It is widely accepted that symptoms in chronic mild traumatic brain injury (mTBI) are caused by injury to the white matter, which affects information transfer within and between brain regions, but the specific substrates for particular symptoms are unclear. One of the symptoms – memory problem – may be related to mTBI damage to the hippocampus, but the exact mechanism is not known nor a biomarker is currently available. The purpose of this work is to use quantitative tissue specific R2* measurements¹ to measure tissue specific R2* relaxation rate parameter as a biomarker to detect mTBI related abnormalities before detectable anatomical changes appear.This study was approved by the Washington University IRB. Twenty one healthy control subjects (7 males and 14 females, mean age 44 years) and ten chronic mTBI patients (7 males and 3 females) with mean age of 42 participated. On average, patients were 34 months post-injury. The following neuropsychological tests were administered: Head Injury Symptom Checklist (HISQ), Brain Injury Screening Questionnaire (BISQ), Center for Epidemiologic Studies Depression Scale (CES-D), PTSD CheckList – Civilian Version (PCL_C). Post-concussive symptoms were measured using the HISQ 1-20. All subjects were scanned using a 3T Trio MRI scanner (Siemens) with a 32-channel phased-array head coil. Tissue specific R2* maps and T1 weighted images were generated using a 3D multi gradient echo sequence with resolution 1×1×2 mm³ (read, phase, slab), FOV 256 mm×192 mm, repetition time TR = 50ms, flip angle 30°, 10 gradient echoes with first echo time TE1 = 4 ms, echo spacing ∆TE = 4ms. A navigator-based method² and a voxel spread function (VSF) approach³ were used to correct physiological fluctuation and field inhomogeneity artifacts, respectively. Standard clinical MP-RAGE images were also collected for segmentation and atlas transformation purposes. Mean R2* values were measured in 26 ROIs representing different functional systems defined in previously published rs-fcfMRI analysis⁴.Mann–Whitney U test (U test) revealed significant differences between R2* of healthy controls and mTBI patients for either grey or white matter in 2 of 26 functional ROIs (Fig. 1 D-G). Those ROIs were frontal pole (Fig. 1 A-C; green ROI) and a medial temporal region partially overlapping with the hippocampus (Fig. 1 B, C; red ROI; henceforth hippocampus). Analysis of R2* values and HISQ 1-20 values (number of reported mTBI-related symptoms) revealed that mTBI patients with reported memory problems after mTBI tended to have lower R2* values in white matter of hippocampus and more mTBI related symptoms (Fig. 2A, B). In this figure, mTBI patients with reported memory problems after mTBI are indicated by open diamonds. Arrow marks mTBI patient without memory problems and with doctorate degree. In an exploratory analysis, we compared R2* values signal in ROIs close to our regions, but identified based on FreeSurfer anatomical segmentation, similar to previous analysis⁵. We used frontal pole and hippocampus ROIs to compare R2* values in patients and controls. There were no significant differences between mTBI patients and controls in those ROIs. To evaluate possible anatomical abnormalities frequently reported in frontal and hippocampal regions after mTBI, we also compared gray matter volume and average cortical thickness in left and right frontal pole as well as the volume of left and right hippocampus based on standard clinical MP-RAGE images by using standard approach implemented in FreeSurfer. We did not observe any significant differences between mTBI patients and controls both with and without age regression.In this work we analyzed quantitative tissue specific R2* values from independently localized functional ROIs. The main result is that mTBI patients demonstrated decreased R2* values in frontal pole and hippocampus, while reduced R2* values in white matter of hippocampus appeared to be related to reported memory problems after mTBI. Importantly, this R2* values reduction was not accompanied by decreased volume of white matter and grey matter inside those regions. Also, we have not observed any R2* values reduction or atrophy in nearby regions, identified based on FreeSurfer segmentation. This data suggest that R2* values extracted from quantitative tissue specific R2* measurements may detect mTBI related abnormalities before detectable anatomical changes appear.