Appendix E


Synopsis of Brain Injury Detection Methods

SCOPE

Methods for detection of brain injury range from observation of the victim’s behavior to advanced noninvasive imaging methods, including the following: report of symptoms and responses to questions that test awareness and memory; sophisticated computer-based neuropsychology computer tests; and advanced sensing methods of magnetic resonance, positron tomography, acoustic, electroencephalographic and impedance measurements that enable noninvasive sensing of blood flow, brain metabolism, brain inflammation, brain accumulation of markers of injury, and brain electrical properties.

The status of these methods relative to detection of traumatic brain injury (TBI) is reviewed here. Blood tests for biomarkers of nerve damage are not discussed because, despite extensive investigations in the search for definitive markers of TBI, none has emerged as specific, timely, and sufficiently sensitive for diagnosis within hours of the concussive incidents (Svetlov et al., 2009).

COGNITIVE TESTS

Detection of brain trauma in the battlefield is based on the signs and symptoms of mental status ranging from unconsciousness to symptoms such as confusion, memory loss, slurred speech, headaches, and dizziness. An assignment of concussion is based on these symptoms. The concept of concussion is imprecise and not related to a specific neurological mechanism, nor have methods of quantification of the severity of a concussive event been available until recently.

The most commonly used method for detection of concussion in combat zones and during sports events is neuropsychological testing. The assessment tool for concussion in the battlefield is the Neuropsychological Assessment Metrics (ANAM). The method is a 20-minute computer based evaluation that tests reflex times and some measures of memory and cognitive abilities. After development by the military more than 10 years ago, it has been used to assess sports injuries. Recently, ANAM was validated in the combat environment. Sixty-six cases and 146 controls were studied with the result that the simple reaction test, if applied within 72 hours of the injury, is a relatively sensitive method to differentiate concussed from non-concussed individuals in the combat environment (Kelly et al., 2012).

There are a multitutude of cognitive tests that neuropsychiatrists and psychologists use to assess and score mental capabilities. Before the computerization of cognitive tests, these were applied in controlled studies of cognitive abilities in old and young subjects years after experiencing TBI. For example, cognitive impairments 10 years following TBI were found to be associated with injury severity using tests of attention, mental processing speed, memory, and executive functions (Draper and Ponsford, 2008). An instrument that specifically assesses the quality of life in patients with TBI (Quality of Life after Brain Injury) has been developed (von Steinbüchel et al., 2010). The European Brain Injury Questionnaire (EBIQ) is a clinically reliable instrument to determine the subjective well-being of individuals with brain injury and to assess changes over time (Sopena et al., 2007).

MRI IMAGING

Of the major methods that have known efficacy in the examination of the brain in vivo (i.e., electroencephalogram [EEG], x-ray computer tomography [CT], emission tomography, magnetic resonance imaging [MRI]). MRI is the one that can provide noninvasive information specific to most of the pathologies (e.g., Gutierrez-Cadavid, 2005; Benson et al., 2012). MRI can provide a wealth of information regarding organ changes associated with ballistic trauma to the body, as has already been shown in studies of blast-injured veterans (Van Boven et al., 2009). Below is a synopsis of the specific capabilities for noninvasive measurements by MRI.



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Appendix E Synopsis of Brain Injury Detection Methods SCOPE than 10 years ago, it has been used to assess sports injuries. Recently, ANAM was validated in the combat environment. Methods for detection of brain injury range from observa- Sixty-six cases and 146 controls were studied with the result tion of the victim’s behavior to advanced noninvasive imag- that the simple reaction test, if applied within 72 hours of ing methods, including the following: report of symptoms the injury, is a relatively sensitive method to differentiate and responses to questions that test awareness and memory; concussed from non-concussed individuals in the combat sophisticated computer-based neuropsychology computer environment (Kelly et al., 2012). tests; and advanced sensing methods of magnetic resonance, There are a multitutude of cognitive tests that neuropsy- positron tomography, acoustic, electroencephalographic and chiatrists and psychologists use to assess and score mental impedance measurements that enable noninvasive sensing capabilities. Before the computerization of cognitive tests, of blood flow, brain metabolism, brain inflammation, brain these were applied in controlled studies of cognitive abili- accumulation of markers of injury, and brain electrical ties in old and young subjects years after experiencing TBI. properties. For example, cognitive impairments 10 years following TBI The status of these methods relative to detection of were found to be associated with injury severity using tests traumatic brain injury (TBI) is reviewed here. Blood tests of attention, mental processing speed, memory, and execu- for biomarkers of nerve damage are not discussed because, tive functions (Draper and Ponsford, 2008).   An instrument despite extensive investigations in the search for definitive that specifically assesses the quality of life in patients with markers of TBI, none has emerged as specific, timely, and TBI (Quality of Life after Brain Injury) has been developed sufficiently sensitive for diagnosis within hours of the con- (von Steinbüchel et al., 2010). The European Brain Injury cussive incidents (Svetlov et al., 2009). Questionnaire (EBIQ) is a clinically reliable instrument to determine the subjective well-being of individuals with brain COGNITIVE TESTS injury and to assess changes over time (Sopena et al., 2007). Detection of brain trauma in the battlefield is based on the signs and symptoms of mental status ranging from uncon- sciousness to symptoms such as confusion, memory loss, MRI IMAGING slurred speech, headaches, and dizziness. An assignment Of the major methods that have known efficacy in the of concussion is based on these symptoms. The concept of examination of the brain in vivo (i.e., electroencephalogram concussion is imprecise and not related to a specific neuro- [EEG], x-ray computer tomography [CT], emission tomog- logical mechanism, nor have methods of quantification of the raphy, magnetic resonance imaging [MRI]). MRI is the one severity of a concussive event been available until recently. that can provide noninvasive information specific to most of The most commonly used method for detection of con- the pathologies (e.g., Gutierrez-Cadavid, 2005; Benson et al., cussion in combat zones and during sports events is neuro- 2012). MRI can provide a wealth of information regarding psychological testing. The assessment tool for concussion in organ changes associated with ballistic trauma to the body, the battlefield is the Neuropsychological Assessment Metrics as has already been shown in studies of blast-injured veterans (ANAM). The method is a 20-minute computer based evalua- (Van Boven et al., 2009). Below is a synopsis of the specific tion that tests reflex times and some measures of memory and capabilities for noninvasive measurements by MRI. cognitive abilities. After development by the military more 132

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APPENDIX E 133 • Brain contusion. Edema is an expected early sign water diffusion (fractional anisotropy). Fractional anisotropy of contusion and will appear as a bright signal on metric varies from 0 to 1. Low values indicate less directional T2-weighted or fluid-attenuated inversion recovery diffusion and relatively less fiber orientation suggestive of (FLAIR) MRI. The appearance of edema on MRI damage. This MRI method has been found to delineate white is variable (Gutiereex-Cadavid, 2005). T1-weighted matter defects in TBI, and these defects were correlated with protocols might give a sensitive diagnosis, as will neuro-cognitive function (Lipton et al., 2008, Kumar et al., other protocols. 2009; Jorge et al., 2012). Some caution should be exercised • Brain edema. Edema resulting from vascular com- in making inferences from the MRI studies as being directly promise (i.e., air emboli from lung damage), pres- related to organic nerve injury. A recent study found DTI sure impulse transmitted from the periphery to the abnormalities in combat-exposed soldiers that normalized brain, or ischemic damage from other causes can after 1.5 years, but the soldiers had neither posttraumatic be detected by MRI diffusion-weighted imaging stress disorder (PTSD) nor TBI (van Wingen et al., 2012). sequences, FLARE, and possibly by T1-weighted As discussed in Chapter 10, a number of clinical imaging protocols. studies with MRI have shown associations between white • Vasospasm. Vasospasm is of major importance and matter neuronal track disruptions inferred from images and perhaps the least understood. Vasospasm is a narrow- symptoms associated with blunt trauma and blast injuries in ing of the small arteries of the brain and frequently veterans months and years after return from the battlefield follows subdural hematoma, but also can occur as (Mac Donald et al., 2011; Yeh et al., 2013). However, in one a consequence of blunt trauma without hematoma. study, white matter injuries were not revealed by magnetic The onset of vascular spasm can be a few days after resonance DTI on veterans with mild TBI, despite their trauma, and as vessel narrowing limits blood supply symptoms of compromised verbal memory (Levin et al., to parts of the brain, vasospasm is a major cause of 2010). morbidity. The importance of vasospasm has not been generally recognized (Ortell et al., 2005). It can be Functional MRI detected by magnetic resonance angiography (MRA) or Doppler ultrasound. The majority of cases of vaso- Functional MRI (fMRI) involves evaluation of the spasm reviewed at the National Naval Medical Center changes in local blood flow and volume due to an external were blast trauma victims (Armonda et al., 2012). stimulus such as a visual challenge or memory test (Figure • Hemorrhage. Early signs of hemorrhage usually E-1). It is also known as blood oxygen level dependent occur due to tears in the tributary surface veins that (BOLD) MRI. This is an objective test of brain functioning bridge the brain surface to the dural venous sinus. and has been found to correlate with some post-concussion T2-weighted MRI can show the accumulation of symptom metrics such as visual memory (Talavage et al., blood as a bright signal initially, with an evolution 2013). to a dark signal in 2 to 3 days and back again to a Instrumentation availability and costs vary widely—from bright signal within the first 2 weeks (Taber et al., a permanent magnet system for small animals at less than 2003, Tong et al., 2003). The choice of magnetic $0.5 million to elaborate systems that combine magnetic resonance (MR) protocol is important here as it has resonance with PET at over $2 million. Most studies can be been shown that susceptibility-weighted MR imaging enabled through collaboration with medical clinics. depicts significantly more small hemorrhagic lesions than does conventional gradient echo (GRE) MR Magnetoencephalography imaging and, therefore, has the potential to improve the diagnosis of small hemorrhagic lesions as well as Mapping the origin of ionic current densities in the brain diffuse axonal injury (Tong et al., 2003). by detection of the induced magnetic fields at the surface of the human head has been employed in neurophysiological investigations and surgical applications to treat epilepsy as Neuronal Architecture Imaging Methods well as to identify functioning tissues in tumor surgery. The Neural axon injury might be the most subtle, yet the principal attribute of magnetoencephalography is its ability most important, pathology that requires early imaging for to provide high temporal fidelity information of the activity diagnosis (Mayorga, 1997). Experience has shown that this of parts of the brain with limited spatial resolution. The com- pathology occurs in the corpus callosum and brain stem. bination of magnetoencephalography with MRI methods, Diffusion-weighted imaging (Huisman et al., 2003) and including MRI tractography (a method of displaying major T1-weighted protocols have been replaced by diffusion nerve bundles in the brain through detection of proton dif- tensor imaging (DTI) because DTI has been found to be a fusion principal tensor component), has promise for identi- sensitive indicator of white matter defects. DTI is able to fication of late manifestions of neuronal dysfunction in TBI detect damage to axonal tracts using a measure of directional patients (Larson-Prior et al., 2013).

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134 REVIEW OF DEPARTMENT OF DEFENSE TEST PROTOCOLS FOR COMBAT HELMETS FIGURE E-1 Brain alterations shown on functional imaging without behavioral changes. fMRI image of highschool football players without clinically diagnosed concussion, performing neurocognitive testing before football season and during football season: Even in the absence of concussion (in 8 out of 21 athletes), fMRI shows changes in stimulated blood flow that are correlated with a poorer performance in neurocognitive testing. SOURCE: Talavage et al. (2013). The publisher of this copyrighted material is Mary nn Liebert, Inc., publishers. PET AND SPECT IMAGING resolution in instruments designed for animal studies can be 2 mm or less. Normally, the spatial resolution for large Whereas magnetic resonance spectroscopy of specific animals and human subjects is 4 to 6 mm. The tracers avail- volumes of the brain can define the chemical status of, for able allow studies of blood flow, glucose uptake (commonly example, bioenergetic molecules (e.g., adenosine triphos- interpreted as cerebral metabolism), dopamine transporters phate [ATP], creatine phosphate, etc.) for most studies and receptors, muscarinic system activity, and blood brain of brain metabolism and neuroreceoptor concentrations, permeability. PET and SPECT instrumentation for small emission tomography (single photon emission tomography animal studies is available from a number of vendors. Large [SPECT] and positron tomography [PET]) is the sensitive animal studies can be accomplished through collaborators at measurement method. Pathophysiological perturbations in medical institutions where the requisite approvals for use of the following parameters can be imaged by PET: radionuclides are already in place. • Oxygen utilization, • Regional glucose metabolism, Metabolism Imaging • Regional blood flow and vasospasm detection, Since the early 1980s, cerebral glucose metabolism • Permeability, associated with dementia has been quantitatively imaged • Neuroreceptor concentrations, in patients using 18F-fluoro-deoxyglucose and positron • Inflammation, tomography. Recent human studies in boxers showed pat- • Beta amyloid deposits associated with dementia, and terns of hypometabolism using the accumulation of 18F- • Tau protein associated with brain trauma and deoxy-glucose (Provenzano et al., 2010), but one must be dementia. careful not to interpret hypometabolism when the reason for less apparent tracer uptake is tissue atrophy or decreases in The methods are noninvasive and can be repeated over blood flow rather than a decrease in the metabolic uptake the course of hours or days. Whereas PET and SPECT are mechanism. An important application of PET evaluation of readily available in medical centers, not all experimentalists brain glucose uptake is to study the effects of low growth will have these instruments and the required radioisotopes hormone associated with trauma-induced hypopituitarism available, particularly for small animal studies. The spatial because brain glucose metabolism increases after growth

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APPENDIX E 135 hormone stimulation in patients with hypopituitarism. PET Tau Protein Imaging using 13N-labeled ammonia was shown to be an important Studies at autopsy have shown the occurrence of tissue method for detection of pituitary dysfunction in a limited responses to trauma, including tau (T-tau) hyperphosphory- study (Zang et al., 2005). lated protein (Blennow et al., 1995; Zetterberg et al., 2001), c-Fos and c-Myc expression, deposition of b-APP (Säljö et Inflammation Imaging al., 2002), glial fibrillar acidic protein (GFAP), and fibril- lar light protein (FL-P). The most recent and promising Detection of inflammation in the brain is facilitated by noninvasive detection method for neurochemistry of the PET compounds that localize in the receptors on the surface brain in mild cognitive impairments (MCIs) and behavioral of brain cells that are part of the inflammation response disorders subsequent to multiple episodes of blunt trauma is (Cagnin et al., 2001; Figure E-2). Amyloid depositions seen 18F-ligands for aggregates of the protein tau known to accu- in nontrauma-based dementia (e.g., Alzheimer’s disease) can mulate in injured brain tissue. A few years ago, a successful be quantified by a 11C- PET agent (Klunk et al., 2001) and study in vitro and in small animals revealed the potential of recently a 18F agent. Because autopsy and spinal fluid assays PET to visualize tau protein using a fluoroethoxyquinoline have demonstrated that a biomarker for dementias and blunt compound and the positron emitter 18F (Fodero-Tavoletti et brain trauma is phosphorylated tau protein, a quest for a al., 2011). The first human studies with another agent for suitable ligand that would specifically accumulate in regions amyloid and tau protein, called FDDPN, was associated with of the brain having excesses of tau protein has led to some the pattern of glucose accumulation deficits in Alzheimer’s successes. Tau protein is the main component in neurofibril- disease patients (Barrio et al., 2008) and shortly thereafter, lary tangles seen in Alzheimer’s disease and the pathologic the accumulation in the brains of symptomatic pro-football protein associated with dementias such as Pick’s disease, cor- veterans was demonstrated (Small et al., 2013). ticobasal degeneration, and progressive supranuclear palsy. ULTRASOUND FOR BRAIN BLOOD FLOW Measurements of blood flow in the brain basal arteries and the carotids by transcranial Doppler (Jaffres et al., 2005; Visocchi et al., 2007) are surrogates for estimating cerebral vascular resistance and are effective methods for detection of vasospasm associated with abnormally high velocities. These measurements rely on the skill of the operator. Vascu- lar spasm can occur late after brain injury (Armonda et al., 2012) and will result in a change in the flow characteristics (Jaffres et al., 2005; Kochanowicz et al., 2006; Oertel et al., 2005) with eventual change in electrical impedance (Fritz et al., 2005). Ultrasound instrumentation is generally more available than the other radiological imaging systems for human studies. Specialized small animal systems are now available to the researcher. ELECTROENCEPHALOGRAPHY AND ELECTRICAL IMPEDANCE Electroencephalography and electrical impedance tomog- raphy are two techniques that might be used to assess parenchymal integrity through measurement of electrical properties both during the acute phase of ballistic trauma and during posttrauma intervals up to years. Both approaches require sensitive instruments and are plagued with electrode coupling noise. However, in previously successful large and small animal experiments, EEG measurements (Drobin FIGURE E-2 Positron tomography image showing sites of inflam- et al., 2007) and impedance measurements (Klein et al., mation using the tracer 11C-PK11195 with superposition of the 1993; Olsson et al., 2006; Harting et al., 2010) have shown positron emission tomography emission on a magnetic resonance the kinetics of brain physiologic response to blunt trauma. imaging anatomical image. SOURCE: Cagnin et al. (2007), with Methods for field measurements of brain electrical potentials kind permission from Springer Science & Business Media.

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