Large Animal Models of Traumatic Injury to the Immature Brain

Pigs continue to grow in importance as a tool in neuroscience. However, behavioral tests that have been validated in the rodent model do not translate well to pigs because of their very different responses to behavioral stimuli. We refined metrics for assessing porcine open field behavior to detect a wide spectrum of clinically relevant behaviors in the piglet post-traumatic brain injury (TBI). Female neonatal piglets underwent a rapid non-impact head rotation in the sagittal plane (n = 8 evaluable) or were instrumented shams (n = 7 evaluable). Open field testing was conducted 1 day prior to injury (day -1) in order to establish an individual baseline for analysis, and at days + 1 and + 4 after injury. Animals were then killed on day + 6 after injury for neuropathological assessment of axonal injury. Injured piglets were less interested in interacting with environmental stimuli and had a lower activity level than did shams. These data were compared with previously published data for axial rotational injuries in neonatal piglets. Acute behavioral outcomes post-TBI showed a dependence on the rotational plane of the brain injury, with animals with sagittal injuries demonstrating a greater level of inactivity and less random usage of the open field space than those with axial injuries. The persistence of axonal injury is also dependent on the rotational plane, with sagittal rotations causing more prolonged injuries than axial rotations. These results are consistent with animal studies, finite element models, and studies of concussions in football, which have all demonstrated differences in injury severity depending upon the direction of head impact rotation.

Section: Discussionsupporting

confidence: 72%

Behavioral Deficits and Axonal Injury Persistence after Rotational Head Injury Are Direction Dependent

Sullivan

Friess

Ralston

et al. 2013

“…No widespread hypoxicischemic brain damage was observed in any animal, perhaps because of the lower sensitivity of sheep to hypoxia-ischemia insults compared with humans and pigs. 29 In summary, within 6 h of shaking, this large animal model with uncontrolled repeated head movements did not produce widespread hypoxic-ischemic brain injury, subarachnoid or subdural hemorrhage, and retinal hemorrhage, which are characteristics often noted in AHT patterns attributed to shaking.…”

Section: Introductionmentioning

confidence: 59%

Cyclic Head Rotations Produce Modest Brain Injury in Infant Piglets

Coats

Binenbaum

Smith

et al. 2017

Self Cite

Repetitive back-and-forth head rotation from vigorous shaking is purported to be a central mechanism responsible for diffuse white matter injury, subdural hemorrhage, and retinal hemorrhage in some cases of abusive head trauma (AHT) in young children. Although animal studies have identified mechanisms of traumatic brain injury (TBI) associated with single rapid head acceleration-decelerations at levels experienced in a motor vehicle crash, few experimental studies have investigated TBI from repetitive head rotations. The objective of this study was to systematically investigate the postinjury pathological time-course after cyclic, low-velocity head rotations in the piglet and compare them with single head rotations. Injury metrics were the occurrence and extent of axonal injury (AI), extra-axial hemorrhage (EAH), red cell neuronal/axonal change (RCNAC), and ocular injury (OI). Hyperflexion/extension of the neck were purposefully avoided in the study, resulting in unscaled angular accelerations at the lower end of reported infant surrogate shaking kinematics. All findings were at the mild end of the injury spectrum, with no significant findings at 6 h post-injury. Cyclic head rotations, however, produced modest AI that significantly increased with time post-injury ( p < 0.035) and had significantly greater amounts of RCNAC and EAH than noncyclic head rotations after 24 h post-injury ( p < 0.05). No OI was observed. Future studies should investigate the contributions of additional physiological and mechanical features associated with AHT (e.g., hyperflexion/extension, increased intracranial pressure from crying or thoracic compression, and more than two cyclic episodes) to enhance our understanding of the causality between proposed mechanistic factors and AHT in infants.

“…We evaluated female five-day-old and four-week-old piglets, of which the brain development corresponds to the human infant and the human toddler, respectively. 24,25 Animals met the inclusion criteria if they: 1) experienced no injury or a single rapid non-impact rotational injury (RNR) in the sagittal plane; 2) were not given any treatments; 3) were sacrificed for neuropathology; and 4) had post-TBI survival times of 3 h to six days. This criteria included 55 five-day-old piglets and 40 four-week-old piglets.…”

Section: Methodsmentioning

confidence: 99%

“…9,17,23 The gyrencephalic piglet brain is similar to the human brain in growth patterns, gray and white matter distribution, and cerebrovascular anatomy and physiology, making it a good translational model. [24][25][26][27] We sought to determine when TAI and ICH reach their peak post-injury, how long they remain elevated, and if their progression is age dependent; provide insight into the optimal window for clinical intervention and the period of increased vulnerability to a second injury; and glean further information about age-specific vulnerabilities that have been observed.…”

mentioning

confidence: 99%

Influences of Developmental Age on the Resolution of Diffuse Traumatic Intracranial Hemorrhage and Axonal Injury

Weeks

Sullivan²,

Kilbaugh³

et al. 2014

This study investigated the age-dependent injury response of diffuse traumatic axonal injury (TAI) and regional subdural and subarachnoid intracranial hemorrhage (ICH) in two pediatric age groups using a porcine head injury model. Fifty-five 5-day-old and 40 four-week-old piglets-which developmentally correspond to infants and toddlers, respectivelyunderwent either a sham injury or a single rapid non-impact rotational injury in the sagittal plane and were grouped by post-TBI survival time (sham, 3-8 h, one day, 3-4 days, and 5-6 days). Both age groups exhibited similar initial levels of ICH and a significant reduction of ICH over time ( p < 0.0001). However, ICH took longer to resolve in the five-day-old age group. At 5-6 days post-injury, ICH in the cerebrum had returned to sham levels in the four-week-old piglets, while the five-day-olds still had significantly elevated cerebral ICH ( p = 0.012). Both ages also exhibited similar resolution of axonal injury with a peak in TAI at one day post-injury ( p < 0.03) and significantly elevated levels even at 5-6 days after the injury ( p < 0.008), which suggests a window of vulnerability to a second insult at one day post-injury that may extend for a prolonged period of time. However, five-day-old piglets had significantly more TAI than four-week-olds overall ( p = 0.016), which presents some evidence for an increased vulnerability to brain injury in this age group. These results provide insight into an optimal window for clinical intervention, the period of increased susceptibility to a second injury, and an age dependency in brain injury tolerance within the pediatric population.