White matter during concussion recovery: Comparing diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging (NODDI)

Concussion pathophysiology in humans remains incompletely understood. Diffusion tensor imaging (DTI) has identified microstructural abnormalities in otherwise normal appearing brain tissue, using measures of fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD). The results of prior DTI studies suggest that acute alterations in microstructure persist beyond medical clearance to return to play (RTP), but these measures lack specificity. To better understand the observed effects, this study combined DTI with neurite orientation dispersion and density imaging (NODDI), which employs a more sophisticated description of water diffusion in the brain. A total of 66 athletes were recruited, including 33 concussed athletes, scanned within 7 days after concussion and at RTP, along with 33 matched controls. Both univariate and multivariate methods identified DTI and NODDI parameters showing effects of concussion on white matter. Spatially extensive decreases in FA and increases in AD and RD were associated with reduced intra-neurite water volume, at both the symptomatic phase of injury and RTP, indicating that effects persist beyond medical clearance. Subsequent analyses also demonstrated that concussed athletes with higher symptom burden and a longer recovery time had greater reductions in FA and increased AD, RD, along with increased neurite dispersion. This study provides the first longitudinal evaluation of concussion from acute injury to RTP using combined DTI and NODDI, significantly enhancing our understanding of the effects of concussion on white matter microstructure

Effects of post-acute COVID-19 syndrome on the functional brain networks of non-hospitalized individuals

IntroductionThe long-term impact of COVID-19 on brain function remains poorly understood, despite growing concern surrounding post-acute COVID-19 syndrome (PACS). The goal of this cross-sectional, observational study was to determine whether there are significant alterations in resting brain function among non-hospitalized individuals with PACS, compared to symptomatic individuals with non-COVID infection.MethodsData were collected for 51 individuals who tested positive for COVID-19 (mean age 41±12 yrs., 34 female) and 15 controls who had cold and flu-like symptoms but tested negative for COVID-19 (mean age 41±14 yrs., 9 female), with both groups assessed an average of 4-5 months after COVID testing. None of the participants had prior neurologic, psychiatric, or cardiovascular illness. Resting brain function was assessed via functional magnetic resonance imaging (fMRI), and self-reported symptoms were recorded.ResultsIndividuals with COVID-19 had lower temporal and subcortical functional connectivity relative to controls. A greater number of ongoing post-COVID symptoms was also associated with altered functional connectivity between temporal, parietal, occipital and subcortical regions.DiscussionThese results provide preliminary evidence that patterns of functional connectivity distinguish PACS from non-COVID infection and correlate with the severity of clinical outcome, providing novel insights into this highly prevalent disorder

Optimizing Preprocessing and Analysis Pipelines for Single-Subject fMRI: 2. Interactions with ICA, PCA, Task Contrast and Inter-Subject Heterogeneity

A variety of preprocessing techniques are available to correct subject-dependant artifacts in fMRI, caused by head motion and physiological noise. Although it has been established that the chosen preprocessing steps (or “pipeline”) may significantly affect fMRI results, it is not well understood how preprocessing choices interact with other parts of the fMRI experimental design. In this study, we examine how two experimental factors interact with preprocessing: between-subject heterogeneity, and strength of task contrast. Two levels of cognitive contrast were examined in an fMRI adaptation of the Trail-Making Test, with data from young, healthy adults. The importance of standard preprocessing with motion correction, physiological noise correction, motion parameter regression and temporal detrending were examined for the two task contrasts. We also tested subspace estimation using Principal Component Analysis (PCA), and Independent Component Analysis (ICA). Results were obtained for Penalized Discriminant Analysis, and model performance quantified with reproducibility (R) and prediction metrics (P). Simulation methods were also used to test for potential biases from individual-subject optimization. Our results demonstrate that (1) individual pipeline optimization is not significantly more biased than fixed preprocessing. In addition, (2) when applying a fixed pipeline across all subjects, the task contrast significantly affects pipeline performance; in particular, the effects of PCA and ICA models vary with contrast, and are not by themselves optimal preprocessing steps. Also, (3) selecting the optimal pipeline for each subject improves within-subject (P,R) and between-subject overlap, with the weaker cognitive contrast being more sensitive to pipeline optimization. These results demonstrate that sensitivity of fMRI results is influenced not only by preprocessing choices, but also by interactions with other experimental design factors. This paper outlines a quantitative procedure to denoise data that would otherwise be discarded due to artifact; this is particularly relevant for weak signal contrasts in single-subject, small-sample and clinical datasets

Impaired Chromatin Remodelling at STAT1-Regulated Promoters Leads to Global Unresponsiveness of Toxoplasma gondii-Infected Macrophages to IFN-γ

Intracellular pathogens including the apicomplexan and opportunistic parasite Toxoplasma gondii profoundly modify their host cells in order to establish infection. We have shown previously that intracellular T. gondii inhibit up-regulation of regulatory and effector functions in murine macrophages (MΦ) stimulated with interferon (IFN)-γ, which is the cytokine crucial for controlling the parasites' replication. Using genome-wide transcriptome analysis we show herein that infection with T. gondii leads to global unresponsiveness of murine macrophages to IFN-γ. More than 61% and 89% of the transcripts, which were induced or repressed by IFN-γ in non-infected MΦ, respectively, were not altered after stimulation of T. gondii-infected cells with IFN-γ. These genes are involved in a variety of biological processes, which are mostly but not exclusively related to immune responses. Analyses of the underlying mechanisms revealed that IFN-γ-triggered nuclear translocation of STAT1 still occurred in Toxoplasma-infected MΦ. However, STAT1 bound aberrantly to oligonucleotides containing the IFN-γ-responsive gamma-activated site (GAS) consensus sequence. Conversely, IFN-γ did not induce formation of active GAS-STAT1 complexes in nuclear extracts from infected MΦ. Mass spectrometry of protein complexes bound to GAS oligonucleotides showed that T. gondii-infected MΦ are unable to recruit non-muscle actin to IFN-γ-responsive DNA sequences, which appeared to be independent of stimulation with IFN-γ and of STAT1 binding. IFN-γ-induced recruitment of BRG-1 and acetylation of core histones at the IFN-γ-regulated CIITA promoter IV, but not β-actin was diminished by >90% in Toxoplasma-infected MΦ as compared to non-infected control cells. Remarkably, treatment with histone deacetylase inhibitors restored the ability of infected macrophages to express the IFN-γ regulated genes H2-A/E and CIITA. Taken together, these results indicate that Toxoplasma-infected MΦ are unable to respond to IFN-γ due to disturbed chromatin remodelling, but can be rescued using histone deacetylase inhibitors

Correction to: Cluster identification, selection, and description in Cluster randomized crossover trials: the PREP-IT trials

An amendment to this paper has been published and can be accessed via the original article

Algorithm and simulation for real-time positron emission based tumor tracking using a linear fiducial marker

The effectiveness of radiotherapy in cancer treatment remains significantly limited by the accuracy of tumor dose delivery. The ideal solution lies in real-time localization of patient tumors during therapy; one such method is by tracking implanted low-acti