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PubMed1989

An analytical model of traumatic diffuse brain injury.

Diffuse axonal injury (DAI) with prolonged coma has been produced in the primate using an impulsive, rotational acceleration of the head without impact. This pathophysiological entity has been studied subsequently from a biomechanics perspective using physical models of the skull-brain structure. Subjected to identical loading conditions as the primate, these physical models permit one to measure the deformation within the surrogate brain tissue as a function of the forces applied to the head. An analytical model designed to approximate these experiments has been developed in order to facilitate an analysis of the parameters influencing brain deformation. These three models together are directed toward the development of injury tolerance criteria based upon the shear strain magnitude experienced by the deep white matter of the brain. The analytical model geometry consists of a rigid, right-circular cylindrical shell filled with a Kelvin-Voigt viscoelastic material. Allowing no slip on the boundary, the shell is subjected to a sudden, distributed, axisymmetric, rotational load. A Fourier series representation of the load allows unrestricted load-time histories. The exact solution for the relative angular displacement (V) and the infinitesimal shear strain (epsilon) at any radial location in the viscoelastic material with respect to the shell was determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

The pathobiology of moderate diffuse traumatic brain injury as identified using a new experimental model of injury in rats.

Experimental models of traumatic brain injury have been developed to replicate selected aspects of human head injury, such as contusion, concussion, and/or diffuse axonal injury. Although diffuse axonal injury is a major feature of clinical head injury, relatively few experimental models of diffuse traumatic brain injury (TBI) have been developed, particularly in smaller animals such as rodents. Here, we describe the pathophysiological consequences of moderate diffuse TBI in rats generated by a newly developed, highly controlled, and reproducible model. This model of TBI caused brain edema beginning 20 min after injury and peaking at 24 h post-trauma, as shown by wet weight/dry weight ratios and diffusion-weighted magnetic resonance imaging. Increased permeability of the blood-brain barrier was present up to 4 h post-injury as evaluated using Evans blue dye. Phosphorus magnetic resonance spectroscopy showed significant declines in brain-free magnesium concentration and reduced cytosolic phosphorylation potential at 4 h post-injury. Diffuse axonal damage was demonstrated using manganese-enhanced magnetic resonance imaging, and intracerebral injection of a fluorescent vital dye (Fluoro-Ruby) at 24-h and 7-day post-injury. Morphological evidence of apoptosis and caspase-3 activation were also found in the cerebral hemisphere and brainstem at 24 h after trauma. These results show that this model is capable of reproducing major biochemical and neurological changes of diffuse clinical TBI.

Animals↗
PubMed2005

Administration of the immunophilin ligand FK506 differentially attenuates neurofilament compaction and impaired axonal transport in injured axons following diffuse traumatic brain injury.

Traumatic axonal injury (TAI) following traumatic brain injury (TBI) remains a clinical problem for which no effective treatment exists. TAI was thought to involve intraaxonal changes that universally led to impaired axonal transport (IAT), disconnection and axonal bulb formation. However, recent, immunocytochemical studies employing antibodies to amyloid precursor protein (APP), a marker of IAT and antibodies to neurofilament compaction (NFC), RM014, demonstrated that NFC typically occurs independent of IAT, indicating the existence of different populations of damaged axons. FK506 administration has been shown to attenuate IAT. However, in light of the above, the ability of FK506 to attenuate axonal damage demonstrating NFC requires evaluation. The current study explored the potential of FK506 to attenuate both populations of damaged axons. Rats were administered FK506 (3 mg/kg) or vehicle 30 min preinjury. Three hours post-TBI, tissue was prepared for the visualization of TAI using antibodies targeting IAT (APP) or NFC (RMO14) or a combined labeling strategy. Confirming previous reports, FK506 treatment reduced the number of axons demonstrating IAT in the CSpT, from 411 +/- 54.70 to 91.00 +/- 33.87 (P <or= 0.05) and in the ML from 78.62 +/- 16.87 to 41.00 +/- 5.80 (P <or= 0.05). FK506 treatment failed to reduce the number of axons demonstrating NFC in either the CSpT or ML. FK506's failure to attenuate NFC suggests that additional therapeutic agents may be necessary to blunt the full burden of TAI. Because FK506 targets IAT, calcineurin appears to be a major target for neuroprotection in damaged axons demonstrating IAT.

Amyloid beta-Protein Precursor↗
PubMed2005

Quantitative analysis of the relationship between intra- axonal neurofilament compaction and impaired axonal transport following diffuse traumatic brain injury.

Traumatic axonal injury (TAI) following traumatic brain injury (TBI) contributes to morbidity and mortality. TAI involves intra-axonal changes assumed to progress to impaired axonal transport (IAT), disconnection, and axonal bulb formation. Immunocytochemical studies employing antibodies to amyloid precursor protein (APP), a marker of IAT and RMO14, a marker of neurofilament compaction (NFC), have shown that TAI involves both NFC and IAT, with the suggestion that NFC leads to IAT. Recently, new data has suggested that NFC may occur independently of IAT. The objective of this study was to determine quantitatively the precise relationship between NFC and IAT. Following TBI, rats were studied at 30 min, 3 h, and 24 h. Using single-label immunocytochemistry employing the antibodies RM014, APP, or a combined labeling strategy targeting APP/RMO14 in aggregate, the immunoreactive (IR) profiles were counted in the corticospinal tract (CSpT) and medial lemniscus (ML). In the CSpT, the number of axons demonstrating RMO14-IR approximated the number of axons showing APP-IR, with the APP-IR population showing a significant increase over 24 h (p < 0.05). The sum of both single-label counts equaled the aggregate APP/RMO14 numbers, demonstrating little relationship between NFC and IAT. In the ML, 75% of fibers demonstrated a separation of APP-IR and NFC-IR; however, 25% of the ML fibers showed co-localization of APP-IR and RMO14. The results of these studies indicate that, in the majority of damaged axons, NFC is not associated with IAT. Our findings argue for the use of multiple markers when evaluating the extent of TAI or the efficacy of therapies targeting the treatment of TAI.

Amyloid beta-Protein Precursor↗
PubMed1983

Head injury in man and experimental animals: neuropathology.

All of the principal types of brain damage that occur in man as a result of a non-missile head injury, viz. cerebral contusions, intracranial haematoma, raised intracranial pressure, diffuse axonal injury, diffuse hypoxic damage, and diffuse swelling have been produced in subhuman primates subjected to inertial, i.e. non-impact, controlled angular acceleration of the head through 60 degrees in the sagittal, oblique and lateral planes.

Animals↗
PubMed2000

[Immunohistochemical methods in the differential diagnosis of primary traumatic and subsequent secondary cerebral changes].

In a 22-year-old man, driver of a personal motor vehicle, who died within 39 hours after a traffic injury, the authors made histological and immunohistochemical examinations of the brain focused on differentiation of primary traumatic and subsequent secondary changes. In haematomas the authors revealed the presence bi- and trivalent iron by Turnbull's and Perl's reaction as well as glycophorin by immunohistochemical reactions. White matter lesions were evaluated histologically by staining according to Palmgren and immunohistochemically by detection of neuron-specific enolase, beta-amyloid protein precursor and low molecular neurofilaments. Minor contusion foci in the corpus callosum and in the peripheral portion of the pons revealed the presence of extracellular bivalent iron and exceptionally also the presence of intracellular iron. Glycophorin was present not only in erythrocyte membranes but also in the form of lumps signalizing haemolysis. In the haematoma in the median portion of the pons neither iron nor free glycophorin were detected. At all investigated sites (subcortical areas of the white matter of the hemispheres, capsula interna, corpus callosum, pons Varolii) the authors detected numerous axonal deformities (oedema or formation of retraction spheroids) which revealed on immunohistochemical examination an intense reaction with antibodies in particular against neuron-specific enolase and beta-amyloid protein precursor, and to a smaller extent against low-molecular neurofilaments. The combination of the mentioned immunohistochemical examinations seemed a suitable method for differentiating primary cerebral injury (diffuse axonal injury and minor contusion foci in the corpus callosum and the margin of the pons) from secondary changes (haemorrhages in the median portion of the pons) which developed shortly before death as a manifestation of haemodynamic disorders associated with cerebral oedema).

Adult↗
PubMed1991

A method to quantitate axonal injury.

The quantitation of diffuse axonal injury provides a more objective approach to the assessment of tissue damage in head injuries. The method designed in this study takes into account the anisotropy and structural inhomogeneity of the brain, and the distribution of lesions in diffuse axonal injury. The number of counts required for the statistical analysis is inversely proportional to the square of the desired accuracy, specified as the percentage of the mean value of the axonal balloons since the true mean is unknown from the outset. The number of fields are examined using an indexed-squares graticule in 10 different areas of the brain. Silver-stained sections from the brains of head injured patients that survived longer than 12 h must be used with this method. Difficulties may arise when patients of different survival times are compared since it takes some time for the axonal balloons to develop. A correlation with the survival time can be established with the quantitative data collected. The morphometric principles and the statistical rationale on which this methodology is based are briefly presented.

Axons↗
PubMedDate not supplied

[Diagnostic imaging in non-accidental brain injuries].

Diagnosis of nonaccidental injury (child abuse) may be difficult because most infants present with non-specific clinical findings and without external signs of trauma. Brain lesions severely disproportionate to the history of trauma, retinal hemorrhages and characteristic fractures or fractures of varying age are key indicators to child abuse when encountered in an infant. It is therefore incumbent upon the radiologist to recognize the radiologic findings of the various forms of nonaccidental injury and to correlate them with the physical findings in order to render a more accurate opinion. Craniocerebral injuries are not uncommon in infants who are physically abused and have a worse long-term outcome than accidental injuries. The particularities of the infant's skull and its content and the pathophysiology of cerebral nonaccidental injuries are remembered. The imaging findings in infants with blunt impact, shaken- and whiplash shaken-injuries are emphasized. The combination of edema, malignant hyperaemic cerebral swelling, hypoxic-ischemic brain injury, diffuse axonal injuries, and bilateral and/or interhemispheric subdural hematomas is almost typical of a shaken infant. MRI, with its multiplanar capability and its sensitivity to cytotoxic edema and to degraded hemoglobin, is the modality of choice for detecting cerebral lesions in nonaccidental injury.

Battered Child Syndrome↗
PubMed2002

Incidence of axonal injury in human brain tissue.

Diffuse axonal injury (DAI) is considered to be the morphological correlate of traumatic brain injury as seen in acceleration/deceleration trauma and is believed to be the main cause for a poor clinical outcome in the absence of detectable intracranial lesions. To estimate the overall incidence of DAI, and since most changes are only seen microscopically to rule out whether there is a high number of undetected cases, 450 non-selected human brains were examined. Samples from two brain areas (pons and cerebrum) were immunostained for beta-amyloid-precursor-protein (betaAPP), and axonal damage was assessed microscopically. Axonal injury was detected in 12% of all cases, but only one third had a history of traumatic brain injury. The majority of the positive cases were associated with drug intoxication, chiefly due to opiates. betaAPP staining was positive in both pons and cerebrum to a much higher extent in intoxication than in trauma cases; the latter showing axonal damage mainly in the pons area. This may reflect a more generalized pathomechanism in the intoxication group as compared to more biomechanical mechanisms in the trauma group. The findings also show that various causes may produce diffuse axonal injury and suggest that traumatic brain injury is not the only and probably not even the main cause of the observed neuropathological changes. A correlation between axonal damage and age-related processes could not be shown.

Adolescent↗
PubMed2001

Current concepts: diffuse axonal injury-associated traumatic brain injury.

OBJECTIVES: To review the probable physical, physiologic mechanisms that result in the medical and neuropsychologic complications of diffuse axonal injury (DAI)-associated traumatic brain injury (TBI). DATA SOURCES: Various materials were accessed: MEDLINE, textbooks, scientific presentations, and current ongoing research that has been recently reported. STUDY SELECTION: Included were scientific studies involving TBI, particularly direct injury to the axons and glia of the central nervous system (CNS) in both in vitro and in vivo models. These studies include pathologic findings in humans as well as the medical complications and behavioral outcomes of DAI. Studies that addressed animal models of DAI as well as cellular and/or tissue models of neuronal injury were emphasized. The review also covered work on the physical properties of materials involved in the transmission of energy associated with prolonged acceleration-deceleration injuries. DATA EXTRACTION: Studies were selected with regard to those that addressed the mechanism of TBI associated with DAI and direct injury to the axon within the CNS. The material was generally the emphasis of the article and was extracted by multiple observers. Studies that correlate the above findings with the clinical picture of DAI were included. DATA SYNTHESIS: Concepts were developed by the authors based on the current scientific findings and theories of DAI. The synthesis of these concepts involves expertise in physical science, basic science concepts of cellular injury to the CNS, acute medical indicators of DAI, neuropsychologic indicators of DAI, and rehabilitation outcomes from TBI. CONCLUSIONS: The term DAI is a misnomer. It is not a diffuse injury to the whole brain, rather it is predominant in discrete regions of the brain following high-speed, long-duration deceleration injuries. DAI is a consistent feature of TBI from transportation-related injuries as well as some sports injuries. The pathology of DAI in humans is characterized histologically by widespread damage to the axons of the brainstem, parasagittal white matter of the cerebral cortex, corpus callosum, and the gray-white matter junctions of the cerebral cortex. Computed tomography and magnetic resonance imaging scans taken initially after injury are often normal. The deformation of the brain due to plastic flow of the neural structures associated with DAI explains the micropathologic findings, radiologic findings, and medical and neuropsychologic complications from this type of injury mechanism. There is evidence that the types of cellular injury in TBI (DAI, anoxic, contusion, hemorrhagic, perfusion-reperfusion) should be differentiated, as all may involve different receptors and biochemical pathways that impact recovery. These differing mechanisms of cellular injury involving specific biochemical pathways and locations of injury may, in part, explain the lack of success in drug trials to ameliorate TBI.

Animals↗
PubMed1993

Neuropsychological outcome and social recovery of head-injured patients.

The Wechsler Adult Intelligence Scale and Yatabe-Guilford personality test were administered to 123 patients hospitalized for head injury who had made a relatively good recovery. Intelligence quotient (IQ) was correlated with clinical condition based on the Glasgow Coma Scale and duration of coma. More severely injured patients tended to show a greater decline in IQ. The type of lesion, as described by computed tomography, was also an important factor in predicting the outcome of intellectual function. The mean IQ of patients with diffuse injury, such as diffuse axonal injury and diffuse brain swelling, and intracerebral hematoma, was significantly lower than that of the control subjects, especially performance IQ (PIQ). Several patients demonstrated improved IQ level during the initial year. In particular, PIQ improved more than verbal IQ. The difference between the IQ of patients achieving social recovery and not was significant (p < 0.001). Causes of difficulty in returning to previous work were decreased IQ and personality change, such as lack of cooperativeness. Neuropsychological evaluation is important in predicting social recovery and selecting necessary neuropsychological rehabilitation.

Adolescent↗
PubMed1999

Traumatic brain injury: diffusion-weighted MR imaging findings.

BACKGROUND AND PURPOSE: Diffuse axonal injury (DAI) accounts for a significant portion of primary intra-axial lesions in cases of traumatic brain injury. The goal of this study was to use diffusion-weighted MR imaging to characterize DAI in the setting of acute and subacute traumatic brain injury. METHODS: Nine patients ranging in age from 26 to 78 years were examined with conventional MR imaging (including fast spin-echo T2-weighted, fluid-attenuated inversion-recovery, and gradient-echo sequences) as well as echo-planar diffusion-weighted MR imaging 1 to 18 days after traumatic injury. Lesions were characterized as DAI on the basis of their location and their appearance on conventional MR images. Trace apparent diffusion coefficient (ADC) maps were computed off-line with the diffusion-weighted and base-line images. Areas of increased signal were identified on the diffusion-weighted images, and regions of interests were used to obtain trace ADC values. RESULTS: In the nine patients studied, isotropic diffusion-weighted images showed areas of increased signal with correspondingly decreased ADC. In one case, decreased ADC was seen 18 days after the initial event. CONCLUSION: Decreased ADC can be demonstrated in patients with DAI in the acute setting and may persist into the subacute period, beyond that described for cytotoxic edema in ischemia.

Adult↗
PubMed1998

Traumatic neuropathology.

The neuropathology of trauma is reviewed based on the mechanism of injury. Pathology is divided into primary and secondary injury, based on the relationship to the time of injury. It is further divided by mechanism, with primary impact injury including skull fracture, epidural hematoma, brain contusion and laceration, and intracerebral hemorrhage; primary inertial injury including subdural hematoma, diffuse axonal injury, and diffuse vascular injury; and secondary injury including hypoxia/ischemia, brain swelling, infection, and increased intracranial pressure. The neuropathology of child abuse is also reviewed.

Axons↗
PubMed2001

Quantitative magnetic resonance imaging in traumatic brain injury.

Quantitative neuroimaging has now become a well-established method for analyzing magnetic resonance imaging in traumatic brain injury (TBI). A general review of studies that have examined quantitative changes following TBI is presented. The consensus of quantitative neuroimaging studies is that most brain structures demonstrate changes in volume or surface area after injury. The patterns of atrophy are consistent with the generalized nature of brain injury and diffuse axonal injury. Various clinical caveats are provided including how quantitative neuroimaging findings can be used clinically and in predicting rehabilitation outcome. The future of quantitative neuroimaging also is discussed.

Atrophy↗
PubMed1995

The pathobiology of traumatically induced axonal injury in animals and humans: a review of current thoughts.

This manuscript provides a review of those factors involved in the pathogenesis of traumatically induced axonal injury in both animals and man. The review comments on the issue of primary versus secondary, or delayed, axotomy, pointing to the fact that in cases of experimental traumatic brain injury, secondary, or delayed, axotomy predominates. This review links the process of secondary axotomy to an impairment of axoplasmic transport which is initiated, depending upon the severity of the injury, by either focal cytoskeletal. misalignment or axolemmal permeability change with concomitant cytoskeletal. collapse. Data are provided to show that these focal axonal changes are related to the focal impairment of axoplasmic transport which, in turn, triggers the progression of reactive axonal change, leading to disconnection. In the context of experimental studies, evidence is also provided to explain the damaging consequences of diffuse axonal injury. The implications of diffuse axonal injury and its attendant deafferentation are considered by noting that with mild injury such deafferentation may lead to an adaptive neuroplastic recovery, whereas in more severe injury a disordered and/or maladaptive neuroplastic re-organization occurs, consistent with the enduring morbidity associated with severe injury. In closing, the review focuses on the implications of the findings made in experimental animals for our understanding of those events ongoing in traumatically brain-injured humans. It is noted that the findings made in experimental animals have been confirmed, in large part, in humans, suggesting the relevance of animal models for continued study of human traumatically induced axonal injury.

Afferent Pathways↗
PubMed1997

Axonal cytoskeletal changes after non-disruptive axonal injury.

In animal models of human diffuse axonal injury, axonal swellings leading to secondary axotomy occur between 2 and 6 h after injury. But, analysis of cytoskeletal changes associated with secondary axotomy has not been undertaken. We have carried out a quantitative analysis of cytoskeletal changes in a model of diffuse axonal injury 4 h after stretch-injury to adult guinea-pig optic nerves. The major site of axonal damage was the middle portion of the nerve. There was a statistically significant increase in the proportion of small axons with a diameter of 0.5 micron and smaller in which there was compaction of neurofilaments. Axons with a diameter greater than 2.0 microns demonstrated an increased spacing between cytoskeletal elements throughout the length of the nerve. However, in the middle segment of the nerve these larger axons demonstrated two different types of response. Either, where periaxonal spaces occurred, there was a reduction in axonal calibre, compaction of neurofilaments but no change in their number, and a loss of microtubules. Or, where intramyelinic spaces occurred there was an increased spacing between neurofilaments and microtubules with a significant loss in the number of both. Longitudinal sections showed foci of compaction of neurofilaments interspersed between regions where axonal structure was apparently normal. Neurofilament compaction was correlated with disruption of the axolemma at these foci present some hours after injury. We suggest that the time course of these axonal cytoskeletal changes after stretch-injury to central axons is shorter than those changes documented to occur during Wallerian degeneration.

Animals↗
PubMed1996

[Diffuse ventricular enlargement outlines the late outcome of diffuse axonal brain injury].

Clinical significance of ventriculomegaly after severe head trauma has not been fully explored yet. We analyzed hospital records of 53 cases of diffuse axonal injury and 7 cases of brain concussion together. The follow-up periods ranged from 6 months to 8 years (average 25 months). Four patients underwent CSF shunting without noticeable effect. We classified their outcome according to our modification of the Glasgow outcome scale: vegetated, severe, moderate, mild, fair, and good. We reviewed initial (within 12 hours after injury) CT scans and late (3 to 6 months after injury) CT scans or MRI's. We measured the ratio of the third ventricular width to the inner diameter of the skull on the axial view. We computed the lateral ventricular volume by our newly-devised method which took the partial volume phenomenon into account. Temporary extracerebral fluid accumulation was noted mostly within 3 months after injury in 25 of 39 cases in the mild level or above, and 2 of the 9 fair or good level cases. Ventriculomegaly occurred early and stabilized around the 3 month period. We found the differences between the late and the initial values of the third ventricular width (%) and the lateral ventricular volume (cc) highly correlated with our outcome scale (Spearman's correlation coefficient rs = 0.531, 0.676, respectively with p < 0.001 unanimously). We found the late values themselves of the third ventricular width and the lateral ventricular volume highly correlated with our outcome scale (rs = 0.575, 0.650, respectively with p < 0.001 unanimously). These 4 parameters were also highly correlated with the duration of the initial unconsciousness (LOC). Thus, posttraumatic diffuse ventriculomegaly affecting the third ventricle as well should outline the late outcome of diffuse axonal injury. Both the ventriculomegaly and the late outcome should be roughly predicted by the duration of the initial unconsciousness.

Adolescent↗
PubMed1998

Proton magnetic resonance spectroscopy for detection of axonal injury in the splenium of the corpus callosum of brain-injured patients.

OBJECT: This study was conducted to determine whether proton magnetic resonance spectroscopy (MRS) is a sensitive method for detecting diffuse axonal injury, which is a primary sequela of traumatic brain injury (TBI). Diffuse axonal injury is characterized by selective damage to white matter tracts that is caused in part by the severe inertial strain created by rotational acceleration and deceleration, which is often associated with motor vehicle accidents. This axonal injury is typically difficult to detect by using conventional imaging techniques because it is microscopic in nature. The splenium was selected because it is a site vulnerable to shearing forces that produce diffuse axonal injury. METHODS: The authors used proton MRS to evaluate the splenium, the posterior commissure of the corpus callosum, in normal control volunteers and in patients with TBI. Proton MRS provided an index of neuronal and axonal viability by measuring levels of N-acetyl aspartate (NAA). CONCLUSIONS: A majority of mildly brain injured patients, as well as those more severely injured, showed diminished NAA/creatine (Cr) levels in the splenium compared with normal control volunteers. The patients displaying lowered NAA/Cr in the splenium were also likely to exhibit lowered NAA/Cr in lobar white matter. Also, the levels of NAA/Cr in the splenium of normal volunteers were higher compared with those found in lobar white matter. Decreases in NAA/Cr levels in the splenium may be a marker for diffuse injury. A proton MRS examination may be particularly useful in evaluating mildly injured patients with unexplained neurological and cognitive deficits. It is concluded that MRS is a sensitive tool in detecting axonal injury.

Acceleration↗