor imaging (DTI) of white matter fiber tracts, subserving anatomical connections between distant and proximal brain regions, could offer complementary information for understanding the anatomical underpinnings of AVH.MethodsTract-based spatial statistics (TBSS) allows voxel-wise analysis of multi-subject diffusion data based on fractional anisotropy (FA), assessing microstructural properties of white matter tracts. This study investigates brain white matter tracts in 85 schizophrenia patients and 111 healthy, matched controls using TBSS analysis. Patients were grouped into sub-groups (hallucinating and non-hallucinating) based on the Positive and Negative Syndrome Scale (PANSS), with a cut-off PANSS P3 >= 3 in a 12 months period. Additionally, a comparison between the whole patient sample and controls was performed. The whole-brain analysis was performed with permutation analysis of linear models (PALM).2 Two-tailed t-test was used for group comparison of the patients and controls and a 2 x 2 factorial design was used for hemispheric comparison between patients and controls.ResultsTBSS results shows significantly lower fractional anisotropy in the right inferior longitudinal fasciculus in schizophrenia patients in comparison to healthy controls (FDR correction p < 0.05). However, after subtracting non-hallucinating patients from the group this effect was no longer present. Hemispheric comparison between patients and healthy controls revealed wide- spread FA reduction in several white matter pathways such as: the corpus callosum (genu and body), cingulum cortex, inferior longitudinal fasciculus, superior corona radiata, anterior thalamic radiation (FDR correction p < 0.05). This effect was also present after excluding the non-hallucinating patients from the sample.DiscussionThe present findings indicate reduced white matter integrity in schizophrenia patients compared with controls in the inferior longitudinal fasciculus. However, this observation is most likely not related to hallucination proneness since it was not present when comparing the hallucinating patient subgroup with the control group. Hemispheric comparison between patients and controls in both the whole data sample as well as hallucinating group showed significant differences in several white matter pathways. This could indicate that schizophrenia patients (with or without AVH) have altered FA differences between the hemispheres. More research is needed to further understand the implications of these findings.

Objective: To analyze age-related change in cerebral matter tract, especially fractional anisotropy, based on automating fiber-tract quantification(AFQ). Methods: A total of 64 years old normal persons and 43 young volunteers were enrolled respectively from the Affiliated Drum Tower Hospital of Nanjing University Medical School and community from January 2015 to June 2016.All of them underwent MRI scan, which included DTI and 3D T(1)WI sequence .All cases were divided into 3 groups according to their ages, the young group 20-35 years old, the middle old group 60-75 years old, the old group 76-90 years old.AFQ was used to identify 20 major white matter tracts in brains of all subjects and make measurements at anatomically equivalent locations along their trajectories. Results: The FA change trend of each fiber was similar among three groups. The old and the middle old group had different FA value in both sides of inferior fronto-occipital fasciculus(left t=-2.73, right t=-6.12, P<0.05), thalamic radiation(left t=-4.79, right t=-19.61, P<0.05), arcuate(left t=10.53, right t=-2.72, P<0.05), callosum forceps(genu t=-2.66, splenium t=28.64, P<0.05), cingulum(left t=-4.53, right t=-2.22, P<0.05)and right corticospinal tract(t=3.10, P<0.05), among which each location of callosum forceps minor was different between the old group and the young group, and this area decreased in the middle group. The old group had different FA value in both sides of uncinate fasciculus(left t=-4.52, right t=-4.53, P<0.05), left corticospinal tract(t=-2.19, P<0.05)and right inferior longitudinal fasciculus(t=11.12, P<0.05). Compared to the young group, there was no statistical difference in the FA of both superior longitudinal fasciculus and left inferior longitudinal fasciculus in the old and the middle old group. Conclusion: AFQ has an impact on the further specific study of the age-related white matter tract.

Purpose: The aim of this study was to evaluate microstructural changes of major white matter (WM) tracts in patients with vascular cognitive impairment (VCI).Method: Diffusion tensor imaging (DTI) data were obtained from 24 subjects with subcortical ischemic vascular disease (SIVD), including 13 subjects with VCI-no dementia (VCIND) and 11 subjects with normal cognition (as a control group). A tract-based spatial statistics approach was performed to investigate WM microstructure in VCIND by integrating multiple indices including fractional anisotropy (FA) and mean diffusivity (MD), which are intra-voxel metrics, and local diffusion homogeneity (LDH), which is an inter-voxel metric.Results: The VCIND group had decreased FA and increased MD values throughout widespread WM areas predominately in the corpus callosum, bilateral internal capsule/corona radiata/posterior thalamic radiation/inferior fronto-occipital fasciculus and right inferior/superior longitudinal fasciculus. There was a slight discrepancy between the distribution of areas with decreased FA and LDH. The FA, MD and LDH values were significantly correlated with cognitive test results. According to a WM tract atlas, 10 major tracts were identified as tracts of interest in which three diffusion metrics simultaneously differed between groups, including bilateral anterior thalamic radiation, forceps minor, right corticospinal tract, bilateral inferior fronto-occipital fasciculus, left inferior and superior longitudinal fasciculus, and bilateral uncinate fasciculus. Receiver operating characteristic (ROC) analysis demonstrated the feasibility of using diffusion metrics along the forceps minor and left anterior thalamic radiation for separating two groups.Conclusion: The results suggest WM microstructural abnormalities contribute to cognitive impairments in SIVD patients. DTI parameters may be potential biomarkers for detecting VCIND from SIVD.

BackgroundVerbal memory is one of the most affected cognitive domains in patients with schizophrenia and related psychoses. Several studies have found associations between cognitive abilities and white matter fractional anisotropy (FA) in schizophrenia; however, only a few tractography studies have investigated FA relative to verbal memory in patients with a first episode of psychosis (FEP) compared with healthy controls (HC). Although white matter tractography differences have been well established between chronic patients and HC, the direction of findings from FEP studies has been inconsistent. Thus, the present study aims to examine whole-brain white matter differences and its association with verbal memory in individuals with a FEP relative to HC using tractography.MethodsDiffusion-weighted images were acquired on a 1.5T scanner for patients (n=65) and controls (n=54) at baseline. The Wechsler Memory Scale was used as a measure of verbal memory. Pre-processing was performed on a subject-by-subject basis using MRtrix. Diffusion tractography was generated using a probabilistic anatomically-constrained tractography algorithm, which constrains the reconstruction to specific biological priors. Furthermore, the spherical-deconvolution informed filtering of tractograms (SIFT) tool will be used to ensure the tractogram is biologically meaningful. This results in subject-specific connectomes defining the mean FA between two regions of interest that were defined using the Desikan- Killiany atlas. A linear model was used to test for main effect of group and main effect of verbal memory on white matter tract FA, covarying for age and sex. For both sets of analyses, results were corrected for multiple comparisons using false discovery rate (FDR).ResultsA significant main effect of group on whole-brain average FA was observed, with patients displaying lower average FA compared to healthy controls (Patients=0.291, controls=0.300, p<0.05). Whole-brain white matter tract FA analysis revealed that there are widespread differences between controls and individuals with a FEP. Group most strongly predicted white matter tract FA differences between left caudal anterior cingulate and left lateral orbitofrontal (patients mean FA=0.302, controls mean FA=0.342), left hippocampus and right isthmus cingulate (patient mean FA= 0.217 controls mean FA= 0.318), and finally left lingual and left rostral anterior cingulate (patients mean FA=0.162, controls mean FA= 0.249. However, none survived correction for multiple comparisons. Further, there was no significant association between verbal memory and white matter tract FA in FEP or HC.DiscussionFindings from this study suggest there are some significant differences in whole-brain average FA between individuals experiencing a FEP and healthy controls. However, when analyzing whole-brain tract FA, none of the connections survived corrections for multiple comparisons. These findings might be limited by the scanner resolution included in this study, which may not capture more subtle differences. Nonetheless, these results are consistent with a cross-sectional study comparing healthy individuals to chronic and first-episode patients suggesting that modest differences are present early in the disease and increase as the disease progresses. We suggest that future studies analyze white matter tract using a longitudinal design to identify disease progression.

BackgroundEarly changes in white matter (WM) measured using diffusion tensor imaging (DTI) are sensitive markers of WM degeneration and predict future cognitive decline in mild cognitive impairment (MCI). We sought to examine whether changes in WM integrity differed among empirically derived subtypes of incident MCI.MethodParticipants included 66 individuals with incident MCI enrolled in the population‐based Mayo Clinic Study of Aging (MCSA) previously identified via cluster analysis as having one of four MCI subtypes: subtle cognitive impairment (SCI; n = 13, mean age 78; 15% women), amnestic (n = 24; mean age 79; 54% women), dysnomic (n = 8; mean age 79; 38% women), and dysexecutive (n = 21; mean age 82; 33% women). All participants completed 3T MRI at the time of the MCI diagnosis. We compared the MCI subtypes to 100 cognitively unimpaired (CU) participants (mean age 77; 49% women). We used tract‐based spatial statistics to examine voxel‐level differences in fractional anisotropy (FA). We also fit a linear regression model to regional FA data from the corpus callosum (CC), the major interhemispheric WM connection, to quantify the relative differences in WM damage.ResultAll MCI subtypes except the subtle cognitive impairment group had widespread decreased FA. Relative to CU, the amnestic cluster showed decreased FA in the CC (genu), cingulum, fornix and uncinate fasciculus (UF); the dysnomic cluster showed decreased FA in the CC (genu, splenium), fornix, UF, anterior thalamic radiation (ATR), and corticospinal tract (CST); and the dysexecutive group showed decreased FA in the CC (genu, body, splenium), cingulum, UF, ATR, CST, and superior longitudinal fasciculus. The dysexecutive cluster had the most severe bilateral involvement among all MCI subtypes. The regional analysis showed that the amnestic, dysnomic, and dysexecutive groups (but not the subtle cognitive impairment group) had significantly lower FA of the CC compared to CU (p&lt;0.001; Figure 1).ConclusionWe found widespread WM degeneration in the commissural and long association fibers in amnestic, dysnomic, and dysexecutive incident MCI subtypes. The extent of CC damage seen in Figure 1. confirmed the voxel‐level results and suggests that interhemispheric WM disconnection is relevant to the development of MCI.

Night sleep influences white matter microstructure in bipolar depression