CP #8: Quantitative MRI and 1H-MRS in Traumatic Brain Injury

Significance:

This project aims at elucidating the role of brain iron in mild traumatic brain injury (MTBI), also known as concussion, as a first step in developing new treatments. Traumatic brain injury (TBI) is a growing public health problem with annual U.S. incidence of 1.7 million, ~90% of cases being MTBI. In 2011, the journal Nature described MTBI an “epidemic of brain damage [and] a major challenge for scientists” [1]. Despite typically normal conventional imaging, patients may suffer a combination of physical, cognitive and behavioral deficits leading to an array of persistent symptoms termed Post-Concussive Syndrome (PCS) [2,3] with up to 22% of patients symptomatic 12 months after injury [4]. In addition, Chronic Traumatic Encephalopathy (CTE) is associated with multiple MTBI and is reported to occur even after a single concussive episode [5]. Our group has found measurable regional brain atrophy after a single concussion[6]. The effects on the brain are incompletely known and no good medical treatments or means of predicting outcome exist. It is thus vital to identify disease markers for early stratification of patients and development and monitoring of targeted therapy.

Advances in imaging, including work from our group, now reveal evidence of white matter injury after MTBI with one of most commonly implicated regions being the anterior corona radiata/cingulum [7-15]. Substantial evidence also exists that the thalamus is abnormal after MTBI with alterations in functional connectivity, perfusion and diffusion [12,16-22]. In the previous funding period, using Magnetic Field Correlation (MFC), we demonstrated abnormal thalamic iron levels after MTBI without co-existent evidence of hemorrhage [20] (see Figure 1).  Though vital to neurons, excess iron is toxic via the production of free radicals. A growing body of work suggests that abnormal iron plays a significant role in secondary injury after TBI. Secondary injury cascades are increasingly felt to be important in the pathogenesis of persistent symptoms [20,23,24]. Identifying and quantifying such mechanisms will provide novel pathways for treatment which are currently lacking.

Aims:

The goal of this study is to observe frontal white matter and thalamic iron levels after MBTI in a longitudinal study to determine whether the iron abnormalities can predict further brain injury and dysfunction.

Approach:

A cohort of 90 MBTI patients and 45 matched controls will undergo MR imaging and neuropsychological testing soon after injury and again at 6 and 12 months. Iron levels will be assessed using MFC and R2* measurements. Structural imaging (T2-weighted fast spin-echo, high-resolution SWI and 3D T1-weighted MPRAGE) will be performed to assess changes in frontal white matter and thalamic volume. Diffusion kurtosis acquisitions will be used to assess microstructural changes and resting-state fMRI will assess functional connectivity.  Clinical and neuropsychological assessments will be performed within 1 day of MR imaging.

Push-Pull Relationship with TR&D Projects 1 & 2: 

TR&D#1: Dr. Lui and her team are currently working with BTRC staff to improve T2* mapping and modeling (e.g. to determine the key length scales involved), as well as to tailor diffusion acquisitions and modeling.  Needs of this CP will push TR&D #1 toward developments in these areas.  Use of the EMC-based T2 mapping approach described in TR&D #1 is now being explored to separate T2 and T2* components for this project.  Ultimately, there will also be great value in combining the various anatomical, functional, and parametric mapping acquisitions called for in this project, which currently occupy at least an hour of scan time. Therefore, this CP will serve as a test bed for evaluation of our rapid comprehensive imaging paradigm in Specific Aim 3 of TR&D #1. 

TR&D#2: Quantification of the effects of iron is expected to improve with increasing field strength.  Work on this CP has begun at 3T because of the ready availability of 3T scanners for clinical studies, but the project is well suited for extension to 7T as a research and clinical platform.  Indeed, the approved IRB protocol for the project includes 7T imaging, and preliminary data have already been gathered at 7T in boxers.  T2* assessment using the plug and play parallel transmission technique described in TR&D #2 will be explored for this project, which will also benefit from tailored RF coils for improved SNR and spatial resolution.