This report describes the development of an experimental head injury model capable of producing diffuse brain injury in the rodent. A total of 161 anesthetized adult rats were injured utilizing a simple weight-drop device consisting of a segmented brass weight free-falling through a Plexiglas guide tube. Skull fracture was prevented by cementing a small stainless-steel disc on the calvaria. Two groups of rats were tested: Group 1, consisting of 54 rats, to establish fracture threshold; and Group 2, consisting of 107 animals, to determine the primary cause of death at severe injury levels. Data from Group 1 animals showed that a 450-gm weight falling from a 2-m height (0.9 kg-m) resulted in a mortality rate of 44% with a low incidence (12.5%) of skull fracture. Impact was followed by apnea, convulsions, and moderate hypertension. The surviving rats developed decortication flexion deformity of the forelimbs, with behavioral depression and loss of muscle tone. Data from Group 2 animals suggested that the cause of death was due to central respiratory depression; the mortality rate decreased markedly in animals mechanically ventilated during the impact. Analysis of mathematical models showed that this mass-height combination resulted in a brain acceleration of 900 G and a brain compression gradient of 0.28 mm. It is concluded that this simple model is capable of producing a graded brain injury in the rodent without a massive hypertensive surge or excessive brain-stem damage.

A new model of diffuse brain injury in rats Part I: Pathophysiology and biomechanics

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity both in civilian life and on the battlefield worldwide. Survivors of TBI frequently experience long-term disabling changes in cognition, sensorimotor function and personality. Over the past three decades, animal models have been developed to replicate the various aspects of human TBI, to better understand the underlying pathophysiology and to explore potential treatments. Nevertheless, promising neuroprotective drugs that were identified as being effective in animal TBI models have all failed in Phase II or Phase III clinical trials. This failure in clinical translation of preclinical studies highlights a compelling need to revisit the current status of animal models of TBI and therapeutic strategies.

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Animal models of traumatic brain injury

A controlled cortical impact model of traumatic brain injury in the rat.

Traumatic brain injury in the rat: characterization of a lateral fluid-percussion model

Fluid percussion models produce brain injury by rapidly injecting fluid volumes into the cranial cavity. The authors have systematically examined the effects of varying magnitudes of fluid percussion injury in the rat on neurological, systemic physiological, and histopathological changes. Acute neurological experiments showed that fluid percussion injury in 53 rats produced either irreversible apnea and death or transient apnea (lasting 54 seconds or less) and reversible suppression of postural and nonpostural function (lasting 60 minutes or less). As the magnitude if injury increased, the mortality rate and the duration of suppression of somatomotor reflexes increased. Unlike other rat models in which concussive brain injury is produced by impact, convulsions were observed in only 13% of survivors. Transient apnea was probably not associated with a significant hypoxic insult to animals that survived. Ten rats that sustained a moderate magnitude of injury (2.9 atm) exhibited chronic locomotor deficits that persisted for 4 to 8 days. Systemic physiological experiments in 20 rats demonstrated that all levels of injury studied produced acute systemic hypertension, bradycardia, and increased plasma glucose levels. Hypertension with subsequent hypotension resulted from higher magnitudes of injury. The durations of hypertension and suppression of amplitude on electroencephalography were related to the magnitudes of injury. While low levels of injury produced no significant histopathological alterations, higher magnitudes produced subarachnoid and intraparenchymal hemorrhage and, with increasing survival, necrotic change and cavitation. These data demonstrate that fluid percussion injury in the rat reproduces many of the features of head injury observed in other models and species. Thus, this animal model could represent a useful experimental approach to studies of pathological changes similar to those seen in human head injury.

A fluid percussion model of experimental brain injury in the rat

✓ Mechanical brain injury was produced in 36 cats with a fluid-percussion model in which brain damage or dysfunction is produced by a single, brief, hydraulically-induced pressure transient that is conducted through the brain. Fluid-percussion injury induces elastic deformation of the brain resembling the brain deformation known to occur following head impact. Physiological responses and pathological changes following injury were expressed as a function of peak pressure. Macroscopic central nervous system lesions concentrated at the pontomesencephalic junction, cervicomedullary junction, and in the cerebellar tonsils were consistently observed at and above 2.6 atmospheres (atm). At higher levels of injury (≥ 3.2 atm) there was extensive basal subarachnoid hemorrhage. At very high levels of injury (>4.0 atm) hemorrhagic contusions were noted at the cerebral hemisphere impact site. A spectrum of neuronal alterations was identified in the damaged areas. Computer analysis showed correlation of electroencephal...

Fluid-percussion model of mechanical brain injury in the cat

For rapid changes in cerebrospinal fluid volume an exponential relationship was demonstrated between CSF pressure and CSF volume in 15 cats. This relationship was valid over a CSF pressure range from 7 to 50 mm Hg and for acute increases of up to 9% to total CSF volume (approximately 13 ml for humans). Our data agree well with previous reports for the cat. A similar relationship has been shown in the dog and in humans. It has been claimed that, given the equations for CSF bulk flow and the exponential relationship between CSF pressure and CSF volume, one can calculate CSF outflow resistance by observing the decay of CSF pressure after a bolus injection into the CSF space. This claim was evaluated in an additional 18 cats. In these animals CSF outflow resistance calculated by the bolus method was compared with resistance calculated by a steady-state infusion method over the CSF outflow resistance range of 74 to 293 mm Hg/ml min-1. Resistance calculated by the bolus method underestimated resistance calculated by the steady-state method, and this underestimate grew larger with increasing resistance. The bolus technique is therefore not a valid method for determining CSF outflow resistance. The explanation offered for these results is that the decay of CSF pressure after a bolus injection into the CSF space occurs not only because of runoff of the injected volume of CSF but also because of "pressure relaxation" of the brain parenchyma around the CSF space. The phenomenon of pressure relaxation was not considered in developing the equation for calculation of CSF outflow resistance by the bolus technique. The time dependency of pressure relaxation allows for a fundamental element of hysteresis within the CSF space. A method of quantifying this element of hysteresis is suggested.

Bolus versus steady-state infusion for determination of CSF outflow resistance

Efforts to automate the estimation of left-ventricular volume from serial angiocardiograms have neglected the explicit location of the aortic valve line and the ventricle apex. From heuristic considerations of typical aorta-ventricle outlines, an algorithm has been developed to find these key points. The algorithm tracks the turning of the aorta-ventricle outline and uses this information to find the apex and to nominate points for ends of the aortic valve line. The correct valve points maximize an objective function defined on distance measures and the turn information. The algorithm represents a significant step in the direction of completely automated analysis of ventricular angiocardiograms.

An Algorithm for Locating the Aortic Valve and the Apex in Left-Ventricular Angiocardiograms

We report a two-dimensional, diagrammatic approach to help visualize the interactions which may alter CSF pressure. As shown by the dashed axes of Figure I, we begin with the experimentally determined plot of CSF pressure vs CSF volume change. In defining this curve experimentally, volume loading always begins at equilibrium CSF pressure (Peq) which is taken to be the stable pressure level which results when the craniospinal system is left totally unperturbed under constant physiological conditions.

A Diagrammatic, Two-Dimensional Model for Interpretation of Craniospinal P/V Interactions

CSF outflow resistance Rcsf may be calculated from bolus injections into the CSF space and this method has been employed to evaluate Rcsf in man. The bolus technique is appealing because measurements of Rcsf can be easily made in patients undergoing ventriculography, shunt insertion, or ICP monitoring: however, the bolus technique has not been compared with other, more standard methods of determinations of Rcsf. This comparison affords not only the opportunity for judging the validity of bolus determinations of CSF outflow resistance but, perhaps more importantly, also allows one to test the validity of an unproven assumption utilized in developing the bolus method. The un-proven assumption is that the same CSF P/V relationship holds for both rapid and slow changes in CSF volume.

Richard L. Griffith

Papers

Fluid-percussion model of mechanical brain injury in the cat

Bolus versus steady-state infusion for determination of CSF outflow resistance

An Algorithm for Locating the Aortic Valve and the Apex in Left-Ventricular Angiocardiograms

A Diagrammatic, Two-Dimensional Model for Interpretation of Craniospinal P/V Interactions

Comparison of CSF Outflow Resistance Determined by Bolus and Steady-State Techniques