Moderately Elevated Intracranial Pressure after Diffuse Traumatic Brain Injury is Associated with Exacerbated Neuronal Pathology and Behavioral Morbidity in the Rat

Abstract

Traumatic brain injury (TBI)-induced elevated intracranial pressure (ICP) is correlated with ensuing morbidity/mortality in humans.This relationship is assumed to rely mostly on the recognition that extremely elevated ICP either indicates hematoma/contusions capable of precipitating herniation or alters cerebral perfusion pressure (CPP), which precipitates global ischemia. However, whether subischemic levels of elevated ICP without hematoma/contusion contribute to increased morbidity/mortality remains unknown. To address this knowledge gap, we utilized a model of moderate diffuse TBI in rats followed by either intraventricular ICP monitoring or manual ICP elevation to 20 mm Hg, in which CPP was above ischemic levels. The effects of ICP elevation after TBI on acute and chronic histopathology, as well as on behavioral morbidity, were evaluated. ICP elevation after TBI resulted in increased acute neuronal membrane perturbation and was also associated with reduced neuronal density at 4 weeks after injury. Somatosensory hypersensitivity was exacerbated by ICP elevation and was correlated to the observed neuronal loss. In conclusion, this study indicates that morbidity and increased neuronal damage/death associated with elevated ICP can occur without concurrent global ischemia. Therefore, understanding the pathologies associated with subischemic levels of elevated ICP could lead to the development of better therapeutic strategies for the treatment and management of TBI patients.

Rehabilitation modality and onset differentially influence whisker sensory hypersensitivity after diffuse traumatic brain injury in the rat

“…While our laboratory and others have repeatedly published the development of late-onset sensory hypersensitivity to whisker stimulation, we did not find differences between injured and sham rats in this study (Alwis, Yan, Morganti-Kossmann, & Rajan, 2012;Lafrenaye, Krahe, & Povlishock, 2014;Learoyd & Lifshitz, 2012;McNamara et al, 2010;Thomas et al, 2012). In this set of experiments, it is possible that repeated handling of the rats and rehabilitation in both injured and sham rats muted the normal behavioral response to the WNT in injured rats.…”

Approaches to Monitor Circuit Disruption after Traumatic Brain Injury: Frontiers in Preclinical Research

“…Naïve and uninjured sham rats are ambivalent to the stimulation, whereas TBI results in increased avoidance, evasiveness, and aggressiveness that is significant by 4 weeks and maintained to 8 weeks post-injury [154]. Hypersensitivity to whisker stimulation is exacerbated by elevated intracranial pressure (ICP) following FPI concurrent with neuronal somatic membrane damage and poration [156,157]. The WNT has been a reproducible approach to measuring circuit abnormalities across laboratories [154], injury models [158], and rodent species [159].…”

Experimental Traumatic Brain Injury Induces Chronic Glutamatergic Dysfunction in Amygdala Circuitry Known to Regulate Anxiety-Like Behavior

“…mFPI best models closed head injury with decompressive craniectomy by reproducing diffuse axonal injury without contusion or cavitation encompassing the hallmark pathology of clinical diffuse TBI. While craniectomy is a procedure often carried out in more severe clinical cases in which cerebral herniation is a concern, it provides control of increased intracranial pressure here, which when unregulated can induce a more severe injury with worse outcome (Lafrenaye et al, 2014). After regaining reflexive responses (5-12 min), injured rats require little to no medical intervention in the post-operative period, most similar to mild TBI as defined by a Glasgow Coma Score of 13-15.…”