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Diffusion dispersion and microscopic fractional anisotropy reveal acute sensitivity to mild traumatic brain injury in a mouse model1Medical Biophysics, Western University, London, ON, Canada, 2Robarts Research Institute, London, ON, Canada, 3Anatomy and Cell Biology, Western University, London, ON, Canada
Synopsis
Imaging markers of mild to moderate concussion are notoriously difficult to detect in vivo. Advanced diffusion MRI (dMRI) techniques have shown increased sensitivity and specificity to microstructural changes in various disease and injury models. Oscillating gradient spin-echo (OGSE) dMRI is sensitive to structural disorder and microscopic anisotropy (µA) dMRI is sensitive to water diffusion anisotropy independent of neuron fiber orientation. In this work, we demonstrate that both microscopic fractional anisotropy and diffusion dispersion show acute sensitivity to concussion, while traditional diffusion MRI markers do not.
Introduction
Current neuroimaging techniques lack the specificity required to reliably detect signs of mild traumatic brain injury (mTBI) [1]. Microstructure imaging with advanced diffusion MRI (dMRI) techniques have shown increased sensitivity and specificity to microstructural changes in various disease and injury models. Oscillating gradient spin echo (OGSE) dMRI [2] and microscopic anisotropy (µA) dMRI [3] may provide additional insight by increasing sensitivity to smaller spatial scales and disentangling fiber orientation dispersion from true microstructural changes, respectively. Here, we evaluate mean diffusivity difference (ΔMD: a measure of the diffusion dispersion rate, which characterizes MD dependence on OGSE frequency), microscopic fractional anisotropy, and traditional dMRI metrics longitudinally in sham and concussed mice.Methods
The sham and concussed cohort each consisted of six female C57Bl/6 mice, aged 10-12 weeks at the start of the study. Longitudinal imaging was performed on the sham and concussed cohort at baseline, 2 days post-mTBI, 1-week post-mTBI, and 4 weeks post-mTBI (Fig. 1). The mTBI model used here is the CHI-RF (cortical head injury with rotational force) model, which is designed to elicit a mild concussion as a result of both linear and rotational forces, by matching the stretch/strain in the rodent brain during mTBI to that experienced by the human brain, as measured in athletes [4].Imaging was performed at 9.4T with a 1 T/m gradient insert using single-shot EPI with an in-plane resolution of 0.175mm x 0.2mm, 0.5mm slice thickness, and a total scan time of 2 hours. The OGSE sequence was implemented with b=800s/mm2, TE=37ms, 10 directions and OGSE frequencies of 0, 50, 100, 145, and 190 Hz. The µA sequence was implemented using a single diffusion encoding (SDE) scheme with linear and spherical tensor encodings at b=2000s/mm2 (30 directions) and b=1000s/mm2 (12 directions) [5]. Post processing included PCA denoising [6] and eddy current correction with FSL [7]. Parameters were measured in the corpus callosum (CC) and prefrontal cortex (PFC). For each metric, paired t-tests were performed between each timepoint post-mTBI and the baseline for each cohort.
Results
Parameter maps at baseline and 4 weeks post-mTBI, in one concussed mouse, are shown in Fig. 2. In the PFC, a 7.1 % increase in µFA (Fig. 3) and a 16.7 % increase in ΔMD (Fig. 4) was found 2 days post-mTBI, compared to baseline. In the CC, a 5.1 % decrease in ΔMD was found 2 days post-mTBI (Fig. 4). No significant changes were found in the traditional dMRI metrics, except an increase in FA in the CC for both sham and concussed cohorts.Discussion
While imaging markers of mild concussion are challenging to detect in vivo, the first application of OGSE and µA dMRI in a mild concussion model shows acute sensitivity to concussion. In the PFC, the increase in ΔMD is consistent with neurite beading [8,9] and with preliminary results in the PFC in one mouse 2 days post-mTBI [10]. This is accompanied by an increase in µFA 2 days post-mTBI. However, simulation has predicted a µFA decrease with beading [11]. Simulations have also shown a µFA increase with increasing intracellular compartment volume fraction, which may indicate the presence of cytotoxic edema here. Glial cell processes, such as those present in astrogliosis may also result in highly anisotropic water diffusion. In a previous rodent TBI model (resulting in a more traumatic injury than the mTBI model used in this work), an increase in KLTE in the cortex was associated with increased reactive astrogliosis [12]. This may explain the non-significant increase in KLTE in the PFC at 2 days post-mTBI in our milder model, accompanied by a significant increase in µFA. Although most studies have reported a reduction in µFA in various pathologies [13–15], recently, elevated µFA in acute stroke has been hypothesized to reflect increased trapped water in swollen axons [16].In contrast to the PFC, a decrease in ΔMD is found in the CC at 2 days post-mTBI. There is a trend of increasing ΔMD between 2 days and 1-week post-mTBI, although not significant with a sample size of 6 mice. The decrease and subsequent increase of ΔMD may provide new insight into the interplay of beading and inflammation during concussion recovery. From a preliminary study involving a mild and severe TBI model, we hypothesize that beading and inflammation may affect OGSE contrast in opposing ways [10]. The effect of inflammation on OGSE contrast remains to be explored.
The only change in traditional dMRI metrics is an increase in FA in the CC, at the 4-week timepoint, for both sham and concussed cohorts. This increase may be related to brain maturation, as myelination continues to increase in mice between three and six months [17], and the mice used in this study were 10-12 weeks old at baseline. This merits investigation into MRI changes in healthy mice over time, which remains largely unexplored. Although a decrease in MD has been reported in the acute stage in various rodent TBI models [18–20], no changes in MD are found in this mild concussion model.
In conclusion, we demonstrate that both µFA and diffusion dispersion show acute sensitivity to concussion, while traditional dMRI markers do not.
Acknowledgements
Natural Sciences and Engineering Research Council of Canada (NSERC)
Ontario Graduate Scholarship (OGS)
Canada First Research Excellence Fund to BrainsCAN
New Frontiers in Research Fund (NFRF)
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