Mild traumatic brain injury (mTBI) is an enormous public health problem that can be associated with prolonged neurobehavioral sequelae. Currently mTBI is diagnosed based on clinical assessment, which often includes self-report. As yet there is no objective imaging biomarker of sufficient sensitivity and specificity to be considered a valid and reliable indicator of mTBI. Self-report measures of mTBI may be unreliable¹, heightening interest in neuroimaging biomarkers that could be used to more accurately diagnose mTBI and assist in monitoring recovery and treatment. Diffusion MRI (dMRI) measures water diffusion behaviors in biological systems, and is sensitive to microstructural changes in white matter (WM). Recent developments in dMRI enable direct links of diffusion measurements to WM microstructures. We used multi-shell Hybrid Diffusion Imaging (HYDI)² for non-parametric diffusion analysis, q-space imaging², and parametric analyses including conventional DTI and novel neurite orientation dispersion and density imaging (NODDI)³. NODDI hypothesizes WM microstructures in three compartments: extracellular, intracellular and cerebrospinal fluid compartment. The evaluated NODDI parameters may explain cellular level changes in mTBI.

Participants: Nineteen mTBI patients and 23 trauma-controlled subjects were recruited from the Emergency Department. The demographics of the subjects are listed in Table 1. The MRI studies were performed in the acute stage, within 1 month of injury. MRI: Participants received T1W SPGR and HYDI in a Philips 3T Achieve TX scanner with 8-channel head coil and SENSE parallel imaging. The diffusion-weighting (DW) pulse sequence was a SS-SE-EPI sequence. TR was 3.59 sec. Other MR parameters were: TE = 114.24 ms, δ/Δ=46/58.4 ms, voxel size=2*2 mm², 40 slices with slice thickness =3 mm, parallel-imaging SENSE factor=2. The total scan-time was about 24 min. Similar to reference 2, the diffusion encoding scheme consisted of one b0 and 5 b-value shells (250, 1000, 2250, 4000, and 6250 s/mm²) with total 142 DW directions (6, 21, 24, 30, and 61 in each shell). Image processing: The whole dataset was processed with a non-parametric approach, q-space imaging, and yielded P₀, a tissue restriction index^2,4,5. The first and second shell was processed for DTI, which produces diffusion measures including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). A parametric approach using the NODDI model used the whole HYDI dataset. NODDI produces intracellular (i.e., intra-axonal in WM cases) volume fraction (V_ic), extracellular volume fraction (V_ec), volume fraction (V_iso) of isotropic fast diffusion (e.g., CSF), and fiber orientation dispersion index (ODI)³. The NODDI fitting was performed using AMICO-NODDI package⁶. WM ROI: Forty-eight WM ROIs were defined in the standard MNI space by intersecting subjects’ mean WM skeleton with WM atlas of Johns Hopkins University (JHU) ICBM-DTI-81⁷ (Figure 1). All diffusion measures were non-linearly transformed to standard MNI space with FSL FNIRT⁸. Statistics: Linear model analysis was used to test the significance of diffusion metrics between mTBI and trauma-controlled groups with sex and gender as covariates (model 3 in Table 2). Multiple comparisons across 48 ROIs were adjusted using false discovery rate (FDR) with significant level at q-value < 0.05.

Maps of DTI, q-space and NODDI diffusion metrics of an mTBI subject are shown in Figure 2. Among various diffusion metrics, only the NODDI derived intracellular volume fraction (V_ic) was sensitive to mTBI with significant decreases in 60% of WM ROIs (Table 2). The mTBI subjects had an approximately 4% decrease in V_ic. Given the NODDI microstructural assumption of rigid-stick axons (fixed intra-axonal axial diffusivity and near-zero intra-axonal radial diffusivity), V_ic represents parenchymal axonal density (1-V_iso). In addition, significant decreases of V_ic were accompanied by significant increases of V_ec (i.e., V_ec = 1 - V_ic). Therefore, the results suggest that in the acute stage of mTBI, the density of stick-like axons decreases and the inter-axonal space increases. Furthermore, the organization of axons described by DTI fractional anisotropy (FA) and NODDI orientation dispersion index (ODI) remains unchanged. The overall tissue restriction described by P₀ and DTI axial and radial diffusivities did not show significant difference between groups. The prevalence of V_ic-significant ROIs described a diffuse change in WM in the acute phase of mTBI (Table 2). The affected WM tracts concentrated on pyramidal tracts and its cortical projections (bilateral corona radiatae). Most of the cerebella related tracts and hippocampal tracts are spared. HYDI and its diffusion metrics provide insights about microstructural changes of WM in the acute stage of mTBI and may prove useful as a marker of injury.