Mild traumatic brain injuries, or concussions, often result in transient brain abnormalities not readily detected by conventional imaging methods. Several advanced imaging studies have been evaluated in the past couple decades to improve understanding of microstructural and functional abnormalities in the brain in patients suffering concussions. The thought remains a functional or pathophysiologic change rather than a structural one. The mechanism of injury, whether direct, indirect, or rotational, may drive specific clinical and radiological presentations. This remains a dynamic and constantly evolving area of research. This article focuses on the current status of imaging and future directions in concussion-related research.
Key points
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Conventional neuroimaging techniques like head computed tomography and traditional magnetic resonance imaging (MRI) anatomic sequences are relatively insensitive to microstructural or functional abnormalities that are associated with mild traumatic brain injuries (mTBIs).
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Several advanced neuroimaging techniques, specifically MRI related, are being developed to gain insight into microstructural, functional, and metabolic changes secondary to brain trauma and have become pivotal in understanding mTBI pathophysiology.
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None of the current available techniques can yet be implemented in individual patients seen in a clinical setting.
Introduction
Sports-related concussions (SRCs) affect millions of athletes worldwide each year. In the United States, approximately 3.8 million concussions are diagnosed per year, which is thought to be a gross underestimation because a large number of SRCs go unreported. ,
SRCs also have attracted considerable attention in the public health domain due to possible risk of long-term neurologic sequelae from repetitive head injuries. Although concussions are a subset of mild traumatic brain injury (mTBI), the terms often are used interchangeably; for the purpose of this article as well, mTBI and SRC are used interchangeably.
Noncontrast head CT is the imaging test of choice in evaluating and triaging patients with acute head trauma. The primary role of imaging in the acute setting is detection of intracranial hemorrhage and fractures. Brain contusions often may remain occult in the hyperacute stage; however, they can be seen on noncontrast computed tomography (CT) in the acute to subacute state, underscoring the need for close follow-up in the acute setting.
Magnetic resonance imaging (MRI) anatomic sequences can depict contusions and gross hemorrhage in traumatic brain injury (TBI); however, traditional sequences are relatively insensitive to microstructural or functional abnormalities that are associated with mTBI. These abnormalities could serve as a key prognostic biomarker to predict long-term functional neurologic and cognitive status. As a result, the American college of Radiology, American Academy of Neurology, and the American Medical Society for Sports Medicine do not recommend any routine imaging in patients with mTBI.
The goal of advanced neuroimaging techniques, specifically MRI, is to try to gain insight into microstructural, functional, and metabolic changes secondary to brain trauma and establish potential objective imaging biomarkers that could help predict outcomes.
Structural MRI techniques have focused on studying both macrostructural changes using quantitative morphometry to analyze posttraumatic changes in brain volumes and microstructural white matter changes using diffusion tensor imaging (DTI). Susceptibility-weighted imaging (SWI) is used to detect posttraumatic microhemorrhages. Functional cortical mapping is performed via blood oxygenation level–dependent (BOLD) MRI techniques that use certain imaging sequences sensitive to blood oxygenation levels and are able to evaluate changes in brain connectivity at rest as well as while performing tasks. Proton magnetic resonance spectroscopy (MRS) has been studied to evaluate metabolic changes in the brain after injury. Lastly, studies also have examined changes in cerebral blood flow (CBF) using magnetic resonance (MR) perfusion imaging techniques. These techniques are described in further detail.
Diffusion tensor imaging
Among the advanced imaging modalities currently being studied in evaluating patients with mTBI, DTI has been studied most extensively.
DTI of the brain relies on evaluation of brownian motion of water molecules. This diffusion may be isotropic—that is, similar in all directions, such as unrestricted motion in cerebrospinal fluid—or anisotropic—that is, preferentially in 1 direction. Diffusion in intact white matter tracts is anisotropic preferentially along the direction of tracts. Apparent diffusion coefficient (ADC), mean diffusivity, and fractional anisotropy (FA) are commonly used estimates that can be computed to quantitatively assess the diffusion properties in the brain, acting as a surrogate for structural organization. The FA estimate gives an estimate of degree of anisotropic diffusion along the interrogated tissue volume , ( Fig. 1 ).
DTI can aid assessment of white matter injury resulting from shearing strain seen in the setting of rapid acceleration and deceleration, often without leading to gross disruption in anatomic connections. These changes often are occult on conventional anatomic MRIs.
Imaging analysis in DTI is multifaceted, including evaluation of scalar multiparametric maps for whole-brain FA, MD, and ADC as well as assessment of vector or directionality information available on the color codes maps. This multipronged approach can assist not only in detecting the burden of abnormality but also in characterizing the anatomic location more precisely to assess for clinical functional impact of the injury. Although qualitative assessment of the DTI-based multiparametric maps can be used in individual clinical settings, they often yield greatest information in quantitative evaluation of in grouped comparisons. This can be based on anatomic region of interest–based assessment; deterministic, probabilistic 3-dimensional (3-D) tractographic approach; or global analysis using tract-based spatial statistics.
In a review by Hulkower and colleagues, examining more than 100 studies assessing the role of DTI in TBI, an overwhelming majority of studies demonstrated reduced FA values in TBI regardless of injury severity or time of injury. Brain anatomic areas implicated most commonly in TBI-related DTI studies include the corpus callosum, frontal lobes, internal capsule, and cingulum. Although it is likely that these structures are inherently more susceptible to abnormalities in TBI due to susceptibility to sheer stress–related injuries, it also is possible that being one of the highest FA tracts of the brain, these are more likely to yield statistically significant detectable abnormalities. The abnormalities in these structures also were noted in 7 of 8 studies specifically evaluating DTI in SRC.
Having an adequate control population is also one of the limitations for accurately understanding the DTI changes, because there is inherent variability in normal brain structural organization. In a recently published study by Niogi and colleagues evaluating DTI in active professional football players, the investigators ascertained that comparing athletes’ postconcussion scans to their own premorbid baseline scans might be superior to comparing the study population to healthy age-matched controls.
Changes in DTI parameters are not limited to athletes with clinically diagnosed concussion. Bahrami and colleagues examined the effects of subconcussive impacts resulting from a single season of youth football on changes in specific white matter tracts detected with DTI and found statistically significant changes in FA values in the inferior fronto-occipital fasciculus and the superior longitudinal fasciculus, even in absence of clinically diagnosed concussion.
One of the major limitations of DTI is the lack of ability to resolve multiple fiber orientations within a single voxel. Newer methodologies being investigated to improve the resolution of crossing fibers include high angular resolution diffusion imaging, diffusion spectrum imaging, neurite orientation dispersion and density imaging model, and Q-ball imaging. ,
Despite multiple advances, DTI still remains primarily a research tool. Challenges that have precluded wider adoption of DTI for clinical use are due mainly to the fact that the abnormalities seen are predominantly quantitative in nature; they are detected at a group level, and these findings cannot be reliably translated to individual patients in a standardized fashion. Additionally, there remain inconsistencies and differences in techniques between the reported studies, lack of technically rigorous normative ranges based on large control datasets, lack of premorbid baseline data, and unclear correlation between imaging abnormalities and long-term clinical outcome.
Quantitative brain morphometry
Volumetric brain imaging is performed using high-resolution 3-D T1-weighted imaging sequences, which can be obtained on most MR scanners in routine clinical use. Automated software can be used to segment gray matter and white matter structures and perform volumetric analysis. ,
Although regional and global brain atrophy has been well described in patients with moderate and severe TBI, it has not been well studied in mTBI.
Zhou and colleagues evaluated longitudinal changes in brain volume after mTBI over a 1-year period and described decrease in global brain volume as well as volume loss in anterior cingulate white matter, cingulate gyrus isthmus, and precuneus gray matter in concussed patients compared with age-matched controls. Furthermore, the investigators also reported correlation of volumetric changes with postconcussion symptoms.
Burrowes and colleagues studied 51 mTBI patients with and without history of posttraumatic headache by obtaining MRI scans at 4 time points, within 10 days of injury and then at 1 month, 6 months, and 18 months postinjury. The investigators found decreased gray matter volume in mTBI patients compared with healthy controls and also reported regional decrease in gray matter volumes in patients with posttraumatic headache versus asymptomatic mTBI patients. This suggests that symptomatic mTBI patients may have an exaggerated long-term clinical course compared with asymptomatic mTBI, particularly as it relates to cognitive sequela, which have been shown to be associated with volumetric estimates.
In another recently study, Patel and colleagues studied 70 military personnel with mTBI were found to have reduced mean volume in different regions of the frontal, parietal, and temporal lobes compared with controls. Limitations of morphometric studies include intersubject variations in brain morphology, lack of comparison to patient’s preinjury scans, and relatively small cohort of patients studied. Further larger longitudinal studies may help in establishing a clinical role of morphometric studies in the management of patients with mTBI.
Proton magnetic resonance spectroscopy
Proton MRS like DTI has been studied extensively in patients with mTBI.
Proton MRS, thought to hold promise as a noninvasive tool that can be utilized in individual patients, also known as virtual biopsy, relies on exploiting small changes in the precessing frequency of protons based on their chemical environment, yielding estimates of metabolite peaks (at specific parts per million) with quantifiable concentrations.
When a single voxel is sampled, the interpretation relies on the concentrations as depicted by metabolite ratios or absolute concentrations. When whole-brain multivoxel sampling is performed, however, a metabolite map or MRS imaging can be performed, yielding both quantitative and qualitative information.
Commonly detected metabolites in normal brain include N -acetyl-aspartate (NAA), which is considered a neuronal marker; choline (Cho), which is a measure of cell membrane turnover; creatine (Cr), which is a marker of energy metabolism (and commonly used as an internal reference); myoinositol (ML), which is marker for glial cells; and glutamate and glutamine (combined peak, referred to as Glx) an excitatory neurotransmitter. ,
MRS can be performed using single-voxel or multivoxel techniques. Single-voxel technique has a higher signal-to-noise ratio but it interrogates only a small volume of brain tissue at a time, therefore making placement/selection of the volume of interest crucial. Multivoxel technique on the other hand interrogates a much larger volume of tissue at the expense of lower signal-to-noise ratio and longer acquisition time.
Several studies have evaluated the role of MRS in patients with concussion. NAA, Cho, and Cr are studied most commonly studied. The most consistent finding in most studies is reduced NAA levels in gray matter and white matter and elevated Cho levels. The magnitude of these changes increases with increase in injury severity.
Decreased NAA levels seen in the acute phase after injury may return to normal or remain depressed in the subacute phase, which does not necessarily correlate with neuropsychological recovery.
Elevated Cho levels are believed to be related to cell membrane breakdown in the acute stage and likely secondary to glial proliferation in the chronic stage. Although some studies have shown elevated Cho levels in mTBI, others have demonstrated no statistically significant difference in Cho levels on spectroscopy.
MRS study of symptomatic former National Football League (NFL) players revealed decreased parietal white matter Cr and NAA levels compared with controls. Reduced Cr levels were associated with higher cumulative head impact index. The study also revealed positive correlation between levels of Glx and ML in anterior cingulate gyrus with presence of behavioral or mood symptoms. ,
Overall, the diagnostic utility of proton MRS as a biomarker for mTBI is highly debatable. It is fair to say that it remains to be studied in larger longitudinal studies to evaluate sensitivity and specificity of MRS in mTBI before it can be applied reliably to individual patients.
Magnetic resonance susceptibility–weighted imaging
SWI is the most sensitive MR imaging sequence to detect intracranial hemorrhage, including microhemorrhage that can remain occult on conventional anatomic imaging. Presence of unpaired electrons in deoxyhemoglobin in the acute stage and methemoglobin in subacute stage of hemorrhage result in abnormal magnetic susceptibility detected as areas of signal loss on the SWI image ( Fig. 2 ).
