CLINICAL FEATURES

Some degree of DAI is likely in patients suffering moderate to severe TBI with loss of consciousness,¹ with initial Glasgow Coma Scale (GCS) assessment perhaps reflecting functional impairment of the brainstem and the reticular activating system within the midbrain. Seminal work by Genarelli et al. indicates that DAI can be the sole factor in causing coma after TBI.¹² In such circumstances, improvements in responsiveness and alertness may develop slowly a protracted course over weeks to months of intensive rehabilitation. DAI has been historically defined using histopathological methods,¹ though recent advances in neuroimaging have considerably improved in vivo diagnosis. In terms of functional outcome DAI is likely the most common cause of severe impairment after TBI. Disruptions in consciousness were initially attributed specifically to brainstem injury, however, coma after DAI is also frequently associated with axonal damage in cerebral white matter as well.¹³ Persistent cognitive and memory deficits, seen in TBI in general, are prominent in these patients with deficits in information processing.^14,15 Magnetic resonance imaging (MRI) data concurrently demonstrate a dose-dependent effect of DAI lesions in the brain on cognitive impairment.^16–19

Hypothalamic injury and panhypopituitarism have been associated with DAI, possibly due to shear injury across the pituitary stalk from the same high kinetic energy forces that cause DAI.^20–23 Additionally dopaminergic pathways in the anteroventral third ventricular region mediate arginine vasopressin release and may be disrupted in DAI. This may contribute to sodium and free water derangements seen complicating post-TBI management.²³

INITIAL INJURY AND PRIMARY AXOTOMY

The initial traumatic insult causes dynamic deformation of the brain parenchyma, thereby putting long-tract structures such as axons and blood vessels at risk for stretch and shear injuries. Distortion of the axonal cytoskeleton subsequently disrupts normal axonal transport mechanisms, leading to accumulation of transport products in injured regions²⁴ and alterations in neuronal homeostasis. Until recently, the axonopathy that occurs subsequent to trauma has been characterized as the progressive formation of axonal varicosities within 2 to 3 hours after injury with disconnection by 6 to 12 hours.²⁵ More recently, another form of axonal injury has been described characterized by increased axolemmal permeability, mitochondrial swelling, and cytoskeletal compaction damaging microtubule and neurofilament structures.^26,27 Notably this form of injury is not associated with the characteristic axonal swelling associated histologically with injury, and reversed axonal transport has been considered as a possible mechanism for the observed disturbances in axon function without swelling.²⁸ Shearing of axonal fibers leading to complete disconnection after trauma, or primary axotomy, can cause a more pronounced accumulation of transport products in the injury referred to as an “axonal bulb” (also referred to as a “retraction ball”) (Figure 3.1a). The appearance of these bulbs can appear in transected tissue for years following injury reflecting complete and persistent axonal separation,²⁹ even when varicosities of presumably intact axons resolve, though a full understanding of the temporal course of this process remains to be done. Despite the apparent correlation of traumatic force magnitude with degree of axonal damage, primary axotomy is considered a minor contributor compared to secondary mechanisms in the overall axonopathy seen after TBI.^6,30

FIGURE 3.1

(See color insert.) (a) Silver-stained tissue of juvenile rat brain tissue at 40x following impact-acceleration TBI revealing axonal retraction bulb at center. (b) Silver-stained tissue of juvenile rat brain tissue at 40x following impact-acceleration (more...)

Stretch injury without complete axotomy is considered a greater contributor to the pathology seen in DAI than injury with axotomy. In vitro studies of neuronal preparations reveal that immediately subsequent to stretch injury axonal arrangement is distorted and some axons become undulated and twisted due to cytoskeletal damage (Figure 3.1b). Internodal regions of the axon appear particularly vulnerable, whether due to specific mechanical features of this region, a lack of association with supportive oligodendrocytes,³⁰ or perhaps the density of transmembrane ion channels in this area.³¹ Changes to the cytoskeleton are prominent in the wake of trauma, as neurofilament morphology in some structures changes within 15 minutes after injury²⁵ with subsequent disruption of axonal transport and accumulation of transport products. Though axonal transport is commonly mediated by the microtubule cytoskeleton as opposed to neurofilaments, neurofilament morphology is considered a mirror of concurrent microtubular integrity.²⁵ Supporting this, a loss of microtubules following trauma has also been noted in models of TBI and axonal injury.³² Ultimately, the use of the microtubule stabilizing medication taxol ameliorates microtubule damage after experimental TBI,³³ but cytotoxic effects of the drug preclude its use as a therapy for DAI at this time.³⁴ TBI damage decreases axonal elasticity and prevents recovery of the axon to its original structural conformation.³³ The individual axon response to injury appears idiosyncratic to some degree and governed by multiple factors. Though large-scale traumatic forces would likely render roughly uniform mechanical stresses across microscopic axon bundles, initial histological examination reveals scattered axonopathy in affected tissue. One possible explanation is that myelination varies between neighboring axons, and finely myelinated small axons appear more vulnerable to injury.²⁵ Histologically visible findings likely underestimate injury in neighboring fibers with varying degrees of injury, as the proportion of histologically abnormal axons seen in trauma models and patients is incongruent with the magnitude of DAI symptoms seen after TBI. Also suggests some axons may appear morphologically normal but are functionally incapacitated after trauma.³⁵ Due to the progressive nature of DAI early after trauma, imaging and histological findings are also significantly affected by time of assessment. Staining techniques such as hematoxylin and eosin and silver staining delineating structural features are of limited benefit as they may underestimate the burden of gross axonal pathology.¹⁰ Rather, immunohistochemical stains identifying axonal transport products such as amyloid precursor protein (APP), which can be identified in damaged axons within 2 hours after injury, may be more useful. Commonly seen in neurodegenerative diseases in older patients,³⁶ APP positive damaged axons appear in high frequency in TBI patients who die soon after injury, even in children.^37,38 Therefore importantly, other clinical pathologies affecting axonal transport should be considered in addition to injury mechanisms in the histological evaluation of DAI.³⁹

SECONDARY AXOTOMY AND DISRUPTED NEURONAL HOMEOSTASIS

Traumatic brain injury is intrinsically heterogeneous and therefore axonal injury does not occur in a vacuum, rather multiple injury cascades from oxidative, excitotoxic, and inflammatory pathways occur as well and affect the evolution of axonal pathology. Following trauma, axons that have not been ruptured by primary axotomy may have been injured from physical stretch due to deformation of the brain. Axonal stretch injures cells through several mechanisms. In addition to direct cytoskeletal damage, stretch disrupts membrane permeability and precipitates depolarization.⁴⁰ This in turn alters the electrochemistry of the damaged axon and triggers the release of excitatory neurotransmitters such as glutamate to concentrations as much as 50 times normal in TBI.^41,42 This surge is worsened by dysfunction of normal glutamate reuptake processes by neighboring astrocytes in injury. Glutamate acting on NMDA and AMPA receptors increases cytosolic calcium influx and concentration. This in turn engages secondary messenger systems involving calcium, alters transmembrane ion gradients, and the osmotic load of the neuronal cytosol among other mechanisms that precipitate additional neuronal injury. Calcium ion increases seem dependent on two sources: (1) entry of sodium secondary to depolarization and reversal of the Na+/Ca2+ membrane antiporter^31,43,44 and (2) release of calcium from the endoplasmic reticulum.⁴⁵ Other possible sources of altered axonal electrophysiology include increased sodium ion channel permeability,^31,44,46 decreased Na-K ATPase activity resulting in ATP starvation of the neuron,^47–49 and ectopic distribution of channels.⁵⁰ Calcium induces changes in mitochondria leading to the opening of the mitochondrial permeability transition pore. This ultimately leads to neutralization of the electrochemical gradient essential for mitochondrial function, permits water influx, and instigates mitochondrial demise.⁵¹ Calcium-mediated proteolysis by calpain and caspases in turn leads to further damage to the axonal cytoskeletal as well as ion channel structures.^43,51–53 The effects of these calcium-dependent enzymes are demonstrated in the lysis of the cytoskeletal protein spectrin in disparate products of proteolysis characteristic for each enzyme. Calcineurin inhibition with cyclosporine A and tacrolimus and calpain inactivation has been demonstrated to mitigate axonal injury in vivo^53–58 and may offer potential therapies in the future. Oxidative stress and disrupted neuronal energy metabolism secondary to mitochondrial injury and eventual destruction also plays an important role in neuronal cell death. This is due to cytoskeletal injury, protein alteration, and metabolic failure, a process partially ameliorated by free-radical scavengers.⁵⁹ Neuroinflammatory processes and microglial activation also contribute to local injury processes and endure long after the initial insult.^29,60,61

Axons not severed in primary axotomy may proceed to breakage via secondary axotomy. Secondary axotomy is a process of rapidly progressive axonal deterioration, breakage, and retraction occurring following but not at the time of injury. Axonal bulbs form and the axon assumes a helical appearance as the proximal damaged axon retracts. Concurrently the severed distal axonal fragment begins Wallerian degeneration by 24 hours, a process of progressive lysis and disintegration.²⁵ By 72 hours the damaged, separated segment is consumed by activated glia. Recent evidence suggests that unmyelinated axons are also at higher risk for secondary disconnection compared to myelinated axons as demonstrated in in vitro models where these smaller fibers are more prone to secondary disconnection than larger myelinated axons.^62,63 Myelin sheath integrity changes during the evolution of DAI after injury, with progressive demyelination occurring in affected areas and white matter atrophy up to 1 year after injury.⁶⁴ Of note, oligodendrocytes in apoptosis have been observed in affected tissue following TBI and may reflect myelin degeneration in progress. Appearance of persistent myelin basic protein (MBP) in the cerebrospinal fluid (CSF) of patients following trauma⁶⁵ suggests an ongoing sheath degeneration consistent with the appearance of sheath globoids seen in conjunction with axonal bulbs after DAI.⁶⁶

NEUROINFLAMMATION

The primary inflammatory response seen in the brain after DAI is mediated by microglia, as it is in other TBI. In a study by Oehmichen et al.⁶⁷ immunohistochemical labeling with β-APP for axonal damage and CD68 for microglia identified colocalization of the labels in half of the patients who survived 5 to 15 days in areas of the brain—thereby demonstrating moderate microglial infiltration in areas of axonal injury.⁶⁸ Microglia migrate rapidly into injured areas, and activated microglia extend cytoplasmic processes toward injured axons so as to isolate damaged structures. Thalamic infiltration with astrocytes has been noted at 4 to 8 hours after injury in animal DAI models, with maximal injury markers evident at 48 hours to 2 weeks after injury. Concomitant microglia activation has also been observed in the cortex and hippocampus at 4 hours, with upregulation of MHC Class II epitopes in white matter 24 hours following injury. Macrophages localize to the meninges and perivascular spaces within 24 to 48 hours and persist for up to 2 weeks, however, infiltration into the parenchyma is more limited.⁶⁹

Cytokines involved in neuroinflammation include mediators commonly seen in TBI such as the IL-1 family, IL-6, IL-10, and TNF-α. The IL-1 family includes IL-1α, IL-1β, and IL-18, and is a well-studied constellation of cytokines that stimulate lymphocytes and macrophages, as well as trigger further inflammatory mediators. A study by Lu et al.⁷⁰ demonstrates an increase in cortical IL-1α and β following an impact-acceleration TBI in rats. Hans et al.⁷¹ also using an impact acceleration model noted IL-6 activity increases 1 hour following histologically confirmed DAI peaking at 2 to 4 hours then receding to normal in 24 hours. It was noted that IL-6 mRNA and expression was highest in regions of axonal damage. IL-6 in particular is important in regulation of inflammation and activity of granulocytes, lymphocytes, and NK cells as well as inducing release of soluble TNFR and IL-1 receptor antagonists. In a fluid-percussion model of DAI, Kita and colleagues⁷² identified increasing TNF-α concentrations in the brainstem and corpus callosum over the first 3 hours after trauma. TNF-α is well known as a pro-inflammatory, proapoptotic cytokine with effects on macrophage/monocyte/NK cell stimulation, as well as secretion of platelet activation factor, ICAM, thromboxane A2, prostaglandin E2 as well as endogenous nitric oxide.⁶⁹ TNF-α has been detected in lysosomes of microglia, astrocytes, and oligodendroglia in other models of DAI as well.⁷³’⁷⁴ A factor that has been demonstrated to exacerbate the inflammatory response is hypoxia.⁷⁴ Given that respiratory compromise can occur through impact apnea, mechanical asphyxiation, inhalation injury or other mechanisms associated with TBI, hypoxia compounding DAI likely influences injury evolution following moderate-severe TBI.

The leukocyte adhesion molecule ICAM-1 is another potential mediator of post-DAI secondary injury in that it is upregulated following DAI^75,76 16 hours after injury, peaking 4 days after injury. Lymphocyte adhesion associated chemokines MIP-2 and MCP-1 are also elevated after focal TBI, however, only MCP-1 was increased after DAI in this experimental DAI model. MCP-1 is associated with monocyte recruitment from the bloodstream and interestingly MIP-2 is also a neutrophil attractant.

EVOLUTION OF DAI AND PLASTICITY

Historically, DAI has been described as a process that evolved in days to weeks following trauma, with peak neuropathology occurring at 1 to 2 days after injury.²⁵ Histopathological and imaging evidence,⁷⁷ however, suggests that trauma incites a protracted process of axonal degeneration and impaired transport over months in a progressive, Alzheimer’s-like neurodegenerative process.^29,78 Likewise, the processes of axonal recovery, regrowth, and neuronal plasticity are poorly understood in the healing patient. After experimental DAI in mice NG2 positive oligodendrocyte precursors initially decrease, but then proliferate by three days after injury in the damaged corpus callosum and subventricular zone.⁷⁹ Mature oligodendrocytes demonstrate a similar tendency in total numbers, which decrease during the first 3 days following injury but appear higher at 7 days after injury. Despite diffuse axonal damage, frank demyelination is not seen in the first week after injury, and redundant or disordered myelin may persist.⁸⁰ It can be difficult to assess myelin-sheath-associated proteins in the tissue as a marker of injury due to retention and ongoing breakdown of damaged sheath.⁸⁰ Regrowth of myelin with oligodendrocyte recovery likely influences other recovery and plasticity processes, however, the extent of this interaction is not well characterized.⁷⁹ Basic recovery processes such as restoration of cytoskeletal structures with microtubule and neurofilament turnover and recovery of normal ionic homeostasis in the injured axon have been postulated,¹⁰ and it is possible that axonal varicosities seen with disrupted axonal transport following TBI can resolve with restoration of normal axonal function. The utility of biomarkers to predict recovery is unclear, as the thresholds for marker detection may involve injury beyond the possibility for axon recovery.⁴⁰ Axonal regrowth is normally inhibited by resident myelin sheath proteins such as Nogo-A, oligodendrocyte-myelin glycoprotein (OMgp), and myelin-associated protein (MAP).^68,81,82 Binding of these mediators to Nogo receptors (NgR) results in Rho A mediated inhibition of axonal growth and prevents axonal elongation. Though this is likely protective in normal neuronal architecture, it has been postulated that this process impedes axonal regeneration after trauma. Interference with the Nogo signaling pathway using a NgR inhibitor and other medications in in vitro and in vivo models releases axonal growth inhibition and has been shown to restore some recovery of spinal cord function after hemisection in a rat model.⁶⁸ Further exploration in cerebral axonal disconnection is necessary to determine the manipulability of this pathway for treating DAI.⁷⁷ Altogether parameters governing the extent and degree of these recovery processes, determinants of injured axonal survival or death, as well as their direct effect on outcome are important subjects for further investigation.⁸³

SPECIAL CONSIDERATIONS: BLAST INJURY, CHRONIC TRAUMATIC ENCEPHALOPATHY, AND ABUSIVE HEAD TRAUMA

Interest in blast injury has increased markedly in recent times due to use of explosives as weapons and for breaching structures in theater. Blast injury causes a unique constellation of symptoms, including DAI, due to the high amount of kinetic energy transferred to patients after injury. Multisystem injury can be expected in addition to direct blast injury, including penetrating injury due to shrapnel, and respiratory injury from thermal and toxic exposure. Explosive blasts release energy in the form of acoustic, light, thermal, and electromagnetic energy, which can all potentially interact with a patient.⁸⁴ A mathematically idealized blast wave initially develops with a near instantaneous increase in local air pressure to peak levels, followed by an exponential decrease in pressure that approaches nadir below baseline atmospheric pressure, and then recovers to baseline over roughly twice the time required to reach peak pressure.⁸⁴ Blast forces can reflect off surfaces and redirect as compound waves toward the patient in a closed space, and lead to successive buffeting of the patient from multiple directions.⁸⁴ The primary blast passes on the order of milliseconds through tissue and loses less energy perpetuating through noncompressible fluids and body tissue in comparison to air, which dampens blast forces. Additional injury results from physical displacement of the victim and subsequent contact with other structures as the force of the explosive accelerates the body. This type of additional trauma has been described as a “blast plus” component of injury, possibly incurring additional acceleration-deceleration injuries to the brain or other organs. Though helmets reduce direct deceleration injury in military and civilian trauma, they do not usually stop rotational acceleration/deceleration that is particularly injurious to axons.^85,86 Chronic low level repetitive blast events may also cause some level of cognitive disturbance, as has been demonstrated in military door breachers.⁸⁷ Progressive advances in military blast injury management highlight inefficiencies in civilian blast TBI care⁸⁸ and have contributed to improvements in postblast DAI management.^89,90

Chronic traumatic encephalopathy (CTE) was first described in boxers in 1928⁹¹ and has received increasing attention due to increased recognition and association with contact sports prone to repeated head injury. Though predominantly described in American football and boxing, it has also been described in soccer, hockey,^92,93 and mixed martial arts⁹⁴ though the true burden of CTE is unknown in multiple sports. Because its pathophysiology is a long and usually slow progressive course evolving from frequent repetitive head injuries, it is frequently diagnosed well into its chronic phase when persistent long-term neurological and behavioral effects predominate. Brain histopathology performed on CTE-symptomatic ex-boxers postmortem reveals scattered intracellular accumulation of microtubule associated tau protein and neuropil threads^95–97 and similar findings have been found in postmortem examinations of professional American football players.^98,99 Clinical findings include expected cognitive and neuropsychiatric disturbances with disinhibition,¹⁰⁰ and focal neurological signs may include speech problems, ataxia, spasticity, and extrapyramidal symptoms.⁹⁸ Recent advancements in imaging present an ominous picture of boxing, with 76% of boxers having imaging abnormalities consistent with DAI occurring in a dose-dependent fashion that correlates with career length and number of bouts.¹⁰¹ CTE is also unique as a TBI syndrome in that it rarely involves penetrating injury or skull deformation, and the pathology arises primarily from global acceleration-deceleration forces causing neuropathology primarily through DAI. Consequently, CTE is not well modeled by most current preclinical TBI models. CTE and Alzheimer’s disease (AD) bear similarities histopathologically in terms of progressive axonal degeneration. A number of studies appear to link the history of a single reported TBI with eventual AD, as well as acceleration of dementia onset.^102–112 Given that the apolipoprotein E4 (ApoE4) phenotype is associated with increased severity of AD pathology, TBI patients manifesting ApoE4 are also predisposed to future axonopathic neurodegeneration demonstrated in boxers with severe CTE.¹¹³

Abusive head trauma (AHT) in infants and young children has also been a topic of increasing interest due to the injury pattern and advances in fathoming its unique characteristics. AHT victims frequently suffer significant repetitive injury potentially over time, and a multitude of injury mechanisms in addition to axonal shear and focal lesions. Over 90% of patients who die of AHT also develop subdural hematoma.¹¹⁴ Mechanistically effects of a proportionally larger head with less neck control than an adult would seem to predispose children to greater acceleration-deceleration forces¹¹⁵ reinforced by adult data that brain injury is worse in adult patients when the neck is limp.¹¹⁶ This implicates axonal injury as an important component in the pathology observed. Stresses on the axon likely entail direct shear as well as internal stresses from centripetally displaced axonal cytoplasm within the axon course. This differs from direct contact injury such as that seen in contusion.¹ Frequently a period of medical neglect follows injury, during which the AHT victim may become hypopneic from multiple mechanisms including depressed mental status and direct injury to medullary respiratory centers. Moreover, the physical exam may be complicated by a varied, underreported history of partially healed repeated injuries of the brain and other organs. A series by Geddes et al.⁹⁶ examined 53 cases of inflicted head injury and found that whereas children over a year of age demonstrated DAI patterns similar to adults, infants under the age of 1 year manifested infrequent axonal pathology, however, vascular injury and cerebral edema was more prominent concomitant with anoxic injury. Thirty-one percent of patients do demonstrate axonal injury in the cervical cord or the craniocervical junction consistent with shaking, however, providing a causal relationship for medullary damage in AHT and associated respiratory failure.⁴⁰ The overall low amount of cerebral axonal damage is puzzling given the magnitude of functional deficits seen, and some authors¹¹⁵ propose that myelination protects the mature axon from injury since most axonal damage when seen is in intermodal areas. Several have also postulated that the immature axon may be less susceptible to axonal damage or that shaking injuries mechanistically were insufficient to cause axonal injury.^117,118

MECHANISTICS

Animal, fabricated plastic, and in silico models have all been instrumental in characterizing the mechanical forces that cause DAI pathology. As can be expected there are a multitude of external forces imposed on the brain in TBI leading to rotational, tensile, and compressive strains on the tissues. Moreover the size and complexity of the human brain are important factors as well, due to its inertia, relative freedom of movement on the cervical spine, and variable density of the grey and white matter resulting in separation at significant shear stress. Consequently, only an exact model of the human brain’s unique geometry and environment adequately models shear forces important for human TBI. The falx separating the cerebral hemisphere and tentorium in particular alters shear wave propagation in the brain and can amplify local forces on the brain near the falx’s insertion points.^119–121 Even at the cellular level cytoplasm is displaced by traumatic forces within the axon and can directly damage the cytoskeleton.^25,122 In particular the threadlike structure of axons and small blood vessels in the brain expectedly places them at exquisite risk for shear injury in the brain under deformational stress. Though DAI is attributed to white matter injury, myelination increases the dynamic modulus of white matter axons and makes them stiffer. Per unit length, they are therefore, less susceptible to shear stress than corresponding grey matter structures, a factor balanced by white matter axons being longer and therefore more prone to DAI.^119,123 Evidence suggests normal compliance of the cellular membrane and cytoskeleton permits some pliability in low velocity brain deformation. Under higher, rapidly applied stresses, however, axons become stiffer, brittle, and susceptible to shear.^44,124–127

The substance of the brain is analogous to a semisolid of heterogeneous densities and composition. Therefore, any model must account for this in simulating the shear forces that characterize DAI.¹ When force is applied to a semisolid it is deformed in a manner consistent with its elasticity, viscosity, and plasticity. The tissue response to deformation subsequently depends on the duration and amplitude of the force application. When this force is distributed through the tissue by cells in contact with each other, shear forces develop within that cause permanent damage when the magnitude of shear exceeds the tissues’ elastic threshold. Longer durations of force application increase the amount of energy transferred to the brain and maintain a degree of physical displacement that rents the tissue, therefore causing more damage. Acceleration-deceleration at high speed or in repetitive shaking injuries can result in significant directional forces lasting over 1 second in duration and place the tissue in peril. Moreover high kinetic energy head injury frequently involves multiple directions of acceleration-deceleration that compounds shear forces on the brain. Given that the dynamic modulus, or tolerance of physical stress, of threadlike axons and vascular structures is direction dependent, compounded shear directions in the brain can potentially injure multiple vulnerable long axon pathways. In particular, angular movement causes greater injury than translational movement, and angular head motion in the coronal plane causes greater injury than sagittal movement.¹² In repetitive injury, initial damage caused by DAI may also alter the compliance of affected tissue. In a study of rodent impact-acceleration DAI the modulus of injured axons decreased after initial injury, implying that on successive impacts greater deformation of axons occurs, thereby causing axonopathy.¹²⁸

ANIMAL MODELS

The structural complexity of the human brain contributes to difficulty in modeling of the multitude of dynamic forces acting on it in DAI. Gyrencephalic models best represent the complex dynamics of TBI from an anatomical standpoint; apparatuses that consistently cause reproducible injury with high kinetic stresses are resource intensive and limited by the types of injury caused. Presently, lissencephalic models in smaller animals are more accessible to investigators due to their economy, reproducibility, and capacity for titration of injury magnitude.¹²⁹

GYRENCEPHALIC MODELS

A nonhuman primate model of DAI was first described by Genarelli in 1982 utilizing high velocity acceleration-deceleration kinetics.^12,130 Notably, the investigation also indicated DAI’s strong association with post-traumatic coma independent of mass effect from intracranial hemorrhage. In this inertial acceleration study apparatus, the animal body was restrained in a frame, whereas the head was secured to a rotating armature that caused rapid acceleration and sudden deceleration about the cervical axis through a designated plane. Though primates are reasonably analogous to human injury by virtue of similar brain structure and size (approximately 95 g), significantly higher rotational acceleration was required to cause the same expected mechanical shear seen in human TBI^121,131 as the lighter brains of smaller animals cannot be accelerated by this apparatus to velocities necessary to yield axonal injury.¹³² Subsequent investigations in this laboratory have been performed on miniature swine, which have similarly sized gyrencephalic brains and are more accessible than primate animals.¹²⁹ This model brings the head through a biphasic centroidal rotation of 100 degrees over 20 ms and yields diffuse lesions consistent with DAI. Even with extensive white matter injury in these models, ultimately consciousness was largely dependent on brainstem pathology suggesting location of insult is more important than degree of total injury.¹³³

BLAST INJURY

Blast injury research in animal models has advanced considerably in the past decade pursuant to the extensive use of explosive devices in warfare. A number of models have been described, including open air blast where animals are arrayed around a central explosive,¹³⁴ and models of enclosed vehicle spaces to simulate explosive attacks.¹³⁵ Open field models, especially those that simulate vehicle or confined space situations where the blast environment is simulated, provide realistic situation-specific injury models.¹³⁶ The most straightforward and commonly used apparatuses for blast injury, however, particularly for small animals, are blast tube models.¹³⁷ Blast tubes produce calibrated blast peak pressure levels of 20 kPa-350 kPa and replicate the kinetics of blast overpressure to the brain.¹³⁸ A compressed gas shock tube used to produce this type of injury (Figure 3.2d) consists of a compression chamber separated from an expansion chamber by Mylar sheets, which rupture at a predetermined pressure.¹³⁹ Within the expansion apparatus an animal can be positioned at different angles to the shock wave direction to determine directional effects. Compressed air or helium is pressurized behind the Mylar membrane, and upon rupture the shock wave progresses down the expansion chamber toward the animal. Altogether this model is reproducible and relatively safe to investigators compared to explosive-driven models, though it does not replicate effects of heat and toxic organic compound containing exhaust on the subject. Explosive-driven blast tubes are more commonly used with larger animals models partly due to the amount of energy needed to replicate a larger blast.¹⁴⁰ The explosive charge is placed in the tube prior to the expansion area naturally without a separation membrane.

FIGURE 3.2

(See color insert.) Major experimental models of traumatic brain injury used in simulating DAI in lissencephalic animals: (a) controlled cortical impact, (b) impact acceleration, (c) fluid percussion, (d) compressed gas blast tube.

LISSENCEPHALIC MODELS

Lissencephalic models, primarily rodent models, benefit from simple mechanical designs, economy of scale, relative safety profile for investigators, and the freedom to work with genetically manipulated murine colonies. A disadvantage is that they do not adequately model complex human neuropathology after injury due to the lower cortical complexity seen in rodents.¹⁴¹ Certainly human craniospinal angle, brain and skull geometry, brain functional topography, gray/white matter mass ratio, and junctional surfaces, as well as cortical complexity are not adequately replicated in these models.

BIOMARKER ASSAYS

The various pathological processes described earlier characterizing DAI evolution also produce an array of potential biomarkers for monitoring, some of which are temporally useful for monitoring specific processes. An advantage of using biological samples for assessment of brain injury is sample portability and typically a low risk to the patient. Characteristics of an optimal biomarker include temporal relevance to injury state, and a short half-life and processing time are important such that current status is adequately reflected. Another benefit of timely injury state reporting by a biomarker is that it can assess therapy effect. Other optimal characteristics importantly include specificity to the injury of interest.

NEUROIMAGING IN DIFFUSE AXONAL INJURY

With improvements in imaging technologies, radiographic analysis of the brain following TBI is gaining importance in outcome prediction, as has been demonstrated in predicative models based on head computed tomography.^213,214 Neuroradiology data in the clinical setting is typically evaluated in qualitative terms,²¹⁵ though this is fallible as critical pathology indicative of outcome is missed to more than an insignificant degree even among blinded expert neuroradiologists interpreting CT and magnetic resonance (MR) data in TBI patients.^216,217

Conventional Magnetic Resonance Imaging (MRI)

Like CT, MR neuroimaging is based on tomographic reconstruction of the brain in imaging slices acquired sequentially, but in the case of MR, data is reconstructed from the magnetic resonance properties of hydrogen atoms in a powerful magnetic field. MRI is more sensitive for the diffuse and physically small pathology found in DAI as opposed to head CT.^216,220,221 Shearing forces associated with DAI transect small blood vessels running in parallel with axons, resulting in detectable microscopic hemorrhages forming in these areas. Gradient echo and (T₂ star) weighted MR imaging detects signal dropout caused by iron-containing heme groups in slow-moving blood. Distributions of these microhemorrhages in areas associated with axonal injury such as the corpus callosum, brainstem, and other white matter tracts strongly suggest an imaging diagnosis of DAI. DAI microhemorrhages typically appear as punctate signal-free lesions in the white matter that “bloom” or appear slightly larger than their true anatomic size due to iron-induced magnetic field distortion. Consequently, signal loss caused by punctate hemorrhages from DAI can be visualized for years after injury though lesions fade over time.²²² Confounders that may appear to be microhemorrhages include air and calcium deposits; however, these are uncommon in areas affected by DAI. Density of lesions have been associated with severity of injury in terms of admission GCS^223–225 as well as maximum ICP during admission and 3 month Glasgow Outcome Score.²²⁶ An additional factor is magnet field strength, as 3 Tesla MRI demonstrates practically twice the sensitivity of 1.5 Tesla devices for microhemorrhages,²²⁷ and using different MRI devices utilizing different pulse sequence methods, even of the same field strength between manufacturers, can complicate interpretation between serial exams.

Punctate areas of T₂ signal hyperintensity in the white matter and at gray-white matter junctions in the frontal or occipital lobes are also suggestive of DAI (Figure 3.3).^217,228 These nonhemorrhagic lesions are optimally visualized in high-resolution T₂-weighted sequences with or without fluid attenuated inversion recovery (FLAIR) suppressing CSF signals. Even in the absence of microhemorrhages conventional MRI has been demonstrated superior to CT in evaluating DAI.²²⁹ With regard to outcome, nonhemorrhagic lesions may not necessarily be associated with worsening outcome suggesting different mechanisms for their appearance.²²⁹ In terms of longterm follow-up imaging, atrophy and gliosis as a consequence of DAI may be also be evaluated with conventional MRI.

FIGURE 3.3

MRI imaging of a 2-year-old patient with DAI after being ejected from a motor vehicle. T₂-weighted FLAIR imaging appears on the left, with corresponding susceptibility weighted imaging (SWI) slice appearing on right. Punctate areas of increased T₂ signal (more...)

Susceptibility Weighted Imaging

Similarly to weighted imaging, susceptibility weighted imaging (SWI) is a highresolution three-dimensional imaging sequence that produces images based on local magnetic field aberrations.²³⁰ However, it is much more sensitive than , detecting traumatic microhemorrhages at roughly 6 times the sensitivity of , and renders hemorrhage volume approximately twice the size seen on conventional MRI gradient echo imaging.²³⁰ Though the physics of the sequence are different, it similarly accentuates hemorrhage, calcification, air, or other features causing aberrations in magnetic susceptibility. In patients with severe DAI and resultant cerebral edema, venous stasis in SWI is an ominous sign and prominently appears as dark areas of susceptibility artifacts outlining engorged veins coursing through the brain parenchyma. In severe cerebral edema and associated venous stasis, delayed transit of venous blood causes pronounced SWI signal decrease in the distribution of medullary cerebral veins, appearing as irregular radially distributed rays of signal loss through the white matter, and is described as diffuse vascular injury (Figure 3.4).²³¹

FIGURE 3.4

SWI revealing diffuse vascular injury in an infant after abusive head trauma, appearing as serpentine areas of dark absent signal in the right occipital lobe.

Diffusion Weighted Imaging (DWI) and Diffusion Tensor Imaging (DTI)

Diffusion imaging is performed with serial acquisition of signal data after an initial coding from radiofrequency pulse, thereby identifying fluid movement within a magnetic gradient. DWI has demonstrated improved detection of nonhemorrhagic lesions over conventional MRI in areas of cytotoxic or vasogenic edema. In a series of 74 adult DAI patients, DWI-derived apparent diffusion coefficient (ADC) imaging revealed a higher burden of high intensity ADC signals in the corpus callosum and brainstem, and the magnitude of abnormal signal correlated with duration of coma.²³² In children, identification of deep frontal and temporal white matter and basal ganglia diffusion abnormality was associated with poorer outcome in a subset of severe pediatric TBI patients.²³³ DTI is a further modification of this imaging technique where multiple diffusion vectors are measured in three dimensions, and diffusion magnitude can be determined in multiple directions for a given cube-shaped voxel of space in the brain. Data is aggregated from individual voxels arranged in a threedimensional grid representing the brain in imaged space, with each voxel typically measuring approximately 2 to 3 mm on a side and between 6 and 64 or more diffusion directions measured. Each voxel is assigned vectors measuring a magnitude of diffusion in three perpendicular cardinal directions, with the principal vector being the major axis of diffusion within the voxel space (Figure 3.5). Regarding utility of DTI, data continues to emerge^234,235 on its utility in TBI and it is more sensitive to change following TBI than high-resolution conventional MRI.²³⁶ Multiple metrics have been derived for interpreting DTI data. Axial diffusivity is the magnitude of the major axis of diffusion inside the voxel and may indicate relative integrity of fluid filled tubular structures such as axons.^218,237 Radial diffusivity is the mean magnitude of the two minor axes perpendicular to the major axis, and some authors suggest it may reflect integrity of tubular structures, such as the myelin sheath of axons.²³⁶ Fractional anisotropy (FA) is an approximation of the overall directionality of flow within a voxel, and a value between 0 and 1 is derived from the three eigenvectors of a voxel, with higher values reflecting greater anisotropy or directionality. Given that a standard clinical voxel averages a volume of approximately 8 mm³ and may contain several hundreds of thousands of neurons, these presumptions are potentially prone to inaccuracy particularly in regions with large numbers of crossing structures or varying axon density.^238,239 Despite data suggesting the utility of DTI in describing anatomical changes associated with outcome in significant DAI, DTI have not consistently shown similar significance in mild TBI.^240,241 Tractography is an additional postprocessing technique that utilizes DTI data and “seeds” placed in white matter regions of interest in the brain to track approximated white matter tracts. From these seeds and user-determined tracing thresholds, diffusion tensors in each voxel are used to trace out estimated diffusion tracts. When seeds are placed within white matter, these tracts are presumed to represent bundles of continuous axons. DTI and tractography data must be interpreted considering operator seed placement as well as the effects of multiple cellular entities in addition to axons on diffusion, such as astrocytes, crossing fibers, and vascular structures among others.²⁴² It is worth considering that DTI metrics generalize the myriad diffusivities of hundreds of thousands of cells in a single voxel into just three eigenvectors.

FIGURE 3.5

(See color insert.) Diffusion tensor imaging images of relative fractional anisotropy in an 8-year-old patient after TBI from being struck by a motor vehicle. The left grayscale image reflects FA magnitude and the right image incorporates direction data, (more...)

Strategies have emerged for improving DTI data resolution, including adjustments for complex fluid dynamics in biological systems, such as in diffusion kurtosis imaging (DKI).^243,244 Other methodologies involve increased sampling of diffusion directions such that multiple principal vectors can be derived, as seen in high angular resolution diffusion imaging (HARDI)²⁴⁵ and diffusion spectrum imaging (DSI),²⁴⁶ which permit high-resolution tractography as seen in high-definition fiber tracking (HDFT).²⁴⁷ The utility of these methods in assessing DAI in heterogeneous TBI patients will rely on future imaging investigations. Variability between patients is important in clinical practice given accurate postinjury DTI interpretation requires some estimate of preinjury DTI conditions. A number of studies have indicated reduced anisotropy (evaluated with FA) in DAI-vulnerable white matter voxels (genu and splenium of the corpus callosum, internal capsule) is associated with postinjury cognitive deficits,^248–254 however, significant sample and methodology variance between these studies preclude their generalizability.^255,256 Deciphering the predictive accuracy of DTI on TBI patient outcome therefore is still an important topic of ongoing research. This may be more challenging in DAI than in focal injury patients, since an unaffected hemisphere can often serve as a control in focal injury patients.²⁴⁷ In contrast, DAI patients will likely require aggregate DTI atlas data from large-scale population studies to generalize DTI findings.²⁵⁷ Presently, this information is in development,^257,258 particularly in children where myelination steadily progresses throughout neurodevelopment²⁵⁹ and DTI metrics vary over brain maturation. Moreover the effects of age, subacute or chronic medical conditions on DTI findings over the human lifespan are still being elucidated. Therefore, interpreting abnormal findings in trauma patients across the spectrum of age will require a much more complete picture of normal DTI than is currently available.²⁶⁰

ELECTROPHYSIOLOGY AND MAGNETOENCEPHALOGRAPHY

DAI’s effects on long axons and cerebral connectivity affects neural electrophysiology after injury, manifest in evoked potentials, electroencephalography, as well as magnetoencephalography (MEG). As a functional test of brain activity, MEG records magnetic flux at the head surface caused by neuronal depolarization in shallow cortical structures below the scalp.²⁶¹ The methodology has high temporal and spatial resolution and is a promising means of identifying abnormal cortical areas. In TBI patients, MEG demonstrates changes such as reduced background activity persistently after injury.^282,283 Given that abnormal EEG activity (and therefore MEG as well) in gray matter may be a consequence of white matter de-afferentation by axonal damage,²⁸⁴ regionally abnormal MEG findings may identify affected cortical areas after DAI. In a case series of 10 mild TBI patients with no CT or MR radiographic evidence of injury in nine, combined analysis using DTI and MEG revealed gray matter MEG lesions topographically near areas of reduced anisotropy identified with DTI.²⁸³ MEG machines are not common even in large medical centers, however, and clinical expertise in interpretation, as well as clinical access for patients who cannot easily get into the device, may be challenging. Appropriate MEG helmet sizing for pediatric patients may also be challenging as there will be increased distance between a child’s skull and biomagnetometer coils compared to an adult’s head.²⁸⁵

Electrophysiologic methods identifying altered evoked potentials in DAI patients may also provide insight into patterns of disrupted cerebral connectivity following injury. DAI survivors may demonstrate increased resting corticospinal motor thresholds necessary to initiate MEPs, and reduced area under the MEP waveform indicating damaged cerebral connectivity.²⁸⁶ In a study of 52 adult survivors of TBI associated with motor vehicle accidents and chronic functional impairment from DAI, DTI of the corticospinal tract, and motor evoked potential (MEP) evaluation with transcranial magnetic stimulation,²⁸⁷ revealed that patients who did not generate MEP readings in response to stimulation had lower corticospinal tract FA than DAI patients who did generate MEPs as well as uninjured controls. Though electrophysiology is informative, imaging may provide better lesion localization not captured using these electrophysiological methods. Further research may suggest whether serial evoked potential data is informative regarding functional recovery after TBI.

THERAPEUTICS

SUMMARY

In total DAI is a complex process that merely begins with stretching and shearing of axons, at times proceeding to a persistent syndrome of cerebral disconnection and longstanding functional impairment. Research has improved our understanding of the mechanisms of axonopathy in DAI, its biomarkers, and potential therapeutic targets to treat it. Rapid technological innovations in biomarkers and neuroimaging, especially in MRI, are increasing our understanding of DAI’s evolution following TBI, however, there remain significant hurdles with regard to balancing data granularity and generalizable interpretation methods given the heterogeneous nature of TBI. With increasing scientific attention on brain connectivity, a working knowledge of DAI and its potential future therapies will also likely see significant advances in the near future.

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