Diffusion MRI Model Parameter Estimation to Study Brain Microstructure as it Relates to Cognitive Status in Mild Traumatic Brain Injury

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PROJECT SUMMARY Mild Traumatic Brain Injury (MTBI) is a major public health problem with U.S. annual incidence of over 2 million. We propose to use an innovative paradigm in bicompartment diffusion MRI model parameter estimation to study the dynamic longitudinal microstructural changes that occur after MTBI and to investigate the link between white matter injury, cortical volume loss and cognitive outcome. Our preliminary findings suggest diffusion-based biophysical parameters of axon integrity including intra-axonal diffusivity (Da) and axonal water fraction (f) can detect microstructure changes in MTBI and provide more biophysically relevant information compared with traditional, empirical measures of Diffusion Tensor Imaging (DTI). We will employ a rotationally invariant formalism and parameter estimation scheme for the so-called “Standard Model” of diffusion in white matter which unifies previous attempts of multi-compartment white matter modeling over the past decade, now a widely accepted benchmark for multi-compartment modeling of diffusion in the brain. We will further incorporate spherical tensor encoding (STE) and spherical kurtosis (SK) to increase the precision in axon-specific microstructure parameters central to this project and use an optimized and clinically feasible protocol for this translational project. The proposed work is expected to bridge the gap between macroscopic and microstructural alterations relevant to cognitive status after injury, revealing the dynamic structural changes occurring after injury and pointing to imaging biomarkers most relevant to cognitive outcome. By concentrating on cognitive outcome, we will address one of the main barriers to predicting outcome in MTBI which is heterogeneity of clinical status. The results of this work are expected to be significant from both scientific and clinical perspectives by 1) advancing basic knowledge of injury in an impactful way, 2) discovering biophysically meaningful imaging biomarkers relevant to cognitive status in MTBI, and 3) mechanistically linking microstructural and macrostructural brain alterations, in three respective specific aims. This will provide a means toward quantitative tracking of injury and recovery specific to the cognitive domain, and tracking of efficacy of targeted cognitive therapeutic strategies such as cognitive rehabilitation and integrated behavioral health treatment in patients with MTBI.