The Prognostic Role of Magnetic Resonance Imaging Biomarkers in Mild Traumatic Injury | Traumatic Brain Injury | JAMA Network Open | JAMA Network
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Invited Commentary
March 18, 2021

The Prognostic Role of Magnetic Resonance Imaging Biomarkers in Mild Traumatic Injury

Author Affiliations
  • 1Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
  • 2Department of Radiology, Mayo Clinic, Phoenix, Arizona
JAMA Netw Open. 2021;4(3):e211824. doi:10.1001/jamanetworkopen.2021.1824

Traumatic brain injury (TBI) is a serious public health concern and the reason for nearly 2.8 million of the 26 million injury-related emergency department visits, hospitalizations, and deaths that occurred in the US in 2013. Approximately 70% to 90% of TBIs are considered mild TBI and are treated and discharged from the emergency department.1 But despite the diagnosis of mild injury, nearly half of these patients will experience persistent symptoms significant enough to disrupt their lives. While the diagnosis of TBI is a clinical decision, neuroimaging is vital for guiding management and providing prognostic information. Conventional magnetic resonance imaging (MRI) is able to detect axonal injury and intracranial blood products within hours after injury. Advanced MRI methods can detect even more subtle findings in mild TBI, including changes to brain structure, function, and metabolism. These advanced methods may improve characterization of findings that are associated with acute symptoms and long-term functional outcome, informing treatment decisions and improving prognostication.

In this study by Richter et al,2 the authors present the results of a prospective multicenter observational study that included patients from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) to study the association of white matter changes detected on diffusion tensor imaging (DTI) with persistent symptoms after mild TBI. Richter et al2 addressed 3 fundamental questions: what are the neuroanatomical substrates of mild TBI on MRI, how do these change with evolving or resolving symptoms, and what is the optimal timing of imaging for prognostication? Imaging analysis found that cerebral white matter volume decreased and ventricular and cerebral spinal fluid volume increased after injury in mild TBI compared with controls. These changes were not detected on MRI shortly after injury (ie, <72 hours) but appeared during follow-up (ie, after 2-3 weeks), indicating the possibility of a progressive pathological phenomena after diffuse axonal injury. Common DTI measures (eg, mean diffusivity [MD], fractional anisotropy [FA]) changed significantly in 13 tracts and were associated with the evolution of symptoms after injury. Patients with increasing MD and decreasing FA (indicating progressive injury) between early and follow-up imaging showed worsening of their symptoms.2 Patients with little change in diffusion parameters showed improvement. Patients with decreasing MD and increasing FA (ie, pseudonormalization) had a variable course of recovery. Interestingly, Richter et al2 were able to estimate symptom recovery at 3 months with high accuracy by combining volumetric and DTI data captured early after injury. These findings highlight the potential prognostic value of early imaging findings seen on conventional and advanced MRI.

Advanced MRI methods have shown promise for improved prognostication in mild TBI. The study by Richter et al2 provides further evidence that there is an association between structural changes detected on DTI, such as decreased FA and increased MD, and symptom severity and persistence.3 However, an early paradoxical increase in FA can still occur in the early phase after mild TBI due to transient axonal swelling and loss, particularly in areas of crossing fibers, and changes related to Wallerian degeneration.4 A study by Eierud et al5 reported that the association between DTI metrics and clinical symptoms may be time dependent, with lower neuropsychological performance correlating with higher anisotropy in the acute phase and lower anisotropy in later phases. More research is needed to better understand how changes in diffusion metrics correlate with underlying cellular pathophysiological processes, and to better determine the optimal timing of imaging for detection of meaningful and prognostic features.

To date, the study by Richter et al2 is one of the few pilot studies that extracted diffusion metrics to estimate outcomes of mild TBI. The combination of MRI findings, such as traumatic axonal injury and subarachnoid hemorrhage, and DTI metrics yielded superior estimation performance of symptom recovery at 3 months after injury than MRI findings alone. There is an increasing interest in combining multiple MRI features detected on different imaging modalities (eg, volumetrics, resting-state functional MRI, DTI, magnetic field correlation) to increase the accuracy of differentiating patients with mild TBI from controls. Again, advanced MRI tries to take advantage of pathophysiological changes to identify potential biomarkers of mild TBI. Detection of microhemorrhages in mild TBI is important, as the presence of hemorrhage also correlates with injury severity. Blood oxygen level–dependent functional MRI can highlight areas of altered functional connectivity in patients with mild TBI.6 Likewise, other MRI sequences aim to detect abnormalities in perfusion and metabolic changes after traumatic injury.7 A composite model, incorporating multiple imaging biomarkers associated with distinct pathophysiological processes of mild TBI may improve diagnosis and prognosis on an individual level.

It remains very challenging to determine the optimal timing and specific MRI sequences in the evaluation and management of mild TBI that could have the most revealing prognostic value. Richter et al2 emphasized that the earliest MRI was more revealing of certain biomarkers for estimation of outcomes than later MRIs. Interestingly Richter et al2 used the term ultra-early MRI to highlight the prognostic value of early findings on MRI. Because DTI in the acute period (ie, 48-72 hours postinjury) has shown an increase in FA and an overall decrease in diffusivity postulated to be due to cytotoxic edema after the injury, more research is needed to determine the time course of edema that best manifests on imaging and with outcomes.

Future studies to explore the prognostic value of imaging biomarkers in mild TBI would benefit from larger sample size, external validation of the presented results, and incorporation of time-dependent and multiple sequences to enhance risk prediction of outcomes. Given the large spectrum of mild TBI and the scarcity of imaging data available for research, future efforts should focus on making available sufficiently large, curated, and standardized imaging libraries to allow for more robust analysis of imaging features to better understand their role in diagnosis and prognosis of mild TBI.

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Article Information

Published: March 18, 2021. doi:10.1001/jamanetworkopen.2021.1824

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Massaad E et al. JAMA Network Open.

Corresponding Author: Elie Massaad, MD, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, 25 Shattuck St, Boston, MA 02115 (

Conflict of Interest Disclosures: None reported.

Centers for Disease Control and Prevention. Surveillance report of traumatic brain injury-related emergency department visits, hospitalizations, and deaths: United States, 2014. Accessed February 23, 2021.
Richter  S, Winzeck  S, Kornaropoulos  EN,  et al; Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Magnetic Resonance Imaging (CENTER-TBI MRI) Substudy Participants and Investigators.  Neuroanatomical substrates and symptoms associated with magnetic resonance imaging of patients with mild traumatic brain injury.   JAMA Netw Open. 2021;4(3):e210994. doi:10.1001/jamanetworkopen.2021.0994Google Scholar
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Eierud  C, Craddock  RC, Fletcher  S,  et al.  Neuroimaging after mild traumatic brain injury: review and meta-analysis.   Neuroimage Clin. 2014;4:283-294. doi:10.1016/j.nicl.2013.12.009PubMedGoogle ScholarCrossref
Chen  J-K, Johnston  KM, Frey  S, Petrides  M, Worsley  K, Ptito  A.  Functional abnormalities in symptomatic concussed athletes: an fMRI study.   Neuroimage. 2004;22(1):68-82. doi:10.1016/j.neuroimage.2003.12.032PubMedGoogle ScholarCrossref
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