Differential development of human brain white matter tracts

Neuroscience is increasingly focusing on developmental factors related to human structural and functional connectivity. Unfortunately, to date, diffusion-based imaging approaches have only contributed modestly to these broad objectives, despite the promise of diffusion-based tractography. Here, we report a novel data-driven approach to detect similarities and differences among white matter tracts with respect to their developmental trajectories, using 64-direction diffusion tensor imaging. Specifically, using a cross-sectional sample comprising 144 healthy individuals (7 to 48 years old), we applied k-means cluster analysis to separate white matter voxels based on their age-related trajectories of fractional anisotropy. Optimal solutions included 5-, 9- and 14-clusters. Our results recapitulate well-established tracts (e.g., internal and external capsule, optic radiations, corpus callosum, cingulum bundle, cerebral peduncles) and subdivisions within tracts (e.g., corpus callosum, internal capsule). For all but one tract identified, age-related trajectories were curvilinear (i.e., inverted 'U-shape'), with age-related increases during childhood and adolescence followed by decreases in middle adulthood. Identification of peaks in the trajectories suggests that age-related losses in fractional anisotropy occur as early as 23 years of age, with mean onset at 30 years of age. Our findings demonstrate that data-driven analytic techniques may be fruitfully applied to extant diffusion tensor imaging datasets in normative and neuropsychiatric samples.     

Non-MAO A binding of clorgyline in white matter in human brain

Clorgyline is an irreversible inhibitor of monoamine oxidase (MAO A) which has been labeled with carbon-11 (C-11) and used to measure human brain MAO A with positron emission tomography (PET). In this study we compared [11C]clorgyline and deuterium-substituted [11C]clorgyline ([11C]clorgyline-D2) to better understand the molecular link between [11C]clorgyline binding and MAO A. In PET studies of five normal healthy volunteers scanned with [11C]clorgyline and [11C]clorgyline-D2 2 h apart, deuterium substitution generally produced the expected reductions in the brain uptake of [11C]clorgyline. However, the reduction was not uniform with the C-11 binding in white matter being significantly less sensitive to deuterium substitution than other brain regions. The percentages of the total binding attributable to MAO A is largest for the thalamus and smallest for the white matter and this is clearly seen in PET images with [11C]clorgyline-D2. Thus deuterium-substituted [11C]clorgyline selectively reduces the MAO A binding component of clorgyline in the human brain revealing non-MAO A binding which is most apparent in the white matter. The characterization of the non-MAO A binding component of this widely used MAO A inhibitor merits further investigation.     

Multidimensional analysis and detection of informative features in human brain white matter

The white matter contains long-range connections between different brain regions and the organization of these connections holds important implications for brain function in health and disease. Tractometry uses diffusion-weighted magnetic resonance imaging (dMRI) to quantify tissue properties along the trajectories of these connections. Statistical inference from tractometry usually either averages these quantities along the length of each fiber bundle or computes regression models separately for each point along every one of the bundles. These approaches are limited in their sensitivity, in the former case, or in their statistical power, in the latter. We developed a method based on the sparse group lasso (SGL) that takes into account tissue properties along all of the bundles and selects informative features by enforcing both global and bundle-level sparsity. We demonstrate the performance of the method in two settings: i) in a classification setting, patients with amyotrophic lateral sclerosis (ALS) are accurately distinguished from matched controls. Furthermore, SGL identifies the corticospinal tract as important for this classification, correctly finding the parts of the white matter known to be affected by the disease. ii) In a regression setting, SGL accurately predicts “brain age.” In this case, the weights are distributed throughout the white matter indicating that many different regions of the white matter change over the lifespan. Thus, SGL leverages the multivariate relationships between diffusion properties in multiple bundles to make accurate phenotypic predictions while simultaneously discovering the most relevant features of the white matter.     

Rapid chemical clearing of white matter in the post-mortem human brain by 1,2-hexanediol delipidation

Three-dimensional (3D) imaging based on chemical tissue clearing in the post-mortem human brain is a promising approach for stereoscopic understanding of central nervous system diseases. Especially, delipidation of lipid-rich white matter (WM) is a rate-determining step in human brain clearing by hydrophilic reagents. In this study, we described the rapid delipidation of WM by a 1,2-hexanediol (HxD)-based aqueous solution. HxD delipidation enabled rapid clearing of a formalin-fixed human brain specimen including the WM. Although harsh HxD delipidation was applied to the brain tissue, conventional pathological staining patterns and various types of antigenicity were sufficiently preserved. Furthermore, HxD delipidation was compatible with 3D imaging of fluorescently-labeled tissue samples. HxD delipidation could be useful in future 3D neuropathological diagnosis.     

Bidirectional hyperelastic characterization of brain white matter tissue

Biomechanics and Modeling in Mechanobiology - Biomechanical study of brain injuries originated from mechanical damages to white matter tissue requires detailed information on mechanical...     

A model for diffusion in white matter in the brain

Diffusion of molecules in brain and other tissues is important in a wide range of biological processes and measurements ranging from the delivery of drugs to diffusion-weighted magnetic resonance imaging. Diffusion tensor imaging is a powerful noninvasive method to characterize neuronal tissue in the human brain in vivo. As a first step toward understanding the relationship between the measured macroscopic apparent diffusion tensor and underlying microscopic compartmental geometry and physical properties, we treat a white matter fascicle as an array of identical thick-walled cylindrical tubes arranged periodically in a regular lattice and immersed in an outer medium. Both square and hexagonal arrays are considered. The diffusing molecules may have different diffusion coefficients and concentrations (or densities) in different domains, namely within the tubes' inner core, membrane, myelin sheath, and within the outer medium. Analytical results are used to explore the effects of a large range of microstructural and compositional parameters on the apparent diffusion tensor and the degree of diffusion anisotropy, allowing the characterization of diffusion in normal physiological conditions as well as changes occurring in development, disease, and aging. Implications for diffusion tensor imaging and for the possible in situ estimation of microstructural parameters from diffusion-weighted MR data are discussed in the context of this modeling framework.     

Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain

The subcortical white matter of the adult human brain harbors a pool of glial progenitor cells. These cells can be isolated by fluorescence-activated cell sorting (FACS) after either transfection with green fluorescent protein (GFP) under the control of the CNP2 promoter, or A2B5-targeted immunotagging. Although these cells give rise largely to oligodendrocytes, in low-density culture we observed that some also generated neurons. We thus asked whether these nominally glial progenitors might include multipotential progenitor cells capable of neurogenesis. We found that adult human white-matter progenitor cells (WMPCs) could be passaged as neurospheres in vitro and that these cells generated functionally competent neurons and glia both in vitro and after xenograft to the fetal rat brain. WMPCs were able to produce neurons after their initial isolation and did not require in vitro expansion or reprogramming to do so. These experiments indicate that an abundant pool of mitotically competent neurogenic progenitor cells resides in the adult human white matter.     

alpha-Phenyl-n-tert-butyl-nitrone reduces lipopolysaccharide-induced white matter injury in the neonatal rat brain

Lipopolysaccharide (LPS)-induced white matter injury in the neonatal rat brain is at least partially associated with oxidative stress. alpha-Phenyl-n-tert-butyl-nitrone (PBN) (100 mg/kg) significantly attenuated LPS (1 mg/kg)-induced brain injury, as indicated by the reduction in bilateral ventricular enlargement, apoptotic cell death of oligodendrocytes (OLs), and the loss of OL immunoreactivity in the neonatal rat brain. Protection of PBN was linked with the attenuated oxidative stress induced by LPS, as indicated by the decreased elevation of 8-isoprostane content and by the reduced number of 4-hydroxynonenal or malondialdehyde positive OLs following LPS exposure. Interestingly, while LPS exposure elevated, rather than depleted, levels of the reduced glutathione (GSH) and the GSH/GSSG (oxidized form) ratio, LPS exposure significantly suppressed glutathione peroxidase activity in the rat brain. PBN attenuated LPS-induced alterations in glutathione homeostasis in the rat brain. Additionally, the inflammatory responses were also reduced in the PBN-treated brain, as indicated by the decreased number of activated microglia following LPS exposure and by the consequently decreased elevation of interleukin1-beta and tumor necrosis factor-alpha contents in the rat brain. The overall results suggest that antioxidant PBN, more than a straightforward free radical scavenger, may also involve anti-inflammatory and anti-apoptotic properties in protection of the neonatal rat brain from LPS-induced injury.     

Dynamic mechanical response of bovine gray matter and white matter brain tissues under compression

Dynamic responses of brain tissues are needed for predicting traumatic brain injury (TBI). We modified a dynamic experimental technique for characterizing high strain-rate mechanical behavior of brain tissues. Using the setup, the gray and white matters from bovine brains were characterized under compression to large strains at five different strain rates ranging from 0.01 to 3000/s. The white matter was examined both along and perpendicular to the coronal section for anisotropy characterization. The results show that both brain tissue matters are highly strain-rate sensitive. Differences between the white matter and gray matter in their mechanical responses are recorded. The white matter shows insignificant anisotropy over all strain rates. These results will lead to rate-dependent material modeling for dynamic event simulations.     

Effects of maternal thiamine deficiency on the lipid composition of rat whole brain, gray matter and white matter

Studies were made of the effects of maternal thiamine deficiency on rat whole brain, gray matter and white matter lipids. Mothers were fed a high protein diet (controls) or thiamine deficient high protein diet (thiamine deficient, TD) from 14th day of gestation through lactation. An additional group (pair fed control, PFC) was pair fed with the thiamine deficient group. The TD pups started showing symptoms of abnormalities in posture, arched back and hind limb paralysis from 16th day of lactation. Significant deficits were found in body weight and brain weight of TD and PFC pups. But the deficits seem to be more in the former group. Significant deficits were observed with regard to the concentration of lipids such as galactolipids, phospholipids and plasmalogens in the whole brain of TD and PFC pups at 21 days of age. Additional deficits were also found in the concentration of cholesterol in PFC pups. Gray matter lipids from TD pups seem to be completely spared. However, deficits were found in galactolipid and ganglioside concentrations in PFC pups. The deficits found in the concentration of different lipids in white matter are similar to those observed in whole brain. These results suggest that the effects of thiamine deficiency may be partly due to resultant growth retardation and partly due to the deficiency of thiamine per se.     

Functional diffusion tensor imaging: measuring task-related fractional anisotropy changes in the human brain along white matter tracts

Background

Functional neural networks in the human brain can be studied from correlations between activated gray matter regions measured with fMRI. However, while providing important information on gray matter activation, no information is gathered on the co-activity along white matter tracts in neural networks.

Methodology/Principal Findings

We report on a functional diffusion tensor imaging (fDTI) method that measures task-related changes in fractional anisotropy (FA) along white matter tracts. We hypothesize that these fractional anisotropy changes relate to morphological changes of glial cells induced by axonal activity although the exact physiological underpinnings of the measured FA changes remain to be elucidated. As expected, these changes are very small as compared to the physiological noise and a reliable detection of the signal change would require a large number of measurements. However, a substantial increase in signal-to-noise ratio was achieved by pooling the signal over the complete fiber tract. Adopting such a tract-based statistics enabled us to measure the signal within a practically feasible time period. Activation in the sensory thalamocortical tract and optic radiation in eight healthy human subjects was found during tactile and visual stimulation, respectively.

Conclusions/Significance

The results of our experiments indicate that these FA changes may serve as a functional contrast mechanism for white matter. This noninvasive fDTI method may provide a new approach to study functional neural networks in the human brain.