Background
Concussion, or mild traumatic brain injury (mTBI), is a physical trauma-induced pathophysiological process affecting the brain, resulting in rapid onset of typically transient neurological dysfunction, with or without loss of consciousness [
1]. Concussions are inherently diverse in nature and of unpredictable outcome. The cognitive sequelae from seemingly minor head injuries incurred during sports can be severe and persistent. Conspicuous cognitive, physical, and emotional disturbances manifest within the first 24 h of the injury, and last for several weeks [
2] or longer [
3]. More problematic is that certain physiological disturbances can persist beyond the typical 2-week window of clinical recovery, raising concerns about the super-additive risks associated with repeated injury incurred while the brain is still recovering from the effects of the first impact. Indeed, growing evidence suggests that a concussed individual is at high risk for further concussion, and that repeated injuries within a short time window can provoke cumulative brain damage [
4].
Objective methods that can accurately diagnose the impact of a concussion on the brain, allowing for better understanding of the underlying pathology, and tracking post-concussion recovery, are thus required. Magnetic resonance imaging (MRI) is a non-invasive imaging method with a number of modalities optimised to detect different aspects of the structural and functional integrity of the brain. The non-invasive nature of MRI also allows repeated imaging measurements, making it ideal for tracking the temporal trajectory of the injury.
Diffusion Tensor Imaging (DTI) is an MRI modality that probes the motion of water molecules in biological tissue [
5,
6]. DTI uses a number of metrics to describe water diffusivity in a voxel, namely Fractional Anisotropy (FA) [
7] parallel diffusivity (Dp), radial diffusivity (Dr), and mean diffusivity (MD) [
8]. DTI has been used to study human concussions and white matter pathologies, in particular, though the results have often been contradictory [
9‐
15]; both reduced FA coupled with increased MD [
9‐
12] and increased FA coupled with decreased MD [
13‐
15] have been reported in the white matter following mTBI. A 2014 meta-analysis of 122 studies suggested that following a concussion, changes in FA are time-dependent—FA increases during the acute phase then decreases in the subacute phases following the impact [
16]. Repeated mTBI in rodents [
17,
18], single-impact drop-weight model in rats [
19] and single-impact piston-driven closed-head injury in mice [
20,
21] have shown decreased FA in the white matter. A couple of other studies in rats have shown opposite results: increased FA in the white matter [
22,
23]. DTI changes in the grey matter (GM) received less attention though increased FA has been found in human patients with persistent post-concussive symptoms (PPCS) [
24] and in vivo animal models of traumatic brain injury (TBI) [
25‐
27].
Neurite orientation dispersion and density imaging (NODDI) is yet another approach that provides more specificity to diffusion imaging changes [
28]. NODDI provides measures of neurite (axons and dendrites) density and local structural organisation of neurites by measuring the level of orientation dispersion of restricted anisotropic diffusivities measured with multiple diffusion-weighted directions at higher b-values using orientation dispersion index (ODI) and the contribution fraction of restricted anisotropic diffusion to the total diffusion using neurite density index (NDI) [
28,
29]. The few NODDI studies applied to map brain changes in human concussion have reported different findings. Wu et al. detected decreased NDI without any DTI changes in the white matter (WM) of concussion patients aged 35 years old approximately 2 weeks post-injury [
30]. Similarly, both decreased NDI (associated with decreased FA, and increased Dp and Dr) [
31] and increased NDI (associated with decreased ODI, increased FA and decreased MD) [
32] were found in the WM of concussed athletes. Decreased FA and increased ODI were found in the optic tracts of a mouse model of closed-head injury [
21].
Studies on the associated integrity of the functional connections in the brain, using resting state functional MRI, following a concussion have also been limited. Resting-state functional Magnetic Resonance Imaging (rsfMRI) detects synchronous low-frequency fluctuations (< 0.3 Hz) of blood oxygen level dependent (BOLD) signals among spatially distinct brain regions in subjects at rest [
33]. Regions that have synchronous oscillating fluctuations form brain networks that are functionally connected. The default mode network (DMN) has been the major functional network disrupted after concussion in the absence of structural deficits [
34,
35]. Zhou et al. reported reduced functional connectivity in the posterior cingulate cortex and parietal regions and increased functional connectivity around the medial prefrontal cortex in mTBI patients on average 22 days post-concussion [
34]. The decreased connectivity in the posterior DMN was positively correlated with cognitive deficits (lower ability to rapidly switching between cognitive sets) while the increased connectivity in the frontal DMN was correlated negatively with posttraumatic depressive symptoms [
34]. Similarly, Johnson et al. detected a reduction in the number and strength of the connections in the posterior cingulate cortex and lateral parietal cortices, and an increase in the number and strength of connections in the medial prefrontal cortex in concussed athletes imaged after symptoms had resolved, on average 10 days post-concussion [
35]. Other networks found with decreased functional connectivity after concussion include: the Salience Network (SN) [
36,
37], in the lateralised cognitive control network [
37], and in regions related with motor, sensorimotor, attention, and phonological processing [
36]. Connectivity strength between the left dorso-lateral prefrontal cortex and left lateral parietal cortex was reduced with an increasing number of concussions [
35]. More recently, Kaushal et al. investigated resting-state functional connectivity in concussed athletes and found that at 48 h post-injury, there were no changes in functional connectivity, despite psychological distress, and oculomotor, balance and memory deficits [
38]. At 8 days post-injury, a global increase in functional connectivity was seen with improving symptoms, which recovered by 15 days post-injury [
38]. Similarly, Meier et al. reported increased local intrinsic functional connectivity in the right middle and superior frontal gyri at 24–48 h post-injury, which were normalised at 7 days and 6 months post-medical-clearance [
39]. To the best of the authors’ knowledge no functional imaging study combining stimulus-evoked functional MRI and rsfMRI were published in a mouse model of closed-head injury.
The conflicting findings in human imaging studies described above suggested the difference might be due to the patients’ background (sex, age, medical history), the injury severity, and the imaging time post-concussion, which affect where each patient was along the injury/recovery time course. Therefore, animal models serve as a way to study concussion by allowing precise control of all the variables or their effects on the injury and manifestation on MRI findings. In this study, we attempted to chart the temporal evolution of the microstructural and functional changes post-concussion in a mouse model with the aim of highlighting the functional-structural mismatch in their recovery trajectories.
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