Mild traumatic brain injury and diffuse axonal injury in swine

Abstract

Until recently, mild traumatic brain injury (mTBI) or "concussion" was generally ignored as a major health issue. However, emerging evidence suggests that this injury is by no means mild, considering it induces persisting neurocognitive dysfunction in many individuals. Although little is known about the pathophysiological aspects of mTBI, there is growing opinion that diffuse axonal injury (DAI) may play a key role. To explore this possibility, we adapted a model of head rotational acceleration in swine to produce mTBI by scaling the mechanical loading conditions based on available biomechanical data on concussion thresholds in humans. Using these input parameters, head rotational acceleration was induced in either the axial plane (transverse to the brainstem; n=3), causing a 10- to 35-min loss of consciousness, or coronal plane (circumferential to the brainstem; n=2), which did not produce a sustained loss of consciousness. Seven days following injury, immunohistochemical analyses of the brains revealed that both planes of head rotation induced extensive axonal pathology throughout the white matter, characterized as swollen axonal bulbs or varicosities that were immunoreactive for accumulating neurofilament protein. However, the distribution of the axonal pathology was different between planes of head rotation. In particular, more swollen axonal profiles were observed in the brainstems of animals injured in the axial plane, suggesting an anatomic substrate for prolonged loss of consciousness in mTBI. Overall, these data support DAI as an important pathological feature of mTBI, and demonstrate that surprisingly overt axonal pathology may be present, even in cases without a sustained loss of consciousness.

FIG. 1.

Idealized schematic demonstrating rotational acceleration in the coronal plane (left) and axial plane (right). The movement of the head was circumferential to the brainstem in the coronal plane and transverse to the brainstem in the axial plane. A pneumatic actuator was set to deliver approximate peak accelerations of 28,000–59,000 rad/sec² in the coronal plane, and 14,000–30,000 rad/sec² in the axial plane over 20 msec. Color image is available online at www.liebertonline.com/neu

FIG. 2.

Photomicrographs showing detailed axonal pathology (top), and regionalized schematics (bottom), showing areas of mild (less than 15 profiles) or moderate (greater than 15 profiles) damage following mild traumatic brain injury in swine. Schematics represent coronal sections through the (A) frontal region, (B) anterior commisure level, (C) rostral thalamus, (D) caudal hippocampal level, (E) hippocampal/brainstem, (F) occipital/brainstem region. Schematic G is a transverse section through the ventral surface of the brain. Damaged axons presented as discrete bulbs or swellings. A higher number of moderate profiles were observed in the brains of animals injured in the axial plane, especially in the brainstem (lower profile). The reader is referred to the text for an explanation of axonal profiles (scale bars=100 μm). Color image is available online at www.liebertonline.com/neu

FIG. 3.

Representative photomicrographs showing axonal damage in different regions of the swine brain following rotational injury in the coronal (left) or axial (right) plane. Damaged axons presented as discrete bulbs or swellings in the white matter of the frontal (A and B), parietal (C and D), and medulla (E and F) regions of the brain. Very few axonal profiles were noted in the brainstem region of the animals injured in the coronal plane. In contrast, axonal damage was prominent in the same region of animals injured in the axial plane (scale bar=100 μm). Color image is available online at www.liebertonline.com/neu