James J. Levitt

DTI and MTR abnormalities in schizophrenia: Analysis of white matter integrity

Diffusion tensor imaging (DTI) studies in schizophrenia demonstrate lower anisotropic diffusion within white matter due either to loss of coherence of white matter fiber tracts, to changes in the number and/or density of interconnecting fiber tracts, or to changes in myelination, although methodology as well as localization of such changes differ between studies. The aim of this study is to localize and to specify further DTI abnormalities in schizophrenia by combining DTI with magnetization transfer imaging (MTI), a technique sensitive to myelin and axonal alterations in order to increase specificity of DTI findings. 21 chronic schizophrenics and 26 controls were scanned using Line-Scan-Diffusion-Imaging and T1-weighted techniques with and without a saturation pulse (MT). Diffusion information was used to normalize co-registered maps of fractional anisotropy (FA) and magnetization transfer ratio (MTR) to a study-specific template, using the multi-channel daemon algorithm, designed specifically to deal with multidirectional tensor information. Diffusion anisotropy was decreased in schizophrenia in the following brain regions: the fornix, the corpus callosum, bilaterally in the cingulum bundle, bilaterally in the superior occipito-frontal fasciculus, bilaterally in the internal capsule, in the right inferior occipito-frontal fasciculus and the left arcuate fasciculus. MTR maps demonstrated changes in the corpus callosum, fornix, right internal capsule, and the superior occipito-frontal fasciculus bilaterally; however, no changes were noted in the anterior cingulum bundle, the left internal capsule, the arcuate fasciculus, or inferior occipito-frontal fasciculus. In addition, the right posterior cingulum bundle showed MTR but not FA changes in schizophrenia. These findings suggest that, while some of the diffusion abnormalities in schizophrenia are likely due to abnormal coherence, or organization of the fiber tracts, some of these abnormalities may, in fact, be attributed to or coincide with myelin/axonal disruption.

Caudate, putamen, and globus pallidus volume in schizophrenia: a quantitative MRI study.

Basal ganglia structures have been reported to be abnormal in schizophrenia. However, while component structures of the basal ganglia are functionally differentiated, there have been no evaluations of their separate magnetic resonance imaging (MRI) volumes with small voxel (1.5 mm3) spoiled gradient-recalled acquisition in steady state techniques and multi-plane assessments. We examined MRI scans from 15 male, right-handed, neuroleptic-medicated schizophrenic patients and 15 age-, handedness-, and gender-matched normal volunteers. Compared with normal subjects, schizophrenic patients showed enlarged volumes: 14.2% for total basal ganglia, 27.4% for globus pallidus, 15.9% for putamen, and 9.5% for caudate. Increased volumes, especially of the caudate, were associated with poorer neuropsychological test performance on finger tapping and Hebbs Recurring Digits. These findings indicate abnormalities throughout all basal ganglia structures in at least a subgroup of schizophrenic patients.

A Cross-Sectional and Longitudinal Magnetic Resonance Imaging Study of Cingulate Gyrus Gray Matter Volume Abnormalities in First-Episode Schizophrenia and First-Episode Affective Psychosis

CONTEXT Previous magnetic resonance imaging (MRI) findings have demonstrated psychopathological symptom-related smaller gray matter volumes in various cingulate gyrus subregions in schizophrenia and bipolar disorder. However, it is unclear whether these gray matter abnormalities show a subregional specificity to either disorder and whether they show postonset progression. OBJECTIVE To determine whether there are initial and progressive gray matter volume deficits in cingulate gyrus subregions in patients with first-episode schizophrenia (FESZ) and patients with first-episode affective psychosis (FEAFF, mainly manic) and their specificity to FESZ or FEAFF. DESIGN A naturalistic cross-sectional study at first hospitalization for psychosis and a longitudinal follow-up approximately 1(1/2) years later. SETTING AND PARTICIPANTS Patients were from a private psychiatric hospital. Thirty-nine patients with FESZ and 41 with FEAFF at first hospitalization for psychosis and 40 healthy control subjects (HCs) recruited from the community underwent high-spatial-resolution MRI, with follow-up scans in 17 FESZ patients, 18 FEAFF patients, and 18 HCs. Individual subjects were matched for age, sex, parental socioeconomic status, and handedness. MAIN OUTCOME MEASURES Cingulate gyrus gray matter volumes in 3 anterior subregions (subgenual, affective, and cognitive) and 1 posterior subregion, and whether there was a paracingulate sulcus. RESULTS At first hospitalization, patients with FESZ showed significantly smaller left subgenual (P = .03), left (P = .03) and right (P = .005) affective, right cognitive (P = .04), and right posterior (P = .003) cingulate gyrus gray matter subregions compared with HCs. Moreover, at the 1(1/2)-year follow-up, patients with FESZ showed progressive gray matter volume decreases in the subgenual (P = .002), affective (P < .001), cognitive (P < .001), and posterior (P = .02) cingulate subregions compared with HCs. In contrast, patients with FEAFF showed only initial (left, P < .001; right, P = .002) and progressive subgenual subregion abnormalities (P < .001). Finally, patients with FESZ showed a less asymmetric paracingulate pattern than HCs (P = .02). CONCLUSIONS Patients with FEAFF and FESZ showed differences in initial gray matter volumes and in their progression. Initial and progressive changes in patients with FEAFF were confined to the subgenual cingulate, a region strongly associated with affective disorder, whereas patients with FESZ evinced widespread initial and progressively smaller volumes.

Prefrontal cortex, negative symptoms, and schizophrenia: an MRI study

The present study measured prefrontal cortical gray and white matter volume in chronic, male schizophrenic subjects who were characterized by a higher proportion of mixed or negative symptoms than previous patients that we have evaluated. Seventeen chronic male schizophrenic subjects and 17 male control subjects were matched on age and handedness. Regions of interest (ROI) were measured using high-resolution magnetic resonance (MR) acquisitions consisting of contiguous 1.5-mm slices of the entire brain. No significant differences were found between schizophrenic and control subjects in mean values for prefrontal gray matter volume in either hemisphere. However, right prefrontal white matter was significantly reduced in the schizophrenic group. In addition, right prefrontal gray matter volume was significantly correlated with right hippocampal volume in the schizophrenic, but not in the control group. Furthermore, an analysis in which the current data were combined with those from a previous study showed that schizophrenic subjects with high negative symptom scores had significantly smaller bilateral white matter volumes than those with low negative symptom scores. White matter was significantly reduced in the right hemisphere in this group of schizophrenic subjects. Prefrontal volumes were also associated with negative symptom severity and with volumes of medial-temporal lobe regions - two results that were also found previously in schizophrenic subjects with mostly positive symptoms. These results underscore the importance of temporal-prefrontal pathways in the symptomatology of schizophrenia, and they suggest an association between prefrontal abnormalities and negative symptoms.

Fornix Integrity and Hippocampal Volume in Male Schizophrenic Patients

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

Thalamo-Frontal White Matter Alterations in Chronic Schizophrenia: A Quantitative Diffusion Tractography Study

Diffusion tensor imaging (DTI) and fiber tractography are useful tools for reconstructing white matter tracts (WMT) in the brain. Previous tractography studies have sought to segment reconstructed WMT into anatomical structures using several approaches, but quantification has been limited to extracting mean values of diffusion indices. Delineating WMT in schizophrenia is of particular interest because schizophrenia has been hypothesized to be a disorder of disrupted connectivity, especially between frontal and temporal regions of the brain. In this study, we aim to differentiate diffusion properties of thalamo‐frontal pathways in schizophrenia from normal controls. We present a quantitative group comparison method, which combines the strengths of both tractography‐based and voxel‐based studies. Our algorithm extracts white matter pathways using whole brain tractography. Functionally relevant bundles are selected and parsed from the resulting set of tracts, using an internal capsule (IC) region of interest (ROI) as “source”, and different Brodmann area (BA) ROIs as “targets”. The resulting bundles are then longitudinally parameterized so that diffusion properties can be measured and compared along the WMT. Using this processing pipeline, we were able to find altered diffusion properties in male patients with chronic schizophrenia in terms of fractional anisotropy (FA) decreases and mean diffusivity (MD) increases in precise and functionally relevant locations. These findings suggest that our method can enhance the regional and functional specificity of DTI group studies, thus improving our understanding of brain function. Hum Brain Mapp, 2009.

Prefrontal cortical thickness in first-episode psychosis: A magnetic resonance imaging study

BACKGROUND Findings from postmortem studies suggest reduced prefrontal cortical thickness in schizophrenia; however, cortical thickness in first-episode schizophrenia has not been evaluated using magnetic resonance imaging (MRI). METHODS Prefrontal cortical thickness was measured using MRI in first-episode schizophrenia patients (n = 17), first-episode affective psychosis patients (n = 17), and normal control subjects (n = 17); subjects were age-matched within 2 years and within a narrow age range (18-29 years). A previous study using the same subjects reported reduced prefrontal gray matter volume in first-episode schizophrenia. Manual editing was performed on those prefrontal segmentations before cortical thickness was measured. RESULTS Prefrontal cortical thickness was not significantly different among groups. Prefrontal gray matter volume and thickness were, however, positively correlated in both schizophrenia and control subjects. The product of boundary complexity and thickness, an alternative measure of volume, was positively correlated with volume for all three groups. Finally, age and age at first medication were negatively correlated with prefrontal cortical thickness only in first-episode schizophrenia. CONCLUSIONS This study demonstrates the potential usefulness of MRI for the study of cortical thickness abnormalities in schizophrenia. Correlations between cortical thickness and age and between cortical thickness and age at first medication suggest that the longer the schizophrenic process has been operative, the thinner the prefrontal cortex, although this needs confirmation in a longitudinal study.

A unifying approach to registration, segmentation, and intensity correction

We present a statistical framework that combines the registration of an atlas with the segmentation of magnetic resonance images. We use an Expectation Maximization-based algorithm to find a solution within the model, which simultaneously estimates image inhomogeneities, anatomical labelmap, and a mapping from the atlas to the image space. An example of the approach is given for a brain structure-dependent affine mapping approach. The algorithm produces high quality segmentations for brain tissues as well as their substructures. We demonstrate the approach on a set of 22 magnetic resonance images. In addition, we show that the approach performs better than similar methods which separate the registration and segmentation problems.

White Matter Tract Abnormalities between Rostral Middle Frontal Gyrus, Inferior Frontal Gyrus and Striatum in First-Episode Schizophrenia

BACKGROUND Previous studies have shown that frontostriatal networks, especially those involving dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) mediate cognitive functions some of which are abnormal in schizophrenia. This study examines white matter integrity of the tracts connecting DLPFC/VLPFC and striatum in patients with first-episode schizophrenia (FESZ), and their associations with cognitive and clinical correlates. METHODS Diffusion tensor and structural magnetic resonance images were acquired on a 3T GE Echospeed system from 16 FESZ and 18 demographically comparable healthy controls. FreeSurfer software was used to parcellate regions of interest. Two-tensor tractography was applied to extract fibers connecting striatum with rostral middle frontal gyrus (rMFG) and inferior frontal gyrus (IFG), representing DLPFC and VLPFC respectively. DTI indices, including fractional anisotropy (FA), trace, axial diffusivity (AD) and radial diffusivity (RD), were used for group comparisons. Additionally, correlations were evaluated between these diffusion indices and the Wisconsin Card Sorting Task (WCST) and the Brief Psychiatric Rating Scale (BPRS). RESULTS FA was significantly reduced in the left IFG-striatum tract, whereas trace and RD were significantly increased in rMFG-striatum and IFG-striatum tracts, bilaterally. The number of WCST categories completed correlated positively with FA of the right rMFG-striatum tract, and negatively with trace and RD of right rMFG-striatum and right IFG-striatum tracts in FESZ. The BPRS scores did not correlate with these indices. CONCLUSIONS These data suggest that white matter tract abnormalities between rMFG/IFG and striatum are present in FESZ and appear to be significantly associated with executive dysfunction but not with symptom severity.

Fractional anisotropy and radial diffusivity: Diffusion measures of white matter abnormalities in the anterior limb of the internal capsule in schizophrenia

INTRODUCTION Higher cognitive functioning is mediated by frontal-subcortical cognitive and limbic feedback sub-loops. The thalamo-cortical projection through the anterior limb of the internal capsule (ALIC) serves as the final step in these feedback sub-loops. We evaluated abnormalities in the ALIC fiber tract in schizophrenia using both structural MRI and diffusion tensor imaging (DTI). METHODS 20 chronic schizophrenia patients and 22 male, normal controls group matched for handedness, age, and parental SES, underwent structural and DTI brain imaging on a 1.5 Tesla GE system. We manually measured ALIC volume normalized for intracranial contents (ICC) using structural brain images and then registered these high resolution structural brain scan derived ALIC label maps to DTI space allowing for the measurement in the ALIC of diffusion indices including, fractional anisotropy (FA) mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD). RESULTS We found in the ALIC of chronic schizophrenia subjects, compared with normal controls, bilaterally lower FA and bilaterally higher RD, but no differences in AD, MD, or relative volume. Cognitive correlations in schizophrenia patients showed, in particular, that higher left ALIC FA correlated positively with better verbal and nonverbal declarative/episodic memory performance. DISCUSSION Using a novel approach to assess both diffusion and volume measures in the ALIC in schizophrenia, we found abnormalities in measures of diffusion, but not volume, supporting their importance as sensitive indices of abnormalities in white matter fiber bundles in schizophrenia. Our findings also support the role of ALIC white matter tract FA abnormalities in declarative/episodic memory in schizophrenia.