An Overview of Concussion History and Needed Research

Editor’s Note

This paper summarizes a symposium on concussion held at Case Western Reserve University on June 23–24, 2015, and supported in part by the National Academies of Engineering and Medicine.¹ It reviews evidence for the seriousness of the problem of concussion (also called mild traumatic brain injury, mTBI) and considers relevant engineering, medical, and biological aspects; provides background, including relevant experimental results, on epidemiology, diagnosis, brain tissue injury mechanisms, histopathology, noninvasive imaging detection of brain injury, blood biomarkers, and progress toward prevention and treatment; and summarizes the short papers based on the presentations.

The papers consider concussion in athletics/sports, combat, and road accidents, and address biomechanics and biomarkers, diagnosis, long-term consequences, prevention, treatments, and patient management. They convey the current state of knowledge in these areas as well as what can be learned through experiments and computer simulations and modelling. Answers to questions raised by participants at the symposium are also elaborated in the following pages.

The symposium revealed areas of great need for research, of which the need for understanding the long-term consequences of concussion stood out as the most significant.

History

Concussion is recognized as a brain injury induced by biomechanical forces, that may or may not cause loss of consciousness, and that typically causes rapid onset of short-lived impairment of neurological function with no abnormalities visible on standard structural neuroimaging studies. This definition has evolved over time, as earlier criteria required loss of consciousness and amnesia.

The relationship of brain trauma to behavioral changes became an object of great interest to neuroscientists in 1848, when the head of an affable and well-liked railroad worker, Phineas Gage, was penetrated by an iron spike. After a miraculous recovery his personality changed such that he appeared to be a different person (Harlow 1948). Some 160 years later the same personality changes were found to accompany severe brain pathology in victims of multiple episodes of brain trauma.

Four historical events brought the attention of the public, military, government, engineers, and physicians to the importance of understanding concussion and its effects. The first was the occurrence of 18 deaths and 159 serious injuries from college football within 10 years of the first game between Harvard and the University of Pennsylvania in the early 1880s (Harrison 2014).

The second group of events started with the controversial diagnoses (e.g., psychiatric disorder vs. organic brain trauma) during and after World War I, with reports of physiological consequences (short-term defects in vision, olfaction, and bowel elimination) of artillery shell blasts (Myers 1915). Before that, surgeons during the American Civil War had reported that injured soldiers manifested psychiatric behavior and muscle paralysis unrelated to a specific impact injury to the head or body (Mitchell et al. 1864).

Scientists argued for decades about the mechanisms that explain psychiatric symptoms, though even in 1916 the neuropathological evidence was compelling for veterans of explosions (Mott 1916, 1917). (Mott subsequently countered his contention that brain injury was the cause of shell shock by arguing that the principal cause was psychiatric; Mott 1919.)

The formal recognition of posttraumatic stress disorder (PTSD) by the American Psychiatric Association (APA) in 1980 was a turning point in discussions of causation and diagnosis—and about whether PTSD is the result of psychological stress or physical injury of the central nervous system (Jones and Wessely 2014).

The third historical event was the marked increase in incidents of brain trauma caused by blasts from improvised explosive devices (IEDs) used during the conflicts in the Middle East. Survivors manifested psychological symptoms and behavior changes, and upon death showed histopathology evidence of tissue injuries similar to those of veteran boxers.

The fourth event is the recently clarified pathology of long-term and progressive dysfunction among NFL players whose behaviors changed and who became depressed and even suicidal. They had brain pathologies similar to people who suffered multiple concussions in boxing or survived blast injuries. The diagnosis of cerebral traumatic encephalopathy (CTE) was identified from postmortem studies of these players (McKee et al. 2009; Omalu et al. 2006).

Persistent Questions

What is not well known are the quantitative thresholds for forces and the number of traumatic events that lead to long-term cognitive and physical dysfunction. Data from animal experiments can produce curves defining the probability of injury vs. physical impact, but they are not yet reliable for determining thresholds for human concussion, particularly in different age groups and genders.

There has also been considerable discussion of methods to diagnose and determine whether a concussion has occurred. In athletics, current practice relies on player reports, coach or trainer observation, personal accelerometer data, and video evaluation algorithms. But more than 50 percent of sports players do not report symptoms of concussion.

There is a need to classify individuals who have had some level of brain trauma and to develop a state-level or national registry for the long-term follow-up necessary to answer the questions: What are the long-term consequences of mild brain trauma? And how efficacious are proposed treatment strategies, none of which is currently widely accepted?

Epidemiology

Military

The incidence of brain injury during military engagements has recently become a consequence of major importance because of the use of IEDs in the wars in Iraq and Afghanistan. These weapons produce a rapidly expanding high-pressure blast wave from which soldiers survive (thanks to protective armor) but not without brain injuries.

In 2000–2015 there were 270,000 concussions in the military, and from 2005 to 2011 the yearly incidence of mTBI doubled, to 24,000 cases (figure 1). Data indicate that 84 percent of IED-induced concussions occur within 10 meters of the blast, 93 percent within 30 m (cf. Perl paper, this symposium). Many who have been in close proximity to an IED-generated blast develop neurologic and behavioral systems referred to as postconcussive syndrome (PCS), which is closely related to PTSD.

Symposium papers by Hack, Kovacs, Perl, and Ruff examine the mechanisms, consequences, and treatment of blast injuries.

Sports

There are 300,000 sports-related concussions annually in the United States (Gessel et al. 2007)—more than 10 times the annual military incidence. Attention by the public and healthcare providers to sports-related TBI has focused largely on NFL players who develop serious personality changes and whose brains have shown pathologies similar to those of boxers with histories of repetitive concussions.

There is evidence that high school athletes have the greatest annual concussion incidence—more than 55,000 per year, with the expectation that a concussion will occur 4.7 times per 10,000 athletic events (AE; Gessel et al. 2007). But this statistic is known to be low: in a survey of 1,532 high school players only 47 percent reported their concussions (McCrea et al. 2004).

The National Collegiate Athletic Association (NCAA) collects standardized injury and exposure data for 15 collegiate sports through its Injury Surveillance System (cf. Hainline paper). About 1 million exposure records over a 16-year period (1988–2004) showed 182,000 injuries (Hootman et al. 2007) and a doubling in the concussion rate for all 15 sports, from 1.7 to 3.4 per 10,000 AE. But the NCAA defines an injury as requiring medical attention and at least one day of absence from play, and these criteria result in an underestimate.

Figure 1

Football is the collision sport with the highest incidence of injury. Of 5 million football players (figure 1), 4.8 million are 6–18 years old, and football injuries account for about 25 percent of emergency department visits in this age group. Collegiate football concussions are estimated at a rate of 6.7 per 10,000 AE (Zuckerman et al. 2015).

The seriousness of sports-related concussions is underscored by the known cumulative effects of three or more concussive episodes (Collins et al. 2002; Guskiewicz et al. 2003).

Road Collisions

Road collisions (automobile, motorcycle, pedestrian, bicycle) result in 200,000 head injuries per year in the United States (cf. Michael paper). But these statistics are based on loss of consciousness and hospital admissions, and so, again, do not accurately represent the incidence of concussive events. In addition to the lack of an effective means of diagnosis, there is no agreed definition of a concussive threshold—for example, even whiplash dynamics can cause brain injuries.

Child and Adolescent TBI from All Causes

Traumatic brain injury is the leading cause of disability and death in children and adolescents in the United States. An average of 62,000 children per year sustain brain injuries requiring hospitalization as a result of motor vehicle crashes, falls, sports injuries, physical abuse, and other causes. According to the Centers for Disease Control and Prevention (CDC), the two age groups at greatest risk for TBI are ages 0–4 and 15–19; among children ages 0–14 years, TBI results annually in an estimated in 2,685 deaths, 37,000 hospitalizations, and 435,000 emergency department visits (Langlois et al. 2004). Falls are the leading cause of TBI for children ages 0–4, but approximately 1,300 US children experience severe or fatal brain trauma from child abuse every year.²

Infants and toddlers are in a special class for studies of biomechanical linkages to brain tissue injury because their brain tissues appear to have an unexpected elastic modulus, leading to a critical strain 3.6 times lower in infants relative to toddlers, as inferred from animal studies (Ibrahim et al. 2010). This puts very young babies at a high risk for brain injury from rotational accelerations.

Mechanisms of Brain Trauma

Because the brain is encased in a rigid skull, the primary mode of deformation in response to a blow to the head, fall, or rapid deceleration is isochoric: a combination of shear, tension (stretch), and shape change (distortion) without volume change. If the tissue is compressed in one direction, it is stretched in other directions.

Figure 2

Brain trauma can result from four external processes (figure 2): direct head impact with or from an object (e.g., windshield, floor, another helmet, or projectile), whiplash with no direct head contact, vertical deceleration of the body (e.g., impact between the pelvis and ground), or stress force to the body remote from the head (e.g., high-pressure hit to the thorax).

Direct Head Impacts and Whiplash

An impact to the head—whether from a nonpenetrating bullet, collision with the windshield, contact with the floor, an explosive blast overpressure, or collision between two athletes—can be considered as a force per area or pressure. When the acceleration of the skull and brain initiates at slightly different times, both positive and negative pressures occur over 10 to 50 ms intervals. These range from a fraction of an atmosphere to two atmospheres (Krave et al. 2005) and are induced by rotational accelerations associated with head or body impacts (figure 2).

The rate of change of momentum (mass × velocity) over time is the force. For most head contacts in sports, brain accelerations and decelerations are governed by the conservation of momentum. The force per area in and of itself will not injure the tissues; as explained below, injuries are from differential strains associated with brain deformation, from shears associated with the different material properties of the brain tissues. The shear or elastic modulus (Young’s modulus) is 10,000 times less than the bulk modulus. Thus, for example, an 80 kg body travelling at 6 m/s that strikes a 5 kg head only loosely tethered to a 75 kg body imparts an extremely high rotational velocity over a short period of time, causing an injury that may be proportional to the change in rotational velocity. Rotation of the head accompanies almost every directional hit except to the top of the head.

Injury is also related to the rate of change in velocity—that is, acceleration and deceleration—which explains whiplash as a cause of concussion. Because the brain is not tightly connected to the skull, any rotation results in a differential movement of the brain relative to the skull. The resulting shear stresses are believed to be the basic mechanism of diffuse axonal injury (discussed below).

Vertical Deceleration of the Body and Stress Force to the Body

Concussion can result from impacts and injuries to other areas of the body. Damage from the transmission of kinetic energy from a point of impact on the torso to remote body organs has been observed in a number of cases (Cannon 2001; Krajsa 2009; Sperry 1993). For example, the finding of hemorrhages in the sclera and conjunctiva of the eye in an anterior chest gunshot–wounded subject is evidence that a ballistic impact can lead to the remote transfer of a large pressure pulse through, in this case, the vena cava and vascular circuits (Sperry 1993). More recent evidence for remote organ damage is from a histopathological analysis of 33 deaths from gunshots to the thorax in individuals not wearing protective vests and without head wounds or a history of head trauma (Krajsa 2009). In all cases, microscopic hemorrhages were observed on histological examination of tissue slices from throughout the brain.

A second mechanism of injury to organs remote from the impact site is stroke-like ischemia caused by air embolism, whether from a blast wave or blunt trauma to the torso in a collision or a nonpenetrating bullet hit to a protective vest. Arterial air embolism has been reported to cause immediate death from blast injuries (Rossle 1950).

Factors in Assessing Links between Physical Forces and Brain Injury

A variety of factors must be considered in experiments to evaluate the links between applied forces and injury to the brain. For example, the type of injury will vary depending on the following conditions:

• magnitude of the impact
• stress rate and duration of the impact
• direction of the impact and the body part impacted (e.g., angle of attack on the head, thorax)
• protection
• neck strength (proportion of the momentum transferred to the body mass).

Tissue Injury

Tissue injury thresholds depend on the following:

• Linear acceleration/deceleration resulting in contusions and coup/countercoup trauma.
• Rotational acceleration/deceleration resulting in shear stress (the most likely cause of axonal injury from axonal strains in white matter).
• Rotational velocity, which depends on Newton’s Third Law (conservation of momentum), wherein a hit to the head that is not firmly supported by the body can result in an almost instantaneous velocity higher than that of the attack. A rotational acceleration causes motion of the skull relative to the brain and the resulting strains can rupture blood vessels and render axons dysfunctional. Strain tolerance thresholds of 10–15 percent have been suggested (Maxwell et al. 1997), but this figure may vary widely as different tissues have different material properties and the amount of strain depends on both the maximum applied stress and the stress rate (Donnelly and Medige 1997).
• The material properties of brain tissue: the brain does not compress, but it does distort. Metrics for brain tissue material behavior are characterized by a bulk modulus of 2.5 × 10⁹ Pa (similar to water) and a shear modulus less than 10⁴ Pa, or a force per area difference of 100,000. An analogy is the difference in force needed to compress a deck of playing cards vs. that needed to scatter them by an impact to the side of the deck.
• Variability in shear moduli of brain tissues such as white matter, grey matter, vessels, and coverings. The membranes between the skull and brain—the dura mater, arachnoid structure, and pia mater—have different material properties and are key components involved in brain injuries because they support blood vessels that traverse the space between the skull and brain surface. A rotation of the brain relative to the skull can rupture these vessels. Pressures (positive and negative) can in principle lead to vascular leaks that have not yet been carefully investigated.

Events at the Neuron Level

Diffuse Axonal Injury

Axonal injury is believed to be a primary mechanism responsible for TBI-induced impairments (Smith et al. 1999, and Smith paper in this issue). Diffuse axonal injury (DAI) was first reported in collision-based injuries with limited periods of survival and in autopsy findings of disrupted white matter tracts and normal grey matter (Strich 1956, 1961). Nondisruptive or reactive axonal injuries manifest over long periods and are ascribed to axonal membrane damage. Morphological study of axonal injuries using nonhuman primates subjected to head acceleration has shown that shear forces create varying degrees of axonal damage including fragmentation, although animal models do not accurately reflect spatial and temporal patterns of axonal injury in the human brain (Maxwell et al. 1997).

Loss of Neuronal Functioning

Injuries to neurons are not from pressure itself but from neuronal stretches beyond the critical point (e.g., 10 percent) such that there is a loss of the electrical polarization needed for neuronal functioning and the neural membrane fails, opening channels and allowing a rush inward of sodium ions and calcium (Ommaya et al. 1994; Smith in this issue). The resulting osmotic pressure causes swelling and a cascade leading to dysfunction of the neuron (figure 3).

Figure 3

The neuron functions by facilitating signals using a dynamic change in membrane potential that propagates along the neuron (to induce a nerve firing one has only to bump the elbow or be struck below the knee cap). If there is a loss of the resting membrane potential of −90 mV (established by the different concentrations of sodium, potassium, and chloride ions), the propagation fails. The failure of function after a blow to the head could be the result of a loss of the ability of neurons to maintain the membrane potential. The recovery of that potential might be one second or several days (e.g., coma). If there is an electrical discharge of all or many of the nerves in the brain, brain enzymes need to reestablish membrane potentials for the system to, in effect, reset. Thus at the time of a concussion one would expect loss of nerve reflexes, and that is exactly what was found in the first extensive animal experiments designed to determine the physiology of concussion (Denny-Brown and Russell 1941).

Methods to Study Brain Injury

Sensors to Measure Impact Forces

Understanding of concussion requires knowledge of the characteristics of the physical forces transmitted to the brain. To that end, sensors attached to a helmet, headband, skullcap, mouthguard, or athlete’s head were introduced 40 years ago (Moon et al. 1971; Reid et al. 1971). Studies with instrumented helmets to determine the severity of forces involved in football impacts (Rowson et al. 2009) led to the commercial accelerometer-based Head Impact Telemetry (HIT) System (Simbex, Lebanon, NH), now mounted in football helmets and used to directly measure the head’s linear and rotational acceleration and the helmet impact location without interfering with normal play. Position, magnitude, and trajectory can be calculated for an assessment of the impact history of each player (figure 4).

Figure 4

Studies have gathered impact data from helmet sensors used in elementary, high school, and collegiate football. At the elementary level, no concussions were detected in 3,059 recorded impacts (Young et al. 2014). At the high school and collegiate levels, a study of 289,916 hits to 449 players reported 17 diagnosed concussions and found that a concussion could be predicted with 75 percent accuracy from hits over 96 g in force (Greenwald et al. 2008). Concussion is also a concern for female collegiate ice hockey players (Wilcox et al. 2015).

The sensor technology can be used in all sports activities, and the data can inform biomechanical assessments linking head impact to clinical outcomes of concussion (Crisco et al. 2012; Greenwald et al. 2008; King et al. 2015).

Animal Models to Determine Injury Thresholds

Animal models can provide a controlled laboratory setting to investigate relationships between the risk of concussion and rapid head rotation magnitude and direction, as well as the contributions of age, sex, and previous injury to the biomechanical thresholds for concussion. Animal model–derived biomechanical thresholds provide insight into how head impacts and sudden head movements produce brain deformations and how these deformations result in a spectrum of brain injuries. Methods proposed for human diagnosis are applicable to animal experiments and can enhance this direction of discovery.

The choice of the animal is important as it needs to have anatomy and tissue properties similar to those of the human brain. The rodent has relatively little grey matter; instead, swine and nonhuman primates make good models for head-hit or ballistic injuries. Pigs can be used for post-TBI behavioral, motor, memory, learning, and cognitive assessments and for determination of the importance of the direction of head rotation on head injury responses. They are a poor model for blast injury, however, as the head tissues provide much more protection than those of the human. Animal models are discussed in the papers by Margulies and Radovitzky and colleagues (see also Friess et al. 2009; Sullivan et al. 2013a,b).

Extending results from animal studies to humans also requires proper scaling of the data from animals with brain masses 10 times smaller than the human brain and with head tissue that provides relatively more protection from impacts (cf. Radovitzky et al. paper). In addition, factors must be included to account for changes in brain tissue material properties with age and sex as well as differences in tissue properties between animal and human brains.

Computer Simulations and Modelling

There has been significant progress toward developing the basic science, algorithms, simulation software, and hardware infrastructure to study the complex problem of brain injury, but the full potential of computer modelling and simulation for enhancing understanding of injury biomechanics and the design of protection systems is yet to be realized.

Modelling and simulation of human injury biomechanics are needed because tests cannot be conducted on the living human system, and cadaver studies cannot give reliable results because of postmortem changes in tissue property and brain fluid. Animal testing and physical surrogates yield useful insights in some cases, but, as explained above, they do not provide adequate answers linking the characteristics of a head impact to the tissue injury. In vitro studies use applied strains and strain rates but these do not allow links to the actual forces of the impact. A simulation must include the correct ranges (force per area), rate, and duration of stress.

An example of computer simulations to show the dependence of tissue strains on the direction of a nonpenetrating bullet impact to a helmet is shown in figure 5. These computational simulations can be used to optimize the design of protective helmets for athletes, motorcycle riders, police, and soldiers.

Figure 5

Computer simulations to understand highway collisions and improve protection are used by the National Highway Transportation Safety Agency (NHTSA; see Michael paper). A Simulated Injury Monitor (SIMon) finite element head model uses vehicle dummy head kinematics as an input and calculates the probability of three types of injury: DAI, contusions, and subdural hematomas (Takhounts et al. 2003). An upgraded version of that system has used data from instrumented helmets on professional football players (Takhounts et al. 2008). A more recent study using a finite element model of the human head reported the dynamic response of the brain during the first milliseconds after an impact with velocities of 10, 6, and 2 meters/second (m/s) (von Holst and Li 2013). The results show a dynamic triple maxima sequence: first, strain energy density, then intracranial pressure, followed by the first principal strain.

The main progress in computational modelling of traumatic physical effects on the central nervous system has been on blast-induced TBI. Blasts can cause significant levels of pressure, volumetric tension, and shear stress in focal areas in a short time, with stress patterns dependent on the orientation of the blast wave and the complex geometry of the skull, brain, and tissue interfaces (Moore et al. 2009; Panzer et al. 2012; Radovitzky et al., this issue). These studies showed that direct propagation of blast waves into the brain through soft tissues (eyes, sinuses) was the main mechanism of energy transfer from the shock wave and that blast stresses can cause concussion. Subsequently, a 27,971-element head model—with a brain, CSF, skull, dura mater, pia mater, and scalp, among other components (Chafi et al. 2010)—showed that blasts with overpressures of 243–881 kPa could cause concussion and DAI.

However, simulation strategies are limited by poor spatial resolution. Moreover, the relative motion of the brain and skull is not modelled correctly without a volume element resolution less than 2 mm, and inclusion of the anatomy and correct gauge of the material properties of vessels and other connective tissues between the brain surface and the skull.

Diagnosis of Concussion

Posttraumatic Stress Disorder vs. Traumatic Brain Injury

First it will be helpful to distinguish between concussion and posttraumatic stress disorder, which is not necessarily a long-term consequence of brain trauma. PTSD is the diagnostic term that evolved from abnormal psychological behavior related to battlefield stress; it also applies to the symptoms of patients who survived traumatic psychological experiences after which depression, anxiety episodes, social withdrawal, and other symptoms occurred without evidence of an organic cause. According to the APA definition, PTSD is caused by a psychologically traumatic environmental event, with the assumption that any accompanying biological abnormality must also have been traumatically induced. The development of PTSD also depends on the severity or existence of genetically based, disease-induced, or drug-related neurochemical and neuroanatomical abnormalities.

The complexities of PTSD, particularly in veterans returning from war zones, result in variable correlations between histories of battlefield stress and concussions from blasts or collisions (cf. Ruff paper). An extensive review provides evidence for the neurochemical and neuroanatomical basis of PTSD (Pitman et al. 2012).

Clinical Evaluation

At the time of a concussive event, trainers, coaches, collision witnesses, data from instrumented athletes, and the victim’s reports of symptoms can lead to a diagnosis, though frequently of variable reliability, particularly from a soldier or athlete who is anxious to return to fight or play. The promise of a threshold diagnosis from an instrumented helmet requires an understanding of the links between impact metrics and brain injury as well as knowledge of the threshold for concussion without loss of consciousness (LOC).

Diagnosis of concussion without LOC and postconcussion evaluations currently rely on multiple clinical “symptoms and signs” approaches with four components:

1. Cognitive: concentration, memory, information processing, executive function
2. Motor: reaction time, coordination
3. Vestibular: balance, dizziness, vision/oculomotor function
4. Physical: headache, neck pain, sleep disturbance.

To facilitate concussion diagnosis, posttrauma assessment, and overall management of athletes the Cleveland Clinic has developed an innovative multidisciplinary program that enables quantification of signs associated with these four components using available electronics in iPhones and iPads (e.g., accelerometers, optical methods, voice-guided protocols). The innovation is available as the Cleveland Clinic Concussion (C3) App (cf. Alberts paper).

Based on studies by Robert Ruff described at this symposium, there is also the possibility of a test to assess the olfactory capabilities of a concussed person. Decreased odor detection thresholds are very common in victims of mTBI (Ruff et al. 2012).

Cognitive Testing

A number of cognitive tests are available, some of them computer based and easily performed by the soldier or athlete before and after deployment or sports activities. Two methods appropriate for impact sport evaluations are the Sport Concussion Assessment Tool 3 (SCAT3) (Guskiewicz et al. 2013) and Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) (Van Kampen et al. 2006).

Noninvasive Imaging

Magnetic Resonance Imaging (MRI)

MRI techniques for imaging the brain include structural MRI, functional MRI (fMRI), diffusion-weighted MRI, and magnetic resonance spectroscopy (MRS). Structural MRI reveals anatomic detail that is useful in cases of severe brain trauma, intracranial bleeding, and edema, but it is generally not considered useful for diagnosing mTBI or as a diagnostic method immediately after a concussive event.

The use of fMRI to assess brain blood flow responses to cognitive challenges before, during, and after football play has shown remarkable changes in high school athletes (cf. Talavage paper). As an example, figure 6 shows a decline in brain responsiveness to a cognitive test or stimulation (indicated by blood flow amount and distribution) after football playing in an athlete who was not diagnosed with a concussion (Talavage et al. 2014).

Figure 6

MRI diffusion tensor imaging (tractography) allows calculations and image presentations of the principal directions of the major nerve tracts (oriented axons) in the brain and has shown disruption in the normal pattern of tracts. Diagnostic use with TBI patients has shown remarkable success (Tong et al. 2003; van Boven et al. 2009), but the method is expensive and resolution is limited, although it will improve when magnets with field strengths above 14 Tesla become available (Budinger et al. 2016). This method is applicable to evaluation of the long-term consequences of multiple concussions and provides a means of associating brain connectivity changes to behavior.

Functional connectivity density mapping (FCDM) uses fMRI data to calculate short- and long-range FCD (Caeyenberghs et al. 2015). This method has had success in comparing the circuit connectivity of patients with traumatic axonal injury (TAI) with controls using a stimulus protocol, the sensory organization test (SOT). There was significantly increased short-range FCD in frontal regions in the TAI group and significantly decreased long-range FCD in frontal and subcortical regions, and the latter was associated with lower balance ability. FCDM may thus be a valuable tool for selectively predicting functional motor deficits in TAI patients.

MRS has the unique ability to show the chemical content (neurometabolite) of specific regions of the brain. For example, a brain MRS study of 19 TBI vs. 28 control subjects showed significant changes in metabolites associated with neuron maintenance and energy metabolism over a 6-month period after concussion (Brooks et al. 2000).

Positron Emission Tomography (PET)

Studies of CTE using PET, with an [F-18]FDDNP tracer that accumulates at tissue sites where tau protein exists, show early involvement of the amygdala, thalamus, midbrain (figure 7), and other brain areas that participate in the processing of emotions, mood, and behavior (Barrio et al. 2015; Small et al. 2013). The PET tracer detects phosphorylated tau (p-tau) protein deposits analogous to the tau protein immunostain results from neuropathologists on brain tissue slices as shown in the McKee, Perl, and Kovacs papers. PET imaging studies in 14 CTE subjects showed intense uptake in the amygdala, several areas of the frontal cortex (the anterior cingulate gyrus, medial thalamus, hypothalamus, and dorsal midbrain), but no significant uptake in normal subjects or Alzheimer’s patients (Barrio et al. 2015).

Figure 7

PET may prove useful for noninvasive imaging of brain inflammation (figure 7). Injury to any tissue in the body results in release of cytokines that signal circulating cells and the immune system to commence repair. This leads to inflammation, which is expected to occur in the brain after an injury (further evidence for inflammation after brain trauma comes from autopsy data). More than 3 months after injury, TBI cases displayed extensive, densely packed, reactive microglia, indicative of inflammation, whereas there was no inflammation in control subjects or acutely injured cases (Johnson et al. 2013). Reactive micro-glia and inflammation were present in 28 percent of cases with survival up to 18 years posttrauma, and accompanied with ongoing white matter degradation.

PET imaging has not yet been used to assess concussion, but a clinical trial could yield important new information about diagnostic and prognostic potentials as well as the potentials for nonsteroidal anti-inflammatory treatment of mTBI.

Electroencephalography (EEG)

Advances in the measurement of EEG signals from the brain have been incorporated by the Department of Defense (DOD) for a primary assessment of TBI as an indicator for further evaluation (cf. Hack paper). Quantitative EEG has been shown to be highly sensitive (96 percent) in identifying postconcussion symptoms (Duff et al. 2004).

X-Ray Computed Tomography (CT)

There are no reliable diagnostic patterns for CT use with an asymptomatic victim, unless skull fracture is suspected. However, in cases with progressive physiological signs and loss of consciousness after an alert period, CT can show progressive edema and even hemorrhage. But it is not the preferred brain imaging method for diagnosing brain trauma in the conscious victim.

Brain Tissue Injury Serum Biomarkers

Serum levels of most brain proteins are elevated after concussion, and several have reasonable diagnostic accuracy for distinguishing concussion from nonconcussion (cf. paper by Bazarian). The use of brain imaging to identify levels of S100B, UCH-L1, and GFAP can also predict which concussed patients will have intracranial hemorrhage, early detection of which can be lifesaving. And levels of alpha-II spectrin and p-tau predict postconcussion outcomes such as symptom reduction and timing of return to sports. S100B is used clinically in several European and Asian countries to determine whether an X-ray CT scan should be done; its use in the United States awaits approval by the Food and Drug Administration (FDA).

Serum markers are useful for determining the prognosis and return to normal status of a known concussed individual. But they lack specificity, as aerobic exercise and injuries outside the brain can lead to elevations of these markers of tissue injury; they have not been tested in the first hour after a potentially concussive event; and normal serum levels vary widely among individuals, necessitating pre-event baseline studies.

Hypopituitarism

Chronic hypopituitarism is defined by deficient production of one or more pituitary hormones at least one year after injury. The diagnosis is made by measurement of one or more of the pituitary hormones using serum samples. The incidence of hypopituitarism related to TBI is discussed under Late Effects of Brain Trauma.

Postmortem Brain Pathology

The concussed brain exhibits global atrophy, decreases in volume of specific brain regions (e.g., hippocampus, corpus callosum), and an increase in ventricle volumes. The brain pathology of CTE (cf. McKee et al. 2010, 2013; Omalu et al. 2006) is similar in some respects to that of other forms of dementia (e.g., cerebral atrophy and enlargement of the ventricles) but is distinguished from them by the deposition of p-tau protein in a unique pattern in the brain by immune staining on tissue sections (cf. McKee paper; figure 7).

PET imaging may be useful for in vivo imaging and diagnosis of CTE, but, as a method to monitor progression and evaluate proposed therapies, it must be used well before behavioral symptoms and balance deteriorations are observed.

Late Effects of Brain Trauma

CTE and Other Neurodegeneration

Chronic traumatic encephalopathy develops insidiously many years after exposure to repetitive brain trauma. It is characterized by one or more of the following symptoms: depression, paranoia, impulsivity, rage, headaches, coordination problems, dysarthria, gait changes, and defects in memory (Stern et al. 2013).

Second impact syndrome (SIS) occurs when a person who has sustained an initial head injury, usually a concussion, sustains a second head injury before symptoms associated with the first have fully cleared (e.g., Cantu and Hyman 2012; Guskiewicz et al. 2003; Young et al. 2014). Since the late 1990s it has been recognized as an eventual cause of death in 50 percent of cases. Most commonly reported in football, SIS can occur during any sport that can produce head blows; in the 1920s brain degeneration from repeated blows to the head was noted in boxers (dementia pugilistica).

The phenomenon of SIS has called attention to the consequences of multiple minor head trauma events in youth sports and the possibility that repetitive minor hits without symptoms of concussion can result in the neurodegeneration of CTE decades later. All youths involved in impact sports are at risk.

Basal Brain Structures

There are a number of structures in the base of the brain whose functions are involved in cognitive, psychological, and behavioral changes related to impact head trauma, blast trauma, and PTSD. The anatomy of most of these components is shown in a sagittal section drawing of the brain along with an inset picture of the skull base (figure 8). The amygdala, cingulate gyrus, corpus callosum, hippocampus, hypothalamus and pituitary, olfactory bulb, prefrontal cortex, and putamen show evidence, both at autopsy and by in vivo MRI and PET, of anatomical and functional defects. A few examples illustrate the involvement of these areas in brain trauma and its long-term consequences.

Figure 8

Amygdala–Medial Prefrontal Cortex

The amygdala plays a critical role in processing emotion and mediating fear. Imaging studies in PTSD patients have revealed decreased neural activity in the medial prefrontal cortex (mPFC), which modulates the amygdala, and simultaneously increased amygdala activation (Francati et al. 2007; Shin et al. 2005). An uninhibited or overactive amygdala results in an excessive state of fear and anticipation of fear (Pitman et al. 2012; Whalen 1998).

Hippocampus

Hippocampal volume measurements using MRI can aid in evaluating the progression of previous traumatic brain tissue injuries. Anatomic MRI and quantitative volumetric analysis reveal diminished hippocampal size in patients with mild cognitive impairment (MCI) relative to controls (Jack et al. 1999; Seab et al. 1988). The diminished size was not correlated with overall brain atrophy due, for example, to aging. Stress-induced damage to the hippocampus has been shown in persons with PTSD (Bremner 2001), as has post-TBI loss of neuronal layers in the hippocampal pyramidal layer (Maxwell et al. 2003).

Hypothalamus and Pituitary

The hypothalamus is a major site of deposition of p-tau protein detected via PET imaging in NFL football players and at autopsy in football players, war veterans, and boxers. An essential function of the hypothalamus is the production or stimulation of eight hormones from the pituitary. These hormones are essential for the functions of other organs (e.g., thyroid, adrenal glands, breasts, uterus, gonads) as well as growth, lipid metabolism, and some aspects of behavior.

As many as 40 percent of subjects who have sustained blunt brain trauma have some symptoms and signs of compromised pituitary function (Bondanelli et al. 2005). In contrast, the prevalence of hypopituitarism in the general population is estimated at 0.03 percent. A major symptom of hypopituitarism in 15–20 percent of patients is a decrease in growth hormone (GH), frequently associated with PTSD symptoms (Kelly et al. 2006; Powner et al. 2006). TBI patients also develop gonadal hormone deficiencies, 10–30 percent develop hypothyroidism, and many experience chronic adrenal failure because of low adrenocorticotropic hormone (ACTH) secretion from the pituitary. Adolescent and pediatric patients with TBI have a high incidence of GH deficiency and hypogonadism (Aimaretti et al. 2005).

Incidence and hormonal deficiency patterns differ between victims of blast injury and blunt trauma, with a prevalence of 32 percent vs. only 3 percent, respectively, but the numbers studied were only 13 and 38, respectively (Baxter et al. 2013). In another study 42 percent of veterans with blast injuries showed abnormally low levels of at least one pituitary hormone (Wilkinson et al. 2012). The dysfunction might not be from injury to the pituitary itself; its function is dependent on the health of the hypothalamus, a region known to exhibit pathological changes from brain trauma. (Links between brain trauma and pituitary pathology have not been reported, probably because neuropathologists do not receive the pituitary with the brain; Ann McKee, personal communication, 2015.)

Research on the functioning of the human hypothalamus-pituitary system is important because hormones play a vital role in everyday functioning, from social behavior to neuronal dendritic growth (Cheng et al. 2003). Hormonal deficiencies can be treated.

Putamen

The putamen is involved in executive function, motor control, learning, and, of relevance to mTBI late symptoms, the “hate circuit”—it plays a role in brain activity associated with contempt and disgust (Zeki and Romaya 2008). It is important in the study of TBI because abnormalities have been found in psychopathic individuals (at autopsy as well as through in vivo PET imaging of asymmetric metabolic function; Budinger patient archives, figure 8).

Treatment

There are no FDA-approved diagnostics or therapies for TBI, and more than 30 clinical trials of pharmaceutical products to treat it have failed. There are no agreed protocols other than rest and progressive return to work or play depending on symptoms and signs. Even the determination of the level of rest is controversial.

Causes of the failed clinical trials seem now to have been recognized and there has been progress toward consensus on protocols and measurement methods through cooperation between the DOD, CDC, and FDA (cf. Hack paper). A major disappointment was the failure of progesterone as an efficacious drug in the final analysis, although some trials were successful. Diagnostic scoring sensitivity for the different grades of TBI and the associated heterogeneity of treated and controlled subjects are believed to be important issues for the cooperative group to resolve, as detailed in the Hack paper.

Anti-inflammatory drugs. There is evidence of brain inflammation based on PET imaging and elevated serum proteins as well as autopsy studies of patients who died as a result of blunt trauma to the head. If inflammation is involved (with or without headaches), an early treatment might be nonsteroidal anti-inflammatory drugs. More research is required.

Folic acid. Experimental trials have shown promising results using folic acid to enhance functional recovery in a piglet animal model of recovery after concussion from rotational accelerations (Naim et al. 2010).

Pituitary hormones. Hypopituitarism is easily treated using hormonal replacement regimes (e.g., growth hormone, ACTH, thyroid, oxytocin). But detection methods can be cumbersome. Detection of growth hormone deficits requires infusion of a stimulant such as insulin. Alternatively, a short period of interval exercise will cause an increase in growth hormone (Karagiorgos et al. 1979) that can be detected by a simple blood test before and after exercise.

Hypothermia. Hypothermia has not been successful in clinical trials as a treatment for severe TBI (Kramer et al. 2012), but this may be because the treatment was initiated several hours after brain trauma, whereas in successful animal trials it was initiated much earlier (Smith et al. 2013).

Conclusion

The causes, detection, prevention, and treatment of concussion are persistent challenges. The engineering disciplines of materials, mechanics, modelling, and simulation are needed in the work of physiologists, cell biologists, and clinicians dealing with concussion.

Government agencies (e.g., DOD, VA, NHTSA, DOT, NIH) and the NCAA are increasingly aware of the serious problem of head injuries from football, combat blasts, and vehicle collisions. However, there has been less emphasis on head injuries in pre–high school youths, although this is the largest population engaged in impact sports. The importance of long-term consequences of head injuries has become the focus of attention only in the last few years. The papers in this issue outline the myriad dimensions of concussion that require concentrated research to enhance understanding, prevention, and treatment.

Acknowledgments

This symposium summary and review of the many facets of concussion benefitted from the assistance of Pamela Reynolds, UC Berkeley Department of Bioengineering, who did preliminary editing of the symposium papers; Robert Smith, Lawrence Berkeley National Laboratory, who assisted in the acquisition of reference material; and Cameron Fletcher, NAE managing editor, who gave critical advice that improved this presentation of the status and future understanding and mitigation of concussion in the United States.

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FOOTNOTES