Recent Neuroimaging Techniques in Mild Traumatic Brain Injury

Abstract

Back to table of contents Previous article Next article SPECIALFull AccessRecent Neuroimaging Techniques in Mild Traumatic Brain InjuryHeather G. Belanger Ph.D.Rodney D. Vanderploeg Ph.D.Glenn Curtiss Ph.D.Deborah L. Warden M.D.Heather G. Belanger Ph.D.Search for more papers by this authorRodney D. Vanderploeg Ph.D.Search for more papers by this authorGlenn Curtiss Ph.D.Search for more papers by this authorDeborah L. Warden M.D.Search for more papers by this authorPublished Online:1 Jan 2007AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail E ach year an estimated 1.5 million people in the United States alone sustain a nonfatal traumatic brain injury. 1 Approximately 80% of these injuries are classified as mild 2 with loss of consciousness (LOC) lasting less than 30 minutes, an initial Glasgow Coma Score (GCS) of 13 to 15, and posttraumatic amnesia lasting less than 24 hours. 3 Increasingly, mild traumatic brain injury (TBI) has been recognized as a major public health concern with an annual worldwide incidence ranging from 100 to 550 per 100,000 people. 4 – 7 The economic impact of mild TBI is substantial, accounting for about 44% of the $56 billion annual cost of TBI in the United States. 8 Although it is clear that most patients suffer some acute cognitive difficulties, the nature and course of postacute cognitive recovery remains an area of intense controversy. Most patients recover fully from mild TBI, but 7% to 33% 9 – 11 have persistent problems. Frequently, complaints involve a constellation of physical, emotional, and cognitive symptoms collectively known as postconcussion syndrome, often without demonstrable structural changes to the brain 12 or neuropsychological dysfunction. 13 , 14 Clinical neuroimaging findings are normal in the majority of mild TBI cases. For example, Borg et al. 15 report that 5% of individuals who have a GCS score of 15, 20% with a GCS score of 14, and 30% with a GCS score of 13 have abnormal findings on clinical computed tomography (CT). Thus, a large majority of mild TBI patients, both symptomatic and asymptomatic, have normal CT scans. Similarly, although magnetic resonance imaging (MRI) is more sensitive than CT in mild TBI patients 12 , 16 , 17 and MRI findings have been correlated with neuropsychological performance in mild TBI, 17 many symptomatic patients have normal MRI scans. Indeed, 43% to 68% of mild TBI patients have normal structural scans on MRI. 18 , 19 This may be either because there is no structural brain damage in those symptomatic patients with normal scans or because current technology is unable to detect it. 20 – 22 Certainly, microscopic diffuse axonal injury, reported as present in autopsy studies of mild TBI, 23 – 25 is largely undetectable using traditional neuroimaging techniques. 23 , 26 Alternatively, others contend that persisting symptoms are the result of psychological mechanisms, such as poor coping styles, 27 , 28 emotional reactions to an adverse event, 29 or expectations of symptoms that may occur following a mild TBI. 30 Though postconcussion syndrome has been recognized for at least the last few hundred years, 5 the debate over the persistence of symptoms following mild TBI in a minority of individuals has led to postconcussion syndrome being a particularly controversial diagnosis in the medical-legal arena. When clinical neuroimaging findings are present following a mild TBI, the classification changes to “complicated mild TBI,” which has a 6-month outcome more similar to moderate TBI. 31 Therefore, it is in the symptomatic mild TBI patients with negative clinical neuroimaging that a search for more sensitive imaging techniques or biological markers continues. Newer and experimental neuroimaging techniques provide promise in this regard and may also be useful in demonstrating the physiological mechanisms of rehabilitation treatment effects. 32 These include structural or chemical techniques, such as diffusion tensor imaging (DTI), magnetization transfer imaging (MTI), and magnetic resonance spectroscopy, and functional techniques such as functional MRI (fMRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT). This article critically reviews the existing literature of these newer neuroimaging techniques in individuals with mild TBI. Criteria for Literature ReviewThe following criteria were employed to evaluate the findings from many different technologies and to suggest directions for future research:1. The Technique Should Be Sensitive to Brain InjuryThere must be evidence of convergent validity either with a concurrent history of brain injury or with other tests of brain injury, such as neurological examination, neuropathological examination, or conventional MRI and/or CT findings. Studies conducted with moderately to severely injured patients suggest that this criterion has been met for the aforementioned techniques. One purpose of this review will be to evaluate the extent to which this criterion has been met for patients with mild TBI. This criterion will be met if there are imaging abnormalities in patients with a known history of mild TBI relative to comparison subjects. In meeting this criterion, positive neuroimaging findings should also correspond to known pathology associated with mild TBI. Animal models suggest that there can be structural or functional changes in mild TBI with increased neurofilament reactivity within 30 minutes of injury 33 and subsequent impaired anterograde axoplasmic transport with swelling of the axonal cylinder and disconnection of the axon from its target. 34 The extent of diffuse axonal injury (DAI) is correlated with recovery rate in monkeys. 35 Povlishock and Becker 36 have demonstrated that mild injury can elicit axonal swelling that may persist unchanged, degenerate, or undergo a regenerative response, suggesting some variability in recovery prognosis for mild TBI. Early indication of DAI in mild TBI, however, primarily manifests as misalignment of the cytoskeletal network 33 , 37 observed microscopically. Autopsy evaluations in humans have revealed that the extent of DAI can be identified through postmortem microscopic evaluation. 23 – 25 Autopsy of mild TBI patients who died of unrelated causes suggests that the corpus callosum is the most frequent site of DAI, 38 with other frequently reported areas being the brainstem and lobar white matter. 23 Clearly, finding a new technology with more sensitive identification of these injuries and processes in vivo would be useful, both to clinicians and to patients, who often search for objective markers of their symptoms. 2. The Technique Provides Incremental Validity Above and Beyond That Provided by Conventional Structural MRI and/or CT ScansIf experimental neuroimaging techniques add nothing to current clinical assessment protocols, they simply add to health care costs. This criterion is met if a given neuroimaging technology more fully detects or demonstrates damage in patients whose conventional MRI/CT scans are normal. Alternatively, the technique may detect damage in brain regions that appear normal on conventional scans.3. Ideally, the Technique Should Correlate With Clinical Examination or Symptom Presentation, or Have Predictive ValidityFindings of the neuroimaging technique should be related to functional status as measured in some objective manner (e.g., neurological examination or neuropsychological testing). This establishes that an identified neuroimaging anomaly is not simply an incidental finding. The significance of an unusual pattern of metabolism on PET in an individual who had a mild TBI is unclear if the patient is asymptomatic and presents normally on clinical examination. From a clinical standpoint, correlation with function is important to interpreting the meaning of a positive neuroimaging finding. The first step in meeting this criterion is to demonstrate correlations between abnormal neuroimaging findings and measures of functioning. A clinically useful second step would be to demonstrate correlations between abnormal neuroimaging findings and measures of future functioning. For example, prospective studies in which acute neuroimaging findings predict persistent symptoms beyond the typical 3-month recovery period 39 would be valuable. Structural and Chemical Neuroimaging FindingsDiffusion Tensor Imaging Diffusion tensor imaging (DTI) is a relatively new MRI application that capitalizes on the diffusion of water molecules for imaging the brain. While diffusion-weighted MR imaging measures the diffusion of water molecules in a particular direction, DTI takes this a step further by imaging diffusion in a number of different directions—typically six. This allows for the calculation of a matrix or tensor which represents diffusion in three dimensions. 40 In the white matter, water diffusion is higher along fiber tracts than across them, which allows for directional measurement of diffusion and, hence, measurement of structural integrity. The most robust DTI parameter, 41 fractional anisotropy, provides a measure of tissue microstructure by quantifying the extent to which diffusion occurs in one particular direction within each voxel. Fractional anisotropy is correlated with measures of fine motor speed and verbal fluency in normal aging. 42 , 43 Abnormalities in white matter are detected via DTI in patients with severe head injuries 11 months to 9 years following injury. 44 , 45 Only one study 46 has been conducted with mild TBI patients. This study examined five patients within 24 hours of injury and 10 comparison participants and then retested two of the five patients at 1 month postinjury. Various regions of interest (ROI) were selected, and in each case only from white matter that appeared normal on conventional MR images (i.e., normal-appearing white matter or “NAWM” hereafter). Mild TBI patients demonstrated reduced directional diffusion (fractional anisotropy) in white matter relative to comparison participants, both within 24 hours and at 1 month postinjury. More abnormalities were noted in the internal capsule and the corpus callosum relative to the external capsule. These findings are consistent with animal models of mild TBI. Furthermore, the study found recovery in some areas in two patients who were rescanned 30 days after injury. Based on one study, then, DTI has demonstrated sensitivity to mild TBI at least up to 1 month postinjury. This study also meets the incremental validity criterion as it demonstrated reduced fractional anisotropy in NAWM on conventional MRI. However, this study did not address whether DTI abnormalities in mild TBI are related to clinical variables and/or outcome. Cognitive recovery in head injury correlates with restoration of white matter integrity assessed with xenon-enhanced CT measures of local cerebral perfusion. 47 As such, DTI may be in a unique position to predict recovery in patients with TBI. This will be particularly relevant to mild TBI which results primarily in axonal injury, often within the context of normal clinical CT/MRI scans. The potential ability of DTI to identify subclinical DAI neuropathology explains the excitement about this modality. Magnetization Transfer Imaging Magnetization transfer imaging (MTI) is another technique that increases the contrast between tissues by exploiting the exchange of protons between water and macromolecules. When a radio frequency pulse is applied, it selectively saturates those protons that are bound to macromolecules. 48 This technique provides information about tissue changes not detected with conventional T1- and T2-weighted MR images. The magnetization transfer ratio (MTR) represents a quantitative measure of the structural integrity of tissue, with reductions in MTR suggestive of neuropathology. Only a few studies have been conducted with TBI patients. Results suggest that MTI is able to detect abnormalities not seen on traditional MRI scans among TBI patients of mixed severity, though there is poor correlation with outcome to date. Bagley et al. 49 scanned 28 patients, 21 of whom were symptomatic, of varying severity 1 to 29 days postinjury. Of the five patients with mild TBI (GCS=13 to 15), only one had abnormal MTR findings (in temporal and occipital lobe white matter and the internal capsule). As this patient with mild TBI and abnormal MTR was placed in a long-term care facility 6 months postinjury, it may be that only asymptomatic patients have normal MTR values. Consistent with this hypothesis, these authors conducted another study focusing specifically on 13 patients with persisting cognitive complaints following mild TBI, 50 most of whom were “within months” of injury. Twelve of these patients had normal MRI scans. These investigators found significantly lowered MTR in patients relative to comparison subjects in the splenium of the corpus callosum consistent with autopsy data showing the corpus callosum as the most frequent site of DAI following mild TBI. 38 Regional MTR values correlated with only two of the 25 neuropsychological measures administered. Specifically, MTR values in the splenium were moderately correlated with verbal recognition memory (r=0.59), while MTR values in the pons, although not abnormally low, were moderately correlated (r=0.58) with visual attention span. Finally, Sinson et al. 51 studied 30 patients with a mean admitting GCS score of 11, who were a median of 41 days postinjury. Five of the six patients who had abnormal MTRs had mild TBI (GCS=14 or 15). Their abnormalities were detected in the splenium, internal capsule, pons, and white matter of the temporal and occipital lobes. It is curious that MTR anomalies were more prevalent in mild TBI than in moderate TBI. However, of note is an autopsy study of severe brain injury 52 suggesting the need for intact pathways to cause injury at a distal location; specifically, more damaged frontal cortex related to less damage in the thalamic reticular nucleus. In summary, with mild TBI patients, MTI largely detects abnormalities within the first month or two following mild TBI. A promising aspect of these findings is that demonstrated areas of abnormalities are consistent with known DAI neuropathology in mild TBI (i.e., lobar white matter, corpus callosum). Further study is needed to demonstrate associations with clinical variables.Magnetic Resonance Spectroscopy In contrast to neuroimaging techniques offering structural information about brain integrity, magnetic resonance spectroscopy (MRS) offers in vivo neurochemical information by detecting signals from individual solutes in body tissues. This technique can be used to assess metabolic irregularities following brain injury. MRS is based on measuring magnetic signals from certain nuclei (mostly 1H or 31P) in response to radiofrequency pulses. The main metabolites measured by 1H MRS are: N -acetylaspartate, which is a quantitative marker of neuronal health 53 and is significantly decreased in demyelinated areas in multiple sclerosis; choline, which is a marker of inflammation 54 and is elevated in cell proliferation; 55 myo-inositol, which is a glial marker; 56 lactate, which is an indirect indicator of ischemic and hypoxic conditions; 55 , 57 and creatine and phosphocreatine, which are related to energy metabolism. 58 Data from MRS studies are often expressed as changes in the ratio of N -acetylaspartate to creatine or choline. Reporting metabolite ratios allows investigators to control for reductions in metabolites that may be due to variations in cellular density. 59 Studies conducted with moderately to severely injured patients 1 to 2 months postinjury suggest that MRS is sensitive to injury and correlates with neuropsychological functioning and functional outcomes. 60 – 62 Longitudinal investigations suggest that initially reduced white matter N -acetylaspartate returns to near-normal levels by 2 months in mild TBI patients 63 and by 6 months in moderately to severely injured TBI patients, 61 while gray matter N -acetylaspartate continues to be abnormally low for at least 6 months postinjury 61 in moderate to severe brain injury. However, the study conducted with mild TBI patients sampled from pericontusional areas in white/gray matter that were evident on CT (making these complicated mild TBI patients), while the study conducted with moderate to severe TBI patients sampled only from normal-appearing occipital lobe gray and white matter. Therefore, the recovery rate of white matter N -acetylaspartate for uncomplicated mild TBI may be faster than suggested by these data. Garnett et al. 64 studied a range of injury severity including mild TBI (defined as either GCS=13 to 15 or PTA <24 hours). The eight mild TBI participants were an average of 8 days postinjury and half had normal MRI findings on T2-weighted images. Significant elevations in choline/creatine ratios were detected in mild TBI patients relative to comparison subjects in NAWM of the frontal lobes. Although N -acetylaspartate/creatine ratios were significantly reduced in moderately and severely injured patients, this ratio was not significantly reduced in mild TBI patients. Interestingly, lactate was not apparent in the spectra of any participants, regardless of severity. In mild TBI cases (GCS=14 or 15) with normal clinical MRI scans, Cecil et al. 65 reported N -acetylaspartate/creatine ratios in the splenium of the corpus callosum significantly below comparison subjects in 11 of 16 patients. It is not known whether these abnormalities correlate with clinical variables. Also, given the wide range of time since injury in these patients (i.e., 9 days to 4.5 years), it unclear if the low N -acetylaspartate/creatine ratio values were present only in the acute injury patients or also in the more chronic patients. Govindaraju et al. 66 sampled tissue appearing normal on MRI clinical scans in a study of mild TBI patients (GCS=13 to 15, LOC <30 minutes) who were an average of 13.3 days postinjury. They found no focal abnormalities in metabolites in 15 of the 16 subjects tested, although group data differed significantly from comparison subject data in several regions. Specifically, increased choline/creatine ratios in occipital lobe gray matter, decreased N -acetylaspartate/creatine ratios in parietal white matter regions, and decreased N -acetylaspartate/choline ratios in occipital regions were noted in the patient group. Metabolite ratios did not correlate significantly with clinical measures either acutely or at discharge. In addition, most of these patients (10 out of 16) had abnormal CT scans, calling into question the incremental validity of the neuroimaging data. Son et al., 63 in an investigation of seven mild TBI patients (GCS=13 to 15) with abnormal CT scans, found low N -acetylaspartate/creatine and elevated lactate/creatine ratios in pericontusional areas (mostly temporal lobe) relative to comparison subjects within 7 days of injury. Two months later, there were no significant differences between mild TBI patients and comparison subjects in N -acetylaspartate/creatine ratios, while lactate/creatine ratios were undetectable in two patients and significantly reduced in three others. Clinical correlates or outcomes of these early abnormalities were not examined, although the researchers indicated an “uneventful” course in all patients, with all seven returning to preinjury activities. In summary, MRS offers promise with regard to the sensitivity criterion, although metabolite abnormalities were inconsistent across studies. Specifically, mild TBI resulted in increased lactate acutely in one study 63 but not in another. 64 Similarly, there were significantly reduced N -acetylaspartate/creatine ratios in the splenium of the corpus callosum, 65 in parietal white matter, 66 and in white/gray matter of pericontused areas of the temporal lobes, 63 but not in white matter of the frontal lobes. 64 Finally, two studies found elevated choline/creatine ratios, one in the white matter of the frontal lobes 64 and one in occipital lobe gray matter. 66 Metabolite abnormalities were not apparent in other sampled brain regions, such as the brain stem or cerebellum. 66 Also, the incremental validity of MRS is unclear as most studies were conducted at least in part with patients who had abnormal clinical scans. Further research is also needed to address relationships with functional correlates. The one study that addressed this issue found no relationship between metabolite ratios and outcomes. 66 MRS research, like many of these newer techniques, suffers from disparate acquisition protocols across research groups. In addition, the use of ratios may be problematic in TBI. Creatine, for instance, is used to standardize other brain metabolites because it is relatively invariant and uniform in normal brain tissue. 67 However, it is not known if creatine is stable in TBI. Problems arise if creatine is affected similarly to the metabolite of interest. Indeed, there is suggestion from other literatures that creatine may be reduced in hypermetabolic and raised in hypometabolic states. 68 , 69 As metabolism may be compromised in mild TBI, 71 it is questionable to assume invariance of creatine in mild TBI. Magnetic Source Imaging Magnetic source imaging (MSI) utilizes magnetoencephalograpic technology to acquire electrophysiological data from the brain and combines it with structural data from conventional MRI technology. Only one MSI study has been conducted with mild TBI patients (GCS=13 to 15, LOC<20 minutes) who were 2 to 38 months postinjury. 72 One group (N=10) had normal clinical scans and no postconcussive complaints while the other group (N=20) consisted of patients with continued postconcussive complaints, 10% of whom had abnormal clinical scans. Using MSI, abnormalities were generally detected in symptomatic patients but not in asymptomatic patients. Abnormal low-frequency magnetic activity and magnetic slowing considered in combination were most specific to postconcussive symptoms. Only one patient from the group with mild TBI but no postconcussive complaints had abnormal magnetic slowing. MSI appears to be sensitive in mild TBI patients with postconcussion symptoms, but not necessarily in all mild TBI patients. Incremental validity was also present; the authors reported that MSI was three times more sensitive than MR imaging alone. Functional correlates were not examined. Functional Neuroimaging FindingsFunctional MRI Functional MRI (fMRI) is a widely used neuroimaging technique for measuring brain functioning. The assumption behind blood-oxygen-level-dependent (BOLD) fMRI, which is most commonly utilized, is that an increase in neuronal activity results in an increase in local blood flow, leading to reduced concentrations of deoxyhemoglobin, a product of oxygen consumption. This reduction of deoxyhemoglobin leads to a smaller local magnetic field gradient, which results in a greater T2 image and an increase in MRI signal. However, the relationship between the signal change in T2 weighted images and vascular flow differences are not fully understood and may be nonlinear. There is an initial hypo-oxygenation response to stimulation that is highly localized and then followed by several seconds of widely dispersed hyperoxygenation. Studies of working memory in moderate to severe TBI suggest blood flow abnormalities relative to comparison subjects, particularly in the frontal lobes. 72 – 74 McAllister et al. 75 , 76 studied working memory in mild TBI patients with normal structural scans who were approximately 1 month postinjury. In the first study, 75 12 mild TBI patients (GCS=13 to 15, LOC<30 minutes) were recruited from emergency room records and tested between 6 to 35 days postinjury. These patients had poor memory, trouble concentrating, and difficulty with their jobs, but did not express greater levels of anxiety or depression relative to comparison subjects. Mild TBI patients had poorer performance on neuropsychological measures of simple reaction time and sustained attention, but not on a variety of other measures, including psychomotor speed, executive functions, and memory. In the scanner, they were asked to complete an auditory “n-back” task that entailed successive levels of working memory tested through presentation of a series of letters. During the 1-back condition, for example, participants were asked to discern whether a letter presented aurally represented a target letter presented visually a moment before. During the 2-back condition, they had to decide whether the letter heard matched the letter seen two letters prior. Both patients and comparison subjects activated bilateral frontal and parietal regions in response to increasing demands on working memory but produced different brain activation patterns in response to different processing loads. Whereas comparison subjects primarily showed increases in activation from 0-back to 1-back, mild TBI patients primarily showed increases in activation from 1-back to 2-back. However, the mild TBI patients and comparison subjects showed comparable overall levels of activation on the 2-back task and comparable performance on the n -back task. The authors suggest that, rather than neuronal loss, mild TBI patients may have decreased ability to allocate or modulate resources according to processing load. 75 In a follow-up study, 76 these researchers added a 3-back condition with 18 mild TBI patients, six of whom had participated in the prior study. All 18 mild TBI subjects had normal clinical (or structural) MRI scans. Mild TBI participants again showed more cognitive symptoms than comparison subjects and again had poorer performance than comparison subjects on attention measures. Their scores again were comparable to those of comparison subjects on all n -back conditions and activated similar regions (bilateral frontal and parietal regions) in response to increasing demands on working memory. Consistent with the prior study, the pattern of activation differed between mild TBI and comparison subjects. Mild TBI subjects had higher levels of activation than comparison subjects going from 1-back to 2-back, but less activation than comparison subjects going from 2-back to 3-back. Activation levels between 0-back to 1-back were not reported. This study again suggests subtle differences in brain functioning during increased working memory load. Rather than simply demonstrating additional activation with each increase in task difficulty, the observation was one of variable activation of mild TBI subjects compared to comparison subjects. Finally, Jantzen et al. 77 conducted a prospective fMRI study of mild TBI using four concussed football players (no LOC but transient confusion) and four player comparison subjects. The scores of both groups on tests of sensorimotor coordination, working memory, memory, and mental calculations did not reliably change from preinjury to within 1 week postinjury. At baseline, the cognitive tasks elicited the expected brain activation patterns in frontal, parietal, and cerebellar regions. Within 1 week following injury to the concussed group, both groups showed increased activation during the cognitive tasks. However, the concussed players demonstrated much larger increases in supplementary motor, bilateral premotor cortex, superior and inferior parietal regions, and bilateral cerebellar regions. These studies meet the sensitivity