Evaluation of diffusion measurements reveals radial diffusivity indicative of microstructural damage following acute, mild traumatic brain injury.

PURPOSE: Mild TBI, characterized by microstructural damage, often undetectable on conventional imaging techniques, is a pervasive condition that disturbs brain function and can potentially result in long-term deficits. Deciphering the underlying microstructural damage in mild TBI is crucial for establishing a reliable diagnosis and enabling effective therapeutics. Efforts to capture this damage have been extensive, but results have been inconsistent and incomplete. METHODS: To that effect, we set out to examine the shape of the diffusion tensor in mild TBI during the acute phase of injury. We inspected diffusivity and geometric measurements describing the diffusion tensor's shape and compared mild TBI (N = 34, 20.4-66.6 yo) measurements with those from healthy control (N = 42, 20.7-67.2 yo) participants using voxelwise tract-based spatial statistics. Subsequently, to explore associations between the diffusion measurements in mild TBI, we performed nonparametric statistics and machine learning techniques. RESULTS: Overall, mild TBI displayed a diffuse increase in Dλ2, Dλ3, Dradial, Dmean, and Cspherical, with a diffuse decrease in Afractional, Amode, and Clinear, in addition to no change in Daxial or Cplanar. Most notably, our results provide evidence for Dradial as a potential biomarker for microstructural damage, specifically its main component Dλ2, based on their performance in discriminating between mild TBI and control groups. Afractional was also found to be important for discriminating between groups. CONCLUSION: Our results revealed the importance of a diffusion measurement often overlooked, Dradial, in assessing TBI and suggest differentiating diffusion measurements has the potential utility to detect variations in the underlying pathophysiology after injury.

Glial Fibrillary Acidic Protein (GFAP) Outperforms S100 Calcium-Binding Protein B (S100B) and Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) as Predictor for Positive Computed Tomography of the Head in Trauma Subjects.

OBJECTIVE: Traumatic brain injuries (TBIs) are largely underdiagnosed and may have persistent refractory consequences. Current assessments for acute TBI are limited to physical examination and imaging. Biomarkers such as glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), and S100 calcium-binding protein B (S100B) have shown predictive value as indicators of TBI and potential screening tools. METHODS: In total, 37 controls and 118 unique trauma subjects who received a clinically ordered head computed tomography (CT) in the emergency department of a level 1 trauma center were evaluated. Blood samples collected at 0-8 hours (initial) and 12-32 hours (delayed) postinjury were analyzed for GFAP, UCH-L1, and S100B concentrations. These were then compared in CT-negative and CT-positive subjects. RESULTS: Median GFAP, UCH-L1, and S100B concentrations were greater in CT-positive subjects at both timepoints compared with CT-negative subjects. In addition, median UCH-L1 and S100B concentrations were lower at the delayed timepoint, whereas median GFAP concentrations were increased. As predictors of a positive CT of the head, GFAP outperformed UCH-L1 and S100B at both timepoints (initial: 0.89 sensitivity, 0.62 specificity; delayed: 0.94 sensitivity, 0.67 specificity). GFAP alone also outperformed all possible combinations of biomarkers. CONCLUSIONS: GFAP, UCH-L1, and S100B demonstrated utility for rapid prediction of a CT-positive TBI within 0-8 hours of injury. GFAP exhibited the greatest predictive power at 12-32 hours. Furthermore, these results suggest that GFAP alone has greater utility for predicting a positive CT of the head than UCH-L1, S100B, or any combination of the 3.

Increase in brain atrophy after subdural hematoma to rates greater than associated with dementia.

OBJECTIVEChronic subdural hematoma (cSDH) is a highly morbid condition associated with brain atrophy in the elderly. It has a reported 30% 1-year mortality rate. Approximately half of afflicted individuals report either no or relatively unremarkable trauma preceding their diagnosis, raising the possibility that cSDH is a manifestation of degenerative or inflammatory disease rather than trauma. The purpose of this study was to compare the rates of cerebral atrophy before and after cSDH to determine whether it is more likely that cSDH causes atrophy or that atrophy causes cSDH. The authors also compared atrophy rates in patients with cSDH to the rates in patients with and without dementia.METHODSThe authors developed algorithmic segmentation analysis software to measure whole-brain, CSF, and intracranial space volumes. They then identified military veterans who had undergone at least 4 brain CT scans over a period of 10 years. Within this database, the authors identified 146 patients with 962 head CT scans who had received diagnoses of either cSDH, dementia, or no known dementia condition. Volumetric analyses of brains in 45 patients with dementia (dementia group) and 73 patients without dementia (nondementia group), in whom 262 and 519 head CT scans were obtained, respectively, were compared with 11 patients in whom 81 CT scans were obtained a mean of 4.21 years before a cSDH diagnosis and 17 patients in whom 100 scans were obtained a mean of 4.24 years after SDH. Longitudinal measures were then related to disease status and the time since first scan by using hierarchical models, and atrophy rates between the groups were compared.RESULTSHead CT scans from patients were obtained for an average time period of 4.21 years (SD 1.69) starting at a mean patient age of 74 years. Absolute brain volume loss for the 17 patients in the post-SDH group (13 were treated surgically) was significantly greater, at 16.32 ml/year, compared with 6.61 ml/year in patients with dementia, 5.33 ml/year in patients without dementia, and 3.57 ml/year in pre-SDH patients. The atrophy rate for these individuals prior to enrollment in the study was 2.32 ml/year (p = 0.001). In terms of brain volume normalized to cranial cavity size, the post-SDH group had an atrophy rate of 0.7801%/year, compared with 0.4467%/year in patients with dementia, 0.3474%/year in patients without dementia, and 0.2135%/year in the pre-SDH group.CONCLUSIONSPrior to development of a cSDH, the atrophy rates in patients who ultimately develop cSDH are similar to those of patients without dementia. After development of a cSDH, the atrophy rates increase to more than twice those of patients with dementia. Chronic subdural hematoma is thus associated with a significant increase in brain atrophy rate. These findings suggest the neurotoxic consequences of cSDH and may have implications for better understanding of the pathophysiology of cerebral atrophy and dementia.

Reduced Human Leukocyte Antigen (HLA) Protection in Gulf War Illness (GWI).

BACKGROUND: Gulf War Illness (GWI) is a disease of unknown etiology with symptoms suggesting the involvement of an immune process. Here we tested the hypothesis that Human Leukocyte Antigen (HLA) composition might differ between veterans with and without GWI. METHODS: We identified 144 unique alleles of Class I and II HLA genes in 82 veterans (66 with and 16 without GWI). We tested the hypothesis that a subset of HLA alleles may classify veterans in their respective group using a stepwise linear discriminant analysis. In addition, each participant rated symptom severity in 6 domains according to established GWI criteria, and an overall symptom severity was calculated. FINDINGS: We found 6 Class II alleles that classified participants 84.1% correctly (13/16 control and 56/66 GWI). The number of copies of the 6 alleles was significantly higher in the control group, suggesting a protective role. This was supported by a significant negative dependence of overall symptom severity on the number of allele copies, such that symptom severity was lower in participants with larger numbers of allele copies. INTERPRETATION: These results indicate a reduced HLA protection (i.e. genetic susceptibility) in veterans with GWI. FUNDING: University of Minnesota and U.S. Department of Veterans Affairs.

Departure from Network Equilibrium (DNE): an efficient and scalable measure of instantaneous network dynamics, with an application to magnetoencephalography.

The assessment of the dynamic status of a network is currently unavailable. It is important to know how far a network is away from its equilibrium (as an indicator of instability) at a moment, and over periods of time. Here, we introduce the Departure from Network Equilibrium (DNE), a new measure of instantaneous network dynamics. DNE is simple, fast to compute, and scalable with network size. We present the results of its application on white noise networks (as a basis) and on networks derived from magnetoencephalographic recordings from the human brain.

Motor directional tuning across brain areas: directional resonance and the role of inhibition for directional accuracy.

Motor directional tuning (Georgopoulos et al., 1982) has been found in every brain area in which it has been sought for during the past 30-odd years. It is typically broad, with widely distributed preferred directions and a population signal that predicts accurately the direction of an upcoming reaching movement or isometric force pulse (Georgopoulos et al., 1992). What is the basis for such ubiquitous directional tuning? How does the tuning come about? What are the implications of directional tuning for understanding the brain mechanisms of movement in space? This review addresses these questions in the light of accumulated knowledge in various sub-fields of neuroscience and motor behavior. It is argued (a) that direction in space encompasses many aspects, from vision to muscles, (b) that there is a directional congruence among the central representations of these distributed "directions" arising from rough but orderly topographic connectivities among brain areas, (c) that broad directional tuning is the result of broad excitation limited by recurrent and non-recurrent (i.e., direct) inhibition within the preferred direction loci in brain areas, and (d) that the width of the directional tuning curve, modulated by local inhibitory mechanisms, is a parameter that determines the accuracy of the directional command.

The number of cysteine residues per mole in apolipoprotein E affects systematically synchronous neural interactions in women's healthy brains.

Apolipoprotein E (apoE) is involved in lipid metabolism in the brain, but its effects on brain function are not understood. Three apoE isoforms (E4, E3, and E2) are the result of cysteine-arginine interchanges at two sites: there are zero interchanges in E4, one interchange in E3, and two interchanges in E2. The resulting six apoE genotypes (E4/4, E4/3, E4/2, E3/3, E3/2, E2/2) yield five groups with respect to the number of cysteine residues per mole (CysR/mole), as follows. ApoE4/4 has zero cysteine residues per mole (0-CysR/mole), E4/3 has one (1-CysR/mole), E4/2 and E3/3 each has two (2-CysR/mole), E3/2 has three (3-CysR/mole), and E2/2 has four (4-CysR/mole). The use of the number of CysR/mole to characterize the apoE molecule converts the categorical apoE genotype scale, consisting of 6 distinct genotypes above, to a 5-point continuous scale (0-4 CysR/mole). This allows the use of statistical analyses suitable for continuous variables (e.g. regression) to quantify the relations between various variables and apoE. Using such analyses, here, we show for the first time that apoE affects in a graded and orderly manner neural communication, as assessed by analyzing the relation between the number of CysR/mole and synchronous neural interactions (SNI) measured by magnetoencephalography (MEG) in 130 cognitively healthy women. At the one end of the CysR/mole range, the 4-CysR/mole (E2/2) SNI distribution had the highest mean, lowest variance, lowest range, and lowest coefficient of variation, whereas at the other end, 0-CysR/mole (E4/4) SNI distribution had the lowest mean, highest variance, highest range, and highest coefficient of variation. The special status of the 4-CysR/mole distribution was reinforced by the results of a hierarchical tree analysis where the 4-CysR/mole (E2/2) SNI distribution occupied a separate branch by itself and the remaining CysR/mole SNI distributions were placed at increasing distances from the 4-CysR/mole distribution, according to their number of CysR/mole, with the 0-CysR/mole (E4/4) being farthest away. These findings suggest that the 4-CysR/mole (E2/2) SNI distribution could serve as a reference distribution. When the SNI distributions of individual women were expressed as distances from this reference distribution, there was a substantial overlap among women of various CysR/mole. This refocuses the placement of individual brains along a continuous distance from the 4-CysR/mole SNI distribution, in contrast to the common categorical assignment to a specific apoE genotype. Finally, the orderly variation of SNI with the number of CysR/mole found here is in keeping with recent advances and ideas regarding the molecular mechanisms underlying the differential effects of apoE in the brain which emphasize the healthier stability conferred on the apoE molecule by the increasing number of cysteine-arginine interchanges, with 4-CysR/mole (E2/2) being the best case, as opposed to the instability and increased chance of toxic fragmentation of the apoE molecule with lower number of CysR/mole, with 0-CysR/mole (E4/4) as the worst case (Mahley and Huang in Neuron 76:871-885, 2012a). However, our results also document the appreciable variation of SNI properties within the various CysR/mole groups and individuals which points to the existence and important role of other factors involved in shaping brain function at the network level.