Brain registration to a stereotaxic atlas is an effective way to report anatomic locations of interest and to perform anatomic quantification. However, existing stereotaxic atlases lack comprehensive coordinate information about white matter structures. In this paper, white matter specific atlases in stereotaxic coordinates are introduced. As a reference template, the widely-used ICBM-152 was used. The atlas contains fiber orientation maps and hand-segmented white matter parcellation maps based on diffusion tensor imaging (DTI). Registration accuracy by linear and nonlinear transformation was measured, and automated template-based white matter parcellation was tested. The results showed high correlation between the manual ROI-based and the automated approaches for normal adult populations. The atlases are freely available and believed to be a useful resource as a target template and for automated parcellation methods.

Tractography based on diffusion tensor imaging (DTI) allows visualization of white matter tracts. In this study, protocols to reconstruct eleven major white matter tracts are described. The protocols were refined by several iterations of intra-and inter-rater measurements and identification of sources of variability. Reproducibility of the established protocols was then tested by raters who did not have previous experience in tractography. The protocols were applied to a DTI database of adult normal subjects to study size, fractional anisotropy (FA), and T 2 of individual white matter tracts. Distinctive features in FA and T 2 were found for the corticospinal tract and callosal fibers. Hemispheric asymmetry was observed for the size of white matter tracts projecting to the temporal lobe. This protocol provides guidelines for reproducible DTI-based tract-specific quantification.

Diffusion tensor imaging (DTI) is an exciting new MRI modality that can reveal detailed anatomy of the white matter. DTI also allows us to approximate the 3D trajectories of major white matter bundles. By combining the identified tract coordinates with various types of MR parameter maps, such as T 2 and diffusion properties, we can perform tract-specific analysis of these parameters. Unfortunately, 3D tract reconstruction is marred by noise, partial volume effects, and complicated axonal structures. Furthermore, changes in diffusion anisotropy under pathological conditions could alter the results of 3D tract reconstruction. In this study, we created a white matter parcellation atlas based on probabilistic maps of 11 major white matter tracts derived from the DTI data from 28 normal subjects. Using these probabilistic maps, automated tract-specific quantification of fractional anisotropy and mean diffusivity were performed. Excellent correlation was found between the automated and the individual tractography-based results. This tool allows efficient initial screening of the status of multiple white matter tracts.

Structural delineation and assignment are the fundamental steps in understanding the anatomy of the human brain. The white matter has been structurally defined in the past only at its core regions (deep white matter). However, the most peripheral white matter areas, which are interleaved between the cortex and the deep white matter, have lacked clear anatomical definitions and parcellations. We used axonal fiber alignment information from diffusion tensor imaging (DTI) to delineate the peripheral white matter, and investigated its relationship with the cortex and the deep white matter. Using DTI data from 81 healthy subjects, we identified nine common, blade-like anatomical regions, which were further parcellated into 21 subregions based on the cortical anatomy. Four short association fiber tracts connecting adjacent gyri (U-fibers) were also identified reproducibly among the healthy population. We anticipate that this atlas will be useful resource for atlas-based white matter anatomical studies.

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Researchers have long noted an excess of patients with schizophrenia were born during the months of January and March. This winter birth effect has been hypothesized to result either from various causes such as vitamin D deficiency (McGrath, 1999; McGrath et al., 2010), or from maternal infection during pregnancy. Infection with a number of viruses during pregnancy including influenza, and rubella are known to increase the risk of schizophrenia in the offspring (Brown, 2006). Animal models using influenza virus or PolyI:C, a viral mimic, have been able to replicate many of the brain morphological, genetic, and behavioral deficits of schizophrenia (Meyer et al., 2006, 2008a, 2009; Bitanihirwe et al. 2010; Meyer and Feldon, 2010; Short et al., 2010). Using a murine model of prenatal viral infection, our laboratory has shown that viral infection on embryonic days 9, 16, and 18 leads to abnormal expression of brain genes and brain structural abnormalities in the exposed offspring (Fatemi et al., 2005, 2008a,b, 2009a,b). The purpose of the current study was to examine gene expression and morphological changes in the placenta, hippocampus, and prefrontal cortex as a result of viral infection on embryonic day 7 of pregnancy. Pregnant mice were either infected with influenza virus [A/WSN/33 strain (H1N1)] or sham-infected with vehicle solution. At E16, placentas were harvested and prepared for either microarray analysis or for light microscopy. We observed significant, upregulation of 77 genes and significant downregulation of 93 genes in placentas. In brains of exposed offspring following E7 infection, there were changes in gene expression in prefrontal cortex (6 upregulated and 24 downregulated at P0; 5 upregulated and 14 downregulated at P56) and hippocampus (4 upregulated and 6 downregulated at P0; 6 upregulated and 13 downregulated at P56). QRT-PCR verified the direction and magnitude of change for a number of genes associated with hypoxia, inflammation, schizophrenia, and autism. Placentas from infected mice showed a number of morphological abnormalities including presence of thrombi and increased presence of immune cells. Additionally, we searched for presence of H1N1 viral-specific genes for M1/M2, NA, and NS1 in placentas of infected mice and brains of exposed offspring and found none. Our results demonstrate that prenatal viral infection disrupts structure and gene expression of the placenta, hippocampus, and prefrontal cortex potentially explaining deleterious effects in the exposed offspring without evidence for presence of viral RNAs in the target tissues.

In the human brain, different regions of the cortex communicate via white matter tracts. Investigation of this connectivity is essential for understanding brain function. It has been shown that trajectories of white matter fiber bundles can be estimated based on orientational information that is obtained from diffusion tensor imaging (DTI). By extrapolating this information, cortical regions associated with a specific white matter tract can be estimated. In this study, we created population-averaged cortical maps of brain connectivity for 4 major association fiber tracts, the corticospinal tract (CST), and commissural fibers. It is shown that these 4 association fibers interconnect all 4 lobes of the hemispheres. Cortical regions that were assigned based on association with the CST and the superior longitudinal fasciculus (SLF) agreed with locations of their known (CST: motor) or putative (SLF: language) functions. The proposed approach can potentially be used for quantitative assessment of the effect of white matter abnormalities on associated cortical regions.

The glutamatergic hypothesis of schizophrenia suggests that hypoactivity of the N-methyl-D-aspartate receptor (NMDAR) is an important factor in the pathophysiology of schizophrenia and related mental disorders. The environmental neurotoxicant, lead (Pb(2+)), is a potent and selective antagonist of the NMDAR. Recent human studies have suggested an association between prenatal Pb(2+) exposure and the increased likelihood of schizophrenia later in life, possibly via interacting with genetic risk factors. In order to test this hypothesis, we examined the neurobehavioral consequences of interaction between Pb(2+) exposure and mutant disrupted in schizophrenia 1 (mDISC1), a risk factor for major psychiatric disorders. Mutant DISC1 and control mice born by the same dams were raised and maintained on a regular diet or a diet containing moderate levels of Pb(2+). Chronic, lifelong exposure of mDISC1 mice to Pb(2+) was not associated with gross developmental abnormalities but produced sex-dependent hyperactivity, exaggerated responses to the NMDAR antagonist, MK-801, mildly impaired prepulse inhibition of the acoustic startle, and enlarged lateral ventricles. Together, these findings support the hypothesis that environmental toxins could contribute to the pathogenesis of mental disease in susceptible individuals.