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Objective  To determine the utility of fractional amplitude of low frequency fluctuations (fALFF) during resting state fMRI (rs-fMRI) as an advanced neuroimaging biomarker for Mild Traumatic Brain Injury (mTBI).    Background  mTBI is defined by a constellation of functional rather than structural deficits. As a measure of functional connectivity, fALFF has been implicated in long-term outcomes post-mTBI. It is unclear however, how longitudinal changes in fALFF may relate to the clinical presentation of mTBI.    Design/Methods  111 patients and 32 controls (15–50 years old) were enrolled acutely after mTBI and followed with up to 4 standardized serial assessments. Patients were enrolled at either Encounter 1 (E1), within 72 hours, or Encounter 2 (E2), 5–10 days post-injury, and returned for Encounter 3 (E3) at 15–29 days and Encounter 4 (E4) at 83–97 days. Each encounter included a clinical exam, neuropsychological assessment, as well as rs-fMRI imaging. fALFF was analyzed independently in 14 functional networks and, in grey and white matter as a function of symptom severity. Symptom severity scores (SSS) ranged from 0–132 as defined by the SCAT2 symptom evaluation.    Results  In mTBI patients, fALFF scores across 5 functional brain networks (language, sensorimotor, visuospatial, higher-order visual, and posterior salience) differed between mTBI patients with low versus high SSS (SSS  30, respectively). Overall, greater SSS were indexed by reduced connectivity ( p  &lt; 0.03, Bonferroni corrected). Further analysis also identified corresponding network pairs which were most predictive of increased SSS. White matter fALFF was not correlated with symptom severity, however, decreased grey matter fALFF was significantly correlated with greater SSS ( r  = −0.25,  p  = 0.002).    Conclusions  Grey matter fALFF was correlated with mTBI symptom burden suggesting that patterns of neural connectivity relate directly to the clinical presentation of mTBI. Furthermore, differences in functional network connectivity as a function of SSS may reflect which networks are implicated in recovery of mTBI.

Resting State Functional Connectivity is Directly Related to Clinical Presentation of Mild Traumatic Brain Injury