Mild traumatic brain injury (mTBI) is a growing public health problem with more than 1.5 million cases a year in the U.S. and $17 billion annual cost to society.¹ The pathophysiological processes underlying mTBI are complex: biomechanical injury to the brain results in stretching of the axons and depolarization of the normal resting voltage across the cell membrane.² Sodium handling by the brain is critical to restore ionic homeostasis after injury and disordered handling is implicated in the long-term pathophysiology of concussion.^3,4 Sodium channel dysfunction is specifically implicated in repetitive neuronal injury⁵ with individuals at elevated risk for long-term neurological sequelae. With state-of-the-art sodium (23Na) MR imaging, one can achieve improved signal-to-noise ratio (SNR) and obtain high quality sodium images in a clinical setting at 3T. Here we seek to observe patterns of total sodium distribution in brain in individuals with mTBI.MRI Acquisition: sodium MRI scans were performed on a clinical 3T scanner (Prisma, Siemens), with a custom-built 8-channel dual-tuned (1H-23Na) Tx/Rx head coil.⁶ The twisted projection imaging (TPI) sequence (a research prototype)⁷ was used for data acquisition with FOV=220mm, matrix size=64, 3D isotropic, RF duration=0.5ms, TE/TR=0.3/100ms, flip angle=90°, rings=28, p=0.4, averages=4, and TA=10.3min. Human Subjects: 4 symptomatic patients with history of mTBI were studied (age 21-52 years old; 1 male/3 female) and 1 healthy 34-year old male subject. Of the 4 mTBI subjects, 3 had multiple previous concussions and 1 had a single injury. Image Analyses: Total sodium MR images were visually inspected in conjunction with conventional proton T1-weighted structural imaging by an expert neuroradiologist. Relative signal intensity was inspected along a line placed on axial images perpendicular to the falx at the level of the centrum semiovale, two slices cephalad to the lateral ventricles to avoid ventricular CSF volume averaging. In particular, signal intensity of the medial gray matter was examined relative to CSF signal in the interhemispheric fissure and centrum semiovale white matter. In the control subject, we observe differential total sodium signal between cortical gray matter and centrum semiovale white matter with higher sodium concentration in the cortex (Fig.1A). Signal intensity along a line perpendicular to the falx further reveals a central peak of high signal corresponding to CSF in the interhemispheric fissure flanked by two adjacent paracentral zones, corresponding spatially to medial frontoparietal gray matter (Fig. 2A). On visual inspection, in 3 of 4 mTBI subjects, we observe an indistinct border between gray and white matter (Fig. 1B) as well as loss of the paracentral peaks corresponding to medial cortical sodium signal (Fig.2B-D). The remaining mTBI subject is currently being treated for involuntary movements using lamotrigine, a sodium-channel blocker that affectively increases the threshold to action potential and the brain sodium distribution more closely resembles the control subject (Fig. 2E). Of note, lateral peaks in signal are a result of the modulation of coil sensitivities in the Tx/Rx array coil used in this study. We are in the process of making corrections for this intensity modulation.Using the SNR-improved sodium MRI, we can differentiate regions of relatively higher sodium concentration corresponding to cortical gray matter in the supratentorial brain. These differences appear less distinct in our mTBI subjects. In a single mTBI subject on lamotrigine, the sodium distribution more closely mimics the pattern we observed in the control subject. This is supports the notion ionic imbalances relating to sodium channel dysfunction present potential treatment targets. Furthermore, experiments using animal models of head injury show that tetrodotoxin, also a sodium channel blocker, can ameliorate ionic imbalances and improve outcome.^5,8Preliminary observations suggest a) differences in gray and white matter total sodium signal can be detected using a clinically feasible MR sequence, b) the distinction between cortex and white matter may be less prominent in patients with a history of mTBI, possibly reflecting on-going sodium channelopathy, and c) treatment using a sodium channel blocker appears to restore the brain sodium distribution to resemble the control subject.