Emerging MRI and metabolic neuroimaging techniques in mild traumatic brain injury
Correspondence Address: Source of Support: This study is supported by the National Natural Scientific Fundation of China (NSFC; No. 81271540 and No. 81301213) and the Science and Technology Commission of Shanghai Municipality grant (STCSM; No. 08411951200), Conflict of Interest: None DOI: 10.4103/0028-3886.144434
Source of Support: This study is supported by the National Natural Scientific Fundation of China (NSFC; No. 81271540 and No. 81301213) and the Science and Technology Commission of Shanghai Municipality grant (STCSM; No. 08411951200), Conflict of Interest: None
Traumatic brain injury (TBI) is one of the leading causes of death worldwide, and mild traumatic brain injury (mTBI) is the most common traumatic injury. It is difficult to detect mTBI using a routine neuroimaging. Advanced techniques with greater sensitivity and specificity for the diagnosis and treatment of mTBI are required. The aim of this review is to offer an overview of various emerging neuroimaging methodologies that can solve the clinical health problems associated with mTBI. Important findings and improvements in neuroimaging that hold value for better detection, characterization and monitoring of objective brain injuries in patients with mTBI are presented. Conventional computed tomography (CT) and magnetic resonance imaging (MRI) are not very efficient for visualizing mTBI. Moreover, techniques such as diffusion tensor imaging, magnetization transfer imaging, susceptibility-weighted imaging, functional MRI, single photon emission computed tomography, positron emission tomography and magnetic resonance spectroscopy imaging were found to be useful for mTBI imaging.
Keywords: Diffusion tensor imaging, functional magnetic resonance imaging, metabolic imaging, mild traumatic brain injury, neuroimaging
Traumatic brain injury (TBI) is a serious and common problem worldwide. The majority of TBIs are mild (mTBI), as reported by the Committee of the Head Injury Interdisciplinary Special Interest Group of the American Congress of Rehabilitation.  Recently, mTBI has gained attention as a significant public health problem; however, little is known about the short-term and long-term effects of mTBI on cognitive and vocational functioning as well as quality of life. ,,, Of the patients with mTBI, 30% of patients have residual neurologic or cognitive deficits that result in significant disability.  Routine neuroimaging techniques such as computed tomography (CT) and conventional magnetic resonance imaging (MRI) do not usually reveal all the information regarding structural abnormalities even in symptomatic patients.  However, recent advances in neuroimaging techniques made it possible to detect subtle structural, functional and metabolic abnormalities of brain. ,, This review discusses the application of diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), susceptibility-weighted imaging (SWI), functional MRI (fMRI), single photon emission computed tomography (SPECT), positron emission tomography (PET) and magnetic resonance spectroscopy imaging (MRS imaging) in mTBI.
Diffusion tensor imaging
In DTI, the diffusion anisotropy of water molecules in tissues is assessed, since water molecule mobility in tissues is not necessarily the same in all directions. , The speed and direction of the diffusion provide more details on the tissue microstructure of the brain.  Thus, DTI is used to characterize the structural integrity of neural tissue and to noninvasively trace neuronal tracts in the brain. ,,,, With DTI, abnormalities are detected using fractional anisotropy (FA) or other diffusion metrics such as apparent diffusion coefficient (ADC), mean diffusivity (MD) and radial diffusivity (RD). 
Over the past few years, an increasing number of DTI studies on white matter (WM) have been conducted in patients with mTBI; ,,,,,,,,,,,,,,, however, the results are not consistent. Some studies reported reduced FA values and elevated diffusivity (ADC, MD and RD) in the WM regions in patients with mTBI, ,, while other studies reported increased FA values and reduced diffusivity in the WM regions in patients with mTBI.  Furthermore, according to recent reviews and meta-analyses, ,, it has been reported that reduced FA values and elevated diffusivity are observed in the acute and chronic stages: Acute, subacute and chronic stage, ,,, while increased FA values and reduced diffusivity are observed in both the acute and sub-acute stages. ,, In recent studies, reduction in the MD in acute mTBI has been hypothesized to be related to cytotoxic edema,  whereas increased MD may be indicative of vasogenic edema that resolves with time. A steady decrease in WM diffusion anisotropy commensurate with an increase in the diffusivity values may indicate Wallerian degeneration More Details as a result of diffuse axonal injury or axonal transaction.  Some of the inconsistencies in DTI research findings are because of constraints in MRI technology; the time frame of scanning; sample characteristic such as type of injury, injury severity, post-injury interval and location; and study inclusion criteria.  Therefore, more research needs to be conducted to clearly understand the implications of the DTI findings in cases of mTBI.
Nearly all studies investigating abnormalities in the WM in patients with mTBI have used DTI. ,,,, Several studies have found a significant difference in multiple brain regions in trauma patients compared to the controls; ,,,, the regions of the brain usually affected include the corpus callosum, internal and external capsule, and centrum semiovale. Further, one previous study reported that the frontal association pathways (anterior corona radiata, uncinate fasciculus, superior longitudinal fasciculus, and forceps minor) and commissural fibers of the corpus callosum also show differences.  However, some studies have reported that there are no differences between mTBI patients and controls with regard to the DTI findings. A recent meta-analysis  showed varied patterns of WM abnormalities in the mTBI patients over time, and the corpus callosum was identified as the structure that is most likely to show changes on DTI images. Little is known about whether gray matter (GM) abnormalities can be observed on DTI scans of patients with mTBI, although several studies have reported increased diffusivity in GM. ,,, Recently, a research has reported increased FA in GM.  Further, an increase in FA has been reported to be related to gliosis.  However, because the sample size of the study was small, further investigation is necessary to verify the role of FA.
Thus, DTI seems to be helpful in mTBI, but caution is advised in combining data collected from different sites or using different protocols. And the difference in post-processing and analytic methods may produce difference in the results obtained. 
Magnetization transfer imaging
MTI relies on the principle that protons bound in structures exhibit T1 relaxation coupling with protons in the aqueous phase.  It is a quantitative technique that applies an off-resonance saturation pulse to selectively saturate protons associated with macromolecules.  These protons subsequently exchange longitudinal magnetization with free water protons, leading to a reduction in the detected signal intensity.
McGowan et al.  studied 13 patients who had experienced mTBI and 10 healthy volunteers; the patients were subsequently referred for neuropsychological follow-up owing to persistent cognitive deficit(s) based on conventional MR examinations and MTI (1.5 T). In their study, they calculated the average MTR values in the pons and the splenium of the corpus callosum. Their findings indicated that quantitative MTI analysis can detect abnormalities associated with mild head trauma that are undetectable on routine MR images but that are consistent with the results of neurocognitive tests in some patients. Moreover, they speculated that further refinement of this application may enhance the reproducibility of the analysis and aid in the discrimination of smaller abnormalities. Nonetheless, more work needs to be done on the relationship between MTR abnormalities and function outcomes.
Susceptibility weighted imaging
SWI is a modified high-spatial resolution three-dimensional gradient recalled echo (GRE) magnetic resonance technique that accentuates the magnetic properties of blood products.  It can provide information on the blood oxygenation level, which renders it useful in detecting small amounts of altered blood and blood products on neuroimaging. 
SWI is primarily considered to be helpful in the identification of hemorrhagic axonal injury in cases where smaller hemorrhages are not visible on CT or conventional MRI scans. , As has been described in several studies, , SWI can be used to detect the amount and localization of microhemorrhages that appear as low-signal foci after TBI. Further, SWI has been proven to be superior to T2*-weighted imaging and other existing MRI techniques for the detection of iron content and hemorrhage in the brain. However, to date, reports on the usefulness of SWI in cases of mTBI are limited.
Toth et al.  studied 14 patients with mTBI in whom the CT findings were negative. They underwent MRI within 3 days and 1 month after injury; high resolution T1-weighted imaging, DTI and SWI were performed at both time points. No microhemorrhage was found in the SWI scans. To our knowledge, microhemorrhage does not seem to be a frequent occurrence in mTBI. Thus, it is not surprising that microhemorrhages were not detected with SWI in patients with extremely mild injury.
Functional magnetic resonance imaging
mTBI is associated with an increased risk of impairment of cognitive and vocational functions as well as lower quality of life in some individuals. Patients with impaired cognitive performance often show decreased spontaneous brain activity on fMRI. ,, The idea of using fMRI in patients with mTBI has attracted the attention of a wide range of studies. ,,,, fMRI is a valuable method to investigate and identify the neuroanatomic substrates of cognitive disorders and monitor their treatment. 
McAllister et al.  studied the WM function of 12 mTBI patients within 1 month of the injury and 11 healthy controls using an auditory-verbal "N-back" task. The mTBI patients showed a significant increase in bifrontal and biparietal activation (right greater than the left hemisphere) and notable cognitive symptoms compared to the controls, but there were no between-group differences in the results of the N-back task. In a subsequent study, McAllister  scanned 11 mTBI patients and 6 controls after 1 year of injury and found that the mTBI patients showed a greater increase in task-related right frontal activation for the highest WM load relative to the controls. The findings are in agreement with other research  that used a similar N-back task as well as a measure of selective attention. All of these studies focus on WM circuit activation. In contrast, Stulemeijer et al.  examined the effect of mTBI on declarative memory circuit deactivation elicited by the N-back task in 43 patients (within 6 weeks of injury) and 20 healthy controls. Usually, it is difficult to assess the duration of post-traumatic injury (PTI); however, in this study, a significant negative correlation was found between PTI duration and left hippocampal activation. In another study, McAllister et al., studied 23 mTBI patients 1 month after the injury and 15 controls using an event-related fMRI task. The mTBI patients showed a reduction in the intensity and spatial extent of activation relative to the controls. These findings all indicate that fMRI is useful for detecting executive/frontal lobe function and episode memory function.
In addition to the work reviewed above, a few studies have examined alterations in fMRI brain activation patterns after interventions targeting mTBI symptoms, and have shown that patients with mTBI can show improvement. , Thus, fMRI can provide further understanding of mTBI pathophysiology and thereby facilitate the development of therapeutic and possibly preventive strategies. 
The following section reviews metabolic neuroimaging methods, SPECT, PET and MRS, which can provide important information regarding changes in brain metabolism after mTBI.  As the metabolic cascade of changes can occur at the molecular level in mTBI, these techniques are important. 
Single photon emission computed tomography
SPECT is a functional neuroimaging technique that is helpful for studying cerebral blood flow based on the distribution of radioactive pharmaceuticals in the brain.  It utilizes radioactive tracers for detecting a single photon.  Until now, several radioactive pharmaceuticals have been used in studies, such as technetium-99m-hexamethylpropyleneamine oxime ( 99 mTc-HMPAO), indine-123 N-isopropyl-p-iodoamphetamine ( 123 IIMP), technetium-99om-ethylcysteinate dimmer ( 99 mTc-ECD), 57-cobalt chloride ( 57 CoCl 2 ), 123 I-iomazenil (IMZ), 123 I ioflupane and 99 mTc-exametazime. ,
SPECT abnormalities have been found in mTBI patients with reduced perfusion in several studies. , Moreover, the majority of the regions that show hypoperfusion are found in the frontal and parietal lobes, although a number of subjects had hypoperfusion in the basal ganglia, as mentioned in a review.  Previous studies have shown that SPECT shows sensitivity for mTBI imaging;  however, it may not be highly specific, as other comorbid conditions such as migraine headaches, chronic pain, drug abuse and alcohol abuse also show changes in the same brain regions.  Despite this, it is generally accepted that the absence of abnormalities on SPECT images is indicative of good recovery. , Thus, while its specificity and positive predictive value are low, SPECT shows good reliability for assessing mTBI.
Positron emission tomography
Similar to SPECT, PET is also a type of molecular imaging technique. PET utilizes radioactive materials that produce two gamma rays that move in opposite directions.  The most common radioisotope is fluorine-18, which is used as a measure of glucose uptake and metabolism in clinical PET studies; H2 15 O is also a radioisotope that can be used in PET studies. 
Decreased glucose metabolism is found in the medial temporal, posterior temporal, and posterior frontal cortex in mTBI patients.  Moreover, an increase in FDG is also found in the anterior temporal and anterior frontal cortex. , Both hypo- and hypermetabolism in the same region were observed in a study.  However, the findings of FDG-PET are inconsistent. Despite this limitation, FDG-PET can be used to noninvasively measure alterations in cerebral glucose metabolism and can therefore provide important information about mTBI. Nonetheless, it is necessary to conduct further studies on specific PET biomarkers for mTBI and to correlate these findings with the results of neuropsychological tests.
As with all techniques involving radiation, consideration has to be given to the dose received by the patient, and therefore limits the performance of serial examinations. 
Magnetic resonance spectroscopy imaging
MRS imaging is a powerful method that combines MRI and MRS for examining brain metabolism.  MRS obtains chemical signals, or metabolites, from a region of interest (ROI or voxel).  A spectrum of peaks is generated whereby each peak is reflective of a chemical that resonates at a specific frequency, and the height of the peak reflects the concentration of the specific marker in the brain.  Several metabolites, lipids, lactate-N-acetyl aspartate (NAA), glutamate glutamine (Glx), choline (Cho), myo-inositol (mI) and creatine (Cr) are of interest as markers of injury.
In acute and subacute mTBI studies, , the level of NAA, which is a marker for viable neurons, axons and dendrites, is believed to decrease;  moreover, the level of Glx and Cr is increased in the WM but the level of Glx is decreased in the GM.  Glx is the primary excitatory neurotransmitter in the brain and is tightly coupled to glutamine, while Cr is used as an internal reference for the measurement of other peaks.  However, the level of NAA is decreased in WM and the level of choline, which is reflective of diffuse axonal injury, is increased in chronic mTBI. , These findings showing persistent changes appear to contradict previous findings where the metabolite levels normalized after several months. Moreover, recently, a study by Sarmento et al., reported that the NAA/Cr level was lower in those with chronic headache as compared to those with acute headache.
In summary, MRS is a quantitative technique that had good repeatability. Longitudinal MRS studies can also be used to measure injury outcome and monitor therapeutic response. However, we need to further study the sensitivity and specificity of MRS. Further, short-echo time methods or other means of obtaining additional biochemical measures would be advantageous.
Overall, DTI, MTI, SWI, fMRI, SPECT, PET and MRS are powerful, non-invasive, objective tools that can provide a deeper understanding of mTBI, and they all show great promise as potential diagnostic tools for mTBI. Currently, they are used for mTBI studies and are not popular in clinical practice. This review indicates that they have potential for use in clinical assessment.