Brain imaging correlates of verbal working memory in children following traumatic brain injury

Neural correlates of working memory (WM) based on the Sternberg Item Recognition Task (SIRT) were assessed in 40 children with moderate-to-severe traumatic brain injury (TBI) compared to 41 demographically-comparable children with orthopedic injury (OI). Multiple magnetic resonance imaging (MRI) methods assessed structural and functional brain correlates of WM, including volumetric and cortical thickness measures on all children; functional MRI (fMRI) and diffusion tensor imaging (DTI) were performed on a subset of children. Confirming previous findings, children with TBI had decreased cortical thickness and volume as compared to the OI group. Although the findings did not confirm the predicted relation of decreased frontal lobe cortical thickness and volume to SIRT performance, left parietal volume was negatively related to reaction time (RT). In contrast, cortical thickness was positively related to SIRT accuracy and RT in the OI group, particularly in aspects of the frontal and parietal lobes, but these relationships were less robust in the TBI group. We attribute these findings to disrupted fronto-parietal functioning in attention and WM. fMRI results from a subsample demonstrated fronto-temporal activation in the OI group, and parietal activation in the TBI group, and DTI findings reflected multiple differences in white matter tracts that engage fronto-parietal networks. Diminished white matter integrity of the frontal lobes and cingulum bundle as measured by DTI was associated with longer RT on the SIRT. Across modalities, the cingulate emerged as a common structure related to performance after TBI. These results are discussed in terms of how different imaging modalities tap different types of pathologic correlates of brain injury and their relationship with WM.     

Evaluation and comparison of GLM- and CVA-based fMRI processing pipelines with Java-based fMRI processing pipeline evaluation system

Activation patterns identified by fMRI processing pipelines or fMRI software packages are usually determined by the preprocessing options, parameters, and statistical models used. Previous studies that evaluated options of GLM (general linear model)--based fMRI processing pipelines are mainly based on simulated data with receiver operating characteristics (ROC) analysis, but evaluation of such fMRI processing pipelines on real fMRI data is rare. To understand the effect of processing options on performance of GLM-based fMRI processing pipelines with real fMRI data, we investigated the impact of commonly-used fMRI preprocessing steps; optimized the associated GLM-based single-subject processing pipelines; and quantitatively compared univariate GLM (in FSL.FEAT and NPAIRS.GLM) and multivariate CVA (canonical variates analysis) (in NPAIRS.CVA)-based analytic models in single-subject analysis with a recently developed fMRI processing pipeline evaluation system based on prediction accuracy (classification accuracy) and reproducibility performance metrics. For block-design data, we found that with GLM analysis (1) slice timing correction and global intensity normalization have little consistent impact on fMRI processing pipelines, spatial smoothing and high-pass filtering or temporal detrending significantly increases pipeline performance and thus are essential for robust fMRI statistical analysis; (2) combined optimization of spatial smoothing and temporal detrending improves pipeline performance; and (3) in general, the prediction performance of multivariate CVA is higher than that of the univariate GLM, while univariate GLM is more reproducible than multivariate CVA. Because of the different bias-variance trade-offs of univariate and multivariate models, it may be necessary to consider a consensus approach to obtain more accurate activation patterns in fMRI data.     

REX: Response Exploration for Neuroimaging Datasets

Neuroimaging technologies produce large and complex datasets. The challenge of comprehensively analysing the recorded dynamics remains an important field of research. The whole-brain linear modelling of hypothesised response dynamics and experimental effects must utilise simple basis sets, which may not detect unexpected or complex signal effects. These unmodelled effects can influence statistical mapping results, and provide important additional clues to the underlying neural dynamics. They can be detected via exploration of the raw signal, however this can be difficult. Specialised visualisation tools are required to manage the huge number of voxels, events and scans. Many effects can be occluded by noise in individual voxel time-series. This paper describes a visualisation framework developed for the assessment of entire neuroimaging datasets.While currently available tools tend to be tied to a specific model of experimental effects, this framework includes a novel metadata schema that enables the rapid selection and processing of responses based on easily-adjusted classifications of scans, brain regions, and events. Flexible event-related averaging and process pipelining capabilities enable users to investigate the effects of preprocessing algorithms and to visualise power spectra and other transformations of the data. The framework has been implemented as a MATLAB package, REX (Response Exploration), which has been utilised within our lab and is now publicly available for download. Its interface enables the real-time control of data selection and processing, for very rapid visualisation. The concepts outlined in this paper have general applicability, and could provide significant further functionality to neuroimaging databasing and process pipeline environments.     

Self-modulation of primary motor cortex activity with motor and motor imagery tasks using real-time fMRI-based neurofeedback

Advances in fMRI data acquisition and processing have made it possible to analyze brain activity as rapidly as the images are acquired allowing this information to be fed back to subjects in the scanner. The ability of subjects to learn to volitionally control localized brain activity within motor cortex using such real-time fMRI-based neurofeedback (NF) is actively being investigated as it may have clinical implications for motor rehabilitation after central nervous system injury and brain-computer interfaces. We investigated the ability of fifteen healthy volunteers to use NF to modulate brain activity within the primary motor cortex (M1) during a finger tapping and tapping imagery task. The M1 hand area ROI (ROI_m) was functionally localized during finger tapping and a visual representation of BOLD signal changes within the ROI_m fed back to the subject in the scanner. Surface EMG was used to assess motor output during tapping and ensure no motor activity was present during motor imagery task. Subjects quickly learned to modulate brain activity within their ROI_m during the finger-tapping task, which could be dissociated from the magnitude of the tapping, but did not show a significant increase within the ROI_m during the hand motor imagery task at the group level despite strongly activating a network consistent with the performance of motor imagery. The inability of subjects to modulate M1 proper with motor imagery may reflect an inherent difficulty in activating synapses in this area, with or without NF, since such activation may lead to M1 neuronal output and obligatory muscle activity. Future real-time fMRI-based NF investigations involving motor cortex may benefit from focusing attention on cortical regions other than M1 for feedback training or alternative feedback strategies such as measures of functional connectivity within the motor system.     

Health care expenditures associated with venous thromboembolism among children

Introduction

We used health insurance claims data from large samples of Medicaid-enrolled and privately insured children to identify children with venous thromboembolism (VTE) and to assess their use of health services and associated expenditures during 2009.

Materials and Methods

Data from the 2009 Thomson Reuters MarketScan® Commercial Database and Multi-State Medicaid database were used to estimate annual expenditures for children 1-17 years of age with VTE. Generalized linear models were used to calculate adjusted annual expenditures for Medicaid-enrolled and privately insured children with VTE, controlling for age, sex, type of health plan, VTE classification (deep vein thrombosis and/or pulmonary embolism), and type of VTE event (idiopathic or secondary) and race (Medicaid only) or region (Commercial only).

Results

During 2009, Medicaid-enrolled and privately insured children with VTE had an average of 1-2 inpatient admissions and 8-10 non-emergency department visits. Unadjusted mean total expenditures were similar for Medicaid-enrolled and privately insured children with VTE, $105,359 and $87,767, respectively. Adjusted mean expenditures for children with secondary VTE were five times higher than for children with idiopathic VTE.

Conclusions

Given the high frequency of secondary VTE in children, most of the associated expenditures may be due to other health conditions. However, children who develop a VTE incur substantial costs of care, even in the absence of related conditions. Additional research is needed to evaluate the long term outcomes for children with VTE including rates of readmission, complications, and the impact of co-morbid conditions.     

Serotonin system gene polymorphisms are associated with impulsivity in a context dependent manner

Impulsivity is a risk factor for adverse outcomes and characterizes several psychiatric disorders and risk for suicide. There is strong evidence that genetic variation influences individual differences in impulsivity, but the details are not yet understood. There is growing interest in better understanding the context dependency of genetic effects that is reflected in studies examining gender specificity, gene×environment interaction and epistasis (gene-gene interaction). In a cross-sectional study we examined whether polymorphisms in six serotonin system candidate genes and the experience of early life trauma (age 0-12) were associated with individual differences in impulsivity in a non-clinical sample of Caucasian university students (N=424). We specifically tested potential gender specific, gene-gene, and gene×environment (early life trauma) effects. In our main analyses with Barratt Impulsiveness Scale (BIS-11) total score, there were significant (i.e. p<.01 and False Discovery Rate <.10) interactions between (1) gender and TPH2 (rs1386483) genotype; (2) gender and HTR2A (rs6313) genotype; and epistatic interactions among (3) 5-HTTLPR and MAOA uVNTR; (4) 5-HTTLPR and rs6313 and (5) HTR1B (rs6296) and rs6313 genotypes. Our results strongly support the explicit investigation of context dependent genetic effects on impulsivity and may help to resolve some of the conflicting reports in the literature.     

Novel molecular events associated with altered steroidogenesis induced by exposure to atrazine in the intact and castrate male rat

Toxicology is increasingly focused on molecular events comprising adverse outcome pathways. Atrazine activates the hypothalamic-pituitary adrenal axis, but relationships to gonadal alterations are unknown. We characterized hormone profiles and adrenal (intact and castrate) and testis (intact) proteomes in rats after 3 days of exposure. The adrenal accounted for most of the serum progesterone and all of the corticosterone increases in intact and castrated males. Serum luteinizing hormone, androstenedione, and testosterone in intact males shared a non-monotonic response suggesting transition from an acute stimulatory to a latent inhibitory response to exposure. Eight adrenal proteins were significantly altered with dose. There were unique proteomic changes between the adrenals of intact and castrated males. Six testis proteins in intact males had non-monotonic responses that significantly correlated with serum testosterone. Different dose–response curves for steroids and proteins in the adrenal and testis reveal novel adverse outcome pathways in intact and castrated male rats.     

Genetic variants of FOXP3 influence graft survival in kidney transplant patients

FOXP3⁺ regulatory T cells (T_reg) play a role in controlling alloreactivity. It has been shown that short (GT)_n dinucleotide repeats (?(GT)₁₅; S) in the promoter region of the FOXP3 gene enhance the promoter activity when compared to long (GT)_n repeats (?(GT)₁₆; L). The present study retrospectively investigated the influence of this (GT)_n FOXP3 gene polymorphism on renal allograft survival. A total of 599 consecutive first-time kidney transplant patients (median follow-up time 7.7 years) were subdivided according to their FOXP3 genotype into the S-genotype group (SG) and the L-genotype group (LG). The SG was superior to the LG in both general graft survival censored for death (logrank test, p = 0.013) and graft survival following acute rejection (p = 0.021). Multivariate analysis defined the (GT)_n FOXP3 dinucleotide repeat polymorphism as an independent factor and confirmed an advantage for the SG in renal allograft survival (HR = 0.67, 95% CI 0.48–0.94, p = 0.02). This gene association study identified a beneficial effect of FOXP3 genetic variants on graft survival in kidney transplant patients.